Study design
A retrospective cohort study of critically ill patients admitted to intensive care units (ICUs) with confirmed Gram-positive infections (e.g., MSSA, MRSA) who received intravenous vancomycin (weight-based dosing). All patients who met our inclusion criteria during the study period from January 01, 2017 to December 31, 2020 were included. Patients were categorized into two groups based on the timing of achieving therapeutic vancomycin trough level during their ICU stay to an early and late group. We defined the early group as achieving therapeutic vancomycin trough levels (15–20 mg/L (or 10–14 μmol/L)) within 48 h of the first intravenous vancomycin exposure. Vancomycin trough levels were obtained after reaching the steady-state either 30 min before the fourth dose (without a loading dose) or before the third dose (with loading dose). Critical care pharmacists were responsible for vancomycin TDM in their respected critical care units. No specific nomogram was followed. The study was approved by King Abdullah International Medical Research Center (KAIMRC)-Institutional Review Board, Riyadh, Saudi Arabia (Reference No: RC20/587/R).
Gram stain is used to differentiate between Gram-positive and negative bacteria. Blood and MacConkey agar are used to culture microorganisms; after 24 h of incubation, a single colony is selected and smeared directly as a thin film on a Matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF) biomerieux for pathogen identification, then VITEKR 2 is used thereafter to determine susceptibility.
Bacteria were identified in the blood, urine, wound, drainage, cerebrospinal fluid (CSF), and respiratory specimens. Confirmed infection defined as sputum or endotracheal aspiration shows growth ≥ of 100,000 CFU/ml; Bronchoalveolar lavage (BAL) shows growth ≥ of 10,000 CFU of single organism/ml for protected specimen brushes (PSBs), and ≥ 100,000 CFU of single organism/ml for BAL fluid. Additionally, urinary cultures were considered significant if showing a growth of ≥ 100,000 CFU/ml of no more than two species of microorganisms [29]. Cultures were excluded if the laboratory reported them as a "contaminant sample."
Eligibility criteria
Patients were enrolled in the study if they were critically ill, aged 18 years or older with confirmed Gram-positive infection, and received IV vancomycin between January 01, 2017 to December 31, 2020. Exclusion criteria include using vancomycin empirically without continued treatment (Duration < 3 days) or no available vancomycin trough reading. Besides, patients with CKD on hemodialysis (HD), have an initial trough level > 14 μmol/L, contaminant sample, ICU LOS ≤ one day or labeled as "Do-Not-Resuscitate" status within the first 24 h of ICU admission were excluded (Fig. 1).
Setting
This study was conducted in the adult medical, surgical, trauma, and burn ICUs at King Abdulaziz Medical City (KAMC), a tertiary-care academic referral hospital in Riyadh, Saudi Arabia. The ICU admits medical, surgical, trauma, burn patients and operates as closed units with 71 ICU beds capacity with 24/7 onsite coverage by critical care board-certified intensivists and clinical pharmacists.
Data collection
Demographic data, Acute Physiology And Chronic Health Evaluation II (APACHE II) score, Modified Sequential Organ Failure Assessment (mSOFA), comorbidities, laboratory tests, cultures (Blood, Skin, Respiratory, Urine, CSF), microorganism (s), vancomycin date of administration, vancomycin initial trough concentrations, time to reach the therapeutic levels, development of resistant organisms (e.g., Vancomycin Intermediate Staphylococcus Aureus (VISA), Vancomycin-Resistant Staphylococcus Aureus (VRSA) or Vancomycin-Resistant Enterococcus (VRE)), and vancomycin induced nephrotoxicity (VIN) were collected from an electronic record system (Best Care system). All variables have been compiled in an electronic data collection sheet. Patients were followed during ICU stay until death or discharge, whichever occurred first.
Endpoint (s)
The primary endpoint evaluated the association between the timing of achieving therapeutic levels of vancomycin (early vs. late) in critically ill patients and mortality at 30 days from admission. Secondary endpoints include developing a vancomycin-resistant organism, microorganisms eradication within 4–5 days of vancomycin initiation, vancomycin-induced nephrotoxicity, and LOS.
