Study design
A retrospective cohort study in critically ill patients who received standard dosing of selected broad-spectrum Hydrophilic antibiotics (Meropenem, Imipenem, or Piperacillin/Tazobactam) for confirmed infection (Bacteremia, pneumonia, and Urinary Tract Infection (UTI)). The diagnosis of infection was confirmed by lab culture depend on the site of infection. All the patients who met our inclusion criteria during the study period (01/01/2018 – 31/12/2019) were included. Eligible patients have been divided into two groups (augmented renal clearance (ARC) Vs. Non-ARC) according to the estimated creatinine clearance (CrCl) (By Cockroft equation). Patients were followed during their ICU Length of stay (LOS) until ICU discharge after improving or in-hospital death, whichever occurred first.
Participants
Patients were enrolled in the study if they were critically ill admitted to ICU, aged 18-65 years, had a confirmed infection (Bacteremia, pneumonia, and Urinary Tract Infection (UTI)) and received standard dosing of broad-spectrum Hydrophilic antibiotics (Meropenem, Imipenem or Piperacillin/Tazobactam) for these infections. Patients were excluded if the Weight < 40 kg or BMI <16 Kg/m2, on any dialysis, no-code status, previous multi-drug resistance within three months of admission, if the patient received any antibiotics during 90 days before admission or previous admission within 90 days if the first culture for the defined infection resistance to selected antibiotics, an inappropriate dose of antibiotics for selected indication, early dose adjustment (less than three days), duration of antibiotics less than three days, uncontrolled source of infection.
Setting
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 (14).
Ethics approval and consent to participate
The study was approved by the Ministry of National Guard Health Affairs Institutional Review Board, Riyadh, Saudi Arabia (Study Number: RC20/012/R). Participants' confidentiality was strictly observed throughout the study using the anonymous unique serial number for each subject and restricting data only to the investigators. Informed consent was not required due to the research's method as per the governmental and local research center's policy.
Data collection
We collected the following information, demographic data (Table 1, Supplemental), Acute Physiology And Chronic Health Evaluation II (APACHE II) and Sequential Organ Failure Assessment (SOFA) scores, comorbidities, vital signs, laboratory tests within 24 hours of ICU admission, and CrCl (By Cockroft equation) at day #1 AND #3, Antibiotics, baseline cultures, follow-up cultures, evaluation of pathogen resistance, persistence after three days and eradication at 10-14 days. Additionally, ICU LOS, hospital LOS, and ICU mortality were collected and followed. Patients were followed during ICU LOS until ICU discharge after improving, or in-hospital death, whichever occurred first.
Outcomes
The aim of this study is to evaluate the efficacy and clinical outcomes of using standard dosing of selected broad spectrum antibiotics. The primary endpoint was to assess the eradication of pathogen at 10-14 days. The secondary endpoints include the development of resistance and persistence pathogen growth after three days, ICU mortality within 30-day, ICU LOS, and hospital LOS.
Definition (s)
The ARC defined as an estimated CrCl ≥130 ml/min and Non-ARC as an estimated CrCl 50-129 ml/min.
- Estimated CrCl by Cockcroft-Gault (CG) method.
CrCl (male) = ([140-age (years)] × weight (in kg)]/(SrCr (mg/dL) × 72)
CrCl (female) = CrCl (male) × 0.85
- The average of estimated CrCl depend on day 0 and day 3 from admission. If Body Mass Index (BMI)> 30 will use Adjusted Body weight (adjBW) and Adjusted Creatinine Clearance (AdjCrCl), BMI<30 will use Actual Body weight (ActBW) and actual CrCl.
- Infection was identified through the blood, urine, and/or respiratory cultures. The bacterial growth considered significant if the growth is ≥ of 100,000 CFU/ml in sputum or endotracheal aspiration shows; 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" (15).
- Resistant organisms were defined as the non-susceptibility to at least three or more antimicrobial agents. Susceptibility of microorganisms created using documents and breakpoints based on Clinical Laboratory Standards Institute (CLSI) (16).
- Persistence organisms were defined as the presence of the same micro-organism in the repeated culture after three days (17).
- Standard dosing of antibiotics in Lexicomp® depend on micro-organism and type of infection:
- Meropenem:
Respiratory, Bacteremia and UTI infections: 1 gram every 8 hours.
- Imipenem:
Respiratory, Bacteremia and UTI infection: 500 mg every 6 hours.
- Piperacillin/Tazobactam:
- Respiratory infection: 4.5 gram every 6 hours.
- Bacteremia infection: 4.5 gram every 6 hours.
- UTI infection: 3.375 gram every 6 hours, if pseudomonas 4.5 gram every 6hours.
Data management and Statistical analysis
We summarized categorical variables as number (percentage) and numerical variables (continuous variables) as mean and standard deviation (SD). The normality assumptions were assessed for all numerical variables using statistical test (i.e. Shapiro–Wilk test) and using graphical representation (i.e. histograms and Q-Q plots). We compared categorical variables using the chi square or Fisher exact test, normally distributed numerical variables with the t test, and other quantitative variables with the Mann-Whitney U test. Baseline characteristics, baseline severity and outcome variables were compared between the two 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 the two groups and the different outcomes considered in this study. We considered a P value of < 0.05 statistically significant and used SAS version 9.4 for all statistical analyses.