A retrospective, observational study of critically ill patients admitted to intensive care units (ICUs) with confirmed Gram-positive infections (e.g., MSSA, MRSA) and received intravenous vancomycin (weight-based dosing). All patients who met our inclusion criteria during the study period from 01/01/2017 to 31/12/2018 were included. Patients were divided 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 within 48 hours of the first intravenous vancomycin exposure. The initial therapeutic trough target levels were determined according to infection types as 15–20 mg/L for severe infections (sepsis, pneumonia, meningitis, osteomyelitis, bacteremia, and endocarditis) and 10–15 mg/L for other infections. Vancomycin trough levels were obtained after reaching the steady state either 30 minutes before the fourth dose (without a loading dose) or 30 minutes before the third dose (with loading dose) in all patients included. Clinical pharmacy is a consulting service at KAMC. Critical care pharmacists are responsible for vancomycin TDM in their respected critical care units. No specific nomogram was followed.
Bacteria were identified in the blood, urine, wound, drainage, cerebrospinal fluid (CSF), and respiratory specimens. Gram stain is used to differentiate between Gram-positive and negative bacteria. Blood and MacConkey agar are used to culture microorganisms; after 24 hours 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.
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 . Cultures were excluded if the laboratory reported them as a "contaminant sample."
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 01/01/2017 to 31/12/2018. Exclusion criteria include using vancomycin empirically without continued treatment (Duration <3 days) and no available vancomycin trough reading. Besides, patients with ICU LOS ≤ 1 day or > 60 days and/or labeled as "Do-Not-Resuscitate" status within the first 24 hours of ICU admission were excluded due to futility of care (Figure 1).
This study was conducted in the adult medical, surgical, trauma, and burn ICUs at 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.
Demographic data, Acute Physiology And Chronic Health Evaluation II (APACHE II) score, comorbidities, laboratory tests, cultures (Blood, Skin, Respiratory, Urine, CSF), microorganism (s), vancomycin date of administration, duration of vancomycin, vancomycin 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)), vancomycin induced acute kidney injury(VIN), the needs of dialysis, ICU mortality, ICU LOS 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.
The primary endpoint was to evaluate the association between timing of achieving therapeutic levels of vancomycin (early vs. late) in critically ill patients and mortality at 30 days from ICU admission. Secondary endpoints include developing a vancomycin-resistant organism, eradicating microorganisms within 4-5 days of vancomycin initiation, vancomycin-induced acute kidney injury (AKI), and ICU LOS.
Definition (s)/Procedure (s)
- Susceptibility of Gram-positive bacteria based on Clinical Laboratory Standards Institute (CLSI) :
- Methicillin-Sensitive Staphylococcus Aureus (MSSA): Clinical isolate of Staphylococcus aureus sensitive to oxacillin; Minimal inhibitory concentration (MIC) < 2 μg/mL.
- Methicillin-Resistant Staphylococcus Aureus (MRSA): Clinical isolate of Staphylococcus aureus resistant to oxacillin; Minimal inhibitory concentration (MIC) > 4 μg/mL.
- Vancomycin Intermediate resistant Staphylococcus aureus (VISA): Clinical isolate of Staphylococcus aureus resistant to vancomycin; MIC 4-8 μg/mL.
- Vancomycin-resistant Staphylococcus aureus (VRSA): Clinical isolate of Staphylococcus aureus that is resistant to vancomycin; MIC >8 μg/mL.
- Vancomycin-Resistant Enterococcus (VRE): Clinical isolate of Enterococcus resistant to vancomycin; MIC >8 μg/mL.
- Acute kidney injury (AKI was defined using Acute Kidney Injury Network (AKIN) definition 29, which is a sudden decrease of renal function within 48 hours, defined by an increase in absolute SCr of at least 26.5 μmol/L (0.3 mg/dL) or by a percentage increase in SCr ≥ 50% (1.5× baseline value) .
Data management and Statistical analysis
Data were entered in Microsoft Excel 2010. Categorical variables were reported using numbers and percentages. 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 and categorical variables using the chi-square / Fisher exact test. The normality assumptions were assessed for all continuous variables using graphical representation (i.e., histograms and Q-Q plots) and statistical test (i.e., Shapiro–Wilk test). The baseline and clinical characteristics were compared between 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.
Multivariate logistic and generalized linear regression analyses were used to determine the relationship between therapeutic levels' timing and the different outcomes considered in this study. Variables that are clinically relevant were included in the model if they were different between study groups and associated with the primary outcome with a p-value of <0.2 and did not overlap with another variable. The odds ratios (OR) estimates with the 95% confidence intervals (CI) were reported for the associations. 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 ICU mortality by 13.3% in the early group (i.e., 11.7%). With 80.003% power to detect a difference in ICU 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.