Definition(s)/procedure(s)
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Critically ill patient was defined as patient who is admitted in the intensive care unit (s) because of life threatening or potential life-threatening physiological alterations requiring intense and vigilant monitoring and medical care.
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The 30-day mortality was defined as the in-hospital death occurring for any cause within 30 days of the admission date during the hospital stay.
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Acute kidney injury (AKI) was defined using Acute Kidney Injury Network (AKIN) definition, which is a sudden decrease of renal function within 48 h, defined by an increase in absolute SCr of at least 26.5 μmol/L (0.3 mg/dL) or an increase in SCr ≥ 50% from baseline (1.5 × baseline value) [10].
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Susceptibility of Gram-positive bacteria based on Clinical Laboratory Standards Institute (CLSI) [11]:
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Methicillin-Sensitive Staphylococcus Aureus (MSSA): Clinical isolate of Staphylococcus aureus sensitive to oxacillin; Minimal inhibitory concentration (MIC) < 2 μg/mL.
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Methicillin-Resistant Staphylococcus Aureus (MRSA): Clinical isolate of Staphylococcus aureus resistant to all beta-lactams except Ceftaroline; MIC < 4 μg/mL.
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Vancomycin Intermediate resistant Staphylococcus aureus (VISA): Clinical isolate of Staphylococcus aureus with intermediate susceptibility to vancomycin; MIC 4–8 μg/mL.
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Vancomycin-resistant Staphylococcus aureus (VRSA): Clinical isolate of Staphylococcus aureus that is resistant to vancomycin; MIC > 8 μg/mL.
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Vancomycin-Resistant Enterococcus (VRE): Clinical isolate of Enterococcus resistant to vancomycin; MIC > 8 μg/mL.
Data management and statistical analysis
Categorical variables were reported using numbers and percentages, while continuous variables were reported using mean with standard deviation (SD) or median with interquartile range (IQR) when appropriate. We compared normally distributed numerical variables with the t-test and other continuous variables with the Mann–Whitney U test. In addition, we compared categorical variables using the Chi-square or Fisher exact test. The normality assumptions were assessed for all continuous variables using graphical representation (i.e., histograms and Q-Q plots) and statistical tests (i.e., Shapiro–Wilk test). The baseline and clinical characteristics were compared between the early and late initiation groups. No imputation was made for missing data as the cohort of patients in our study was not derived from random selection.
Propensity score matching Procedures (Proc PS match) (SAS, Cary, NC) was used to match patients (1:1 ratio) who achieved early therapeutic vancomycin level to patients who did not, based on the patient’s age, serum creatinine, and albumin levels. Clinically relevant variables were included in the model if they differed between study groups and were associated with the primary outcome. A greedy nearest neighbor matching method was used in which one patient in the late group is matched with one patient in the early group (control), which eventually produced the smallest within-pair difference among all available pairs with treated patients. Patients were matched only if the difference in the logits of the propensity scores for pairs of patients from the two groups was less than or equal to 0.5 times the pooled estimate of the standard deviation.
Multivariable Cox proportional hazards regression analyses were performed for the 30-day mortality. For the other outcomes considered in this study, multivariable and negative binomial regression analyses were used as appropriate. Regression analysis was done by considering the PS score as one of the covariates in the model. The odds ratios (OR), hazard ratio (HR), or estimates with the 95% confidence intervals (CI) were reported as appropriate. We considered a P value of < 0.05 statistically significant and used SAS version 9.4 for all statistical analyses.
Sample size calculation
The sample size was calculated using Power Analysis and Sample Size (PASS) software (PASS 15 Power Analysis and Sample Size Software (2017). From a pilot study of 30 patients, the ICU mortality was estimated to be 25% in the late group, and we were expecting a reduction in 30-day mortality by 13.3% in the early group (i.e., 11.7%). With 80% power to detect a difference in the 30-day mortality between the two groups of 13.3% and one-sided Z-test statistics with pooled variance. A total sample size of 209 was considered to assess the study's primary endpoint.