A retrospective cohort observational study was carried out in the ICU department of Al-Gomhoreya General Hospital, Alexandria, Egypt from 01.10.2022 to 31.03. 2024. This study received ethical approval from the Egyptian Institutional Review Board on August 28, 2024. The study aims to evaluate the impact of ASP implementation by comparing a six-month period before ASP implementation from 01.10. 2022 to 31.03. 2023, with a six-month period after implementation from 01.10. 2023 to 31.03.2024, focusing on process and outcome measures; adherence to hospital-specific MRSA management protocol, annual local antibiogram, prior Linezolid authorization, prospective audit, feedback, and antibiotic timeout, collectively enhancing stewardship effectiveness [8, 16]. The total bed capacity was 14. 168 ICU-admitted adults older than 18 and receiving anti-MRSA therapy (vancomycin, teicoplanin or Linezolid) were included in this study. Patients under this age or not using anti-MRSA therapy were excluded. Data was collected from hospital medical records over a six-month period before and after the intervention by clinical pharmacists, with disagreements resolved by consensus. The analysis included patient demographics, consumption of anti-MRSA agents—particularly linezolid—adherence to hospital protocol for MRSA management, and compliance with the time-out process. Additionally, the susceptibility of MRSA to linezolid was assessed using data obtained from the hospital’s annual local antibiogram. The laboratory employed the disk diffusion method (Kirby-Bauer technique) to determine the percentage of MRSA isolates sensitive to linezolid and results were interpreted according to CLSI guidelines (2022), Quality control was conducted using S. aureus ATCC 25,923 as a reference strain, pre-ASP phase encompassed the period from January 1 to December 31, 2023, while the post-ASP phase covered January 1 to December 31, 2024, the percentage of MRSA sensitivity to Linezolid was compared between these two intervals to assess the effectiveness of ASP implementation.
Pre-ASP
From 01.10. 2022 to 31.03. 2023, the empirical coverage of MRSA in ICU without adherence to hospital-specific MRSA management guidelines, this is identified as the primary contributing factor to the rising prevalence of MRSA in Egypt [13].
Linezolid was administered as a first-line agent for MRSA infection. Linezolid was dispensed after prescription without written justification of the indication of prescription and without adherence to timeout process for reassessment. The extensive overuse of linezolid is a prime driver for the emergency of Linezolid-resistant strains [15]. DDD per 100 patient-days for linezolid, vancomycin, and teicoplanin was calculated based on the total antibiotic consumption during the specified period. The total consumption was divided by the WHO-assigned standard DDD values for each antibiotic (1.2 for linezolid, 2.0 for vancomycin, and 0.4 for teicoplanin), followed by normalization per 100 patient-days. The total number of patient-days during this period was 2,547 [17, 18].
Interventions (ASP-implementation)
From 01.04. 2023 to 31.09. 2023, the intervention was governed by clinical pharmacist specializing in infectious diseases, utilizing a robust ASP measurement process and outcome assessment in accordance with Center of Prevention and Control core-elements [3]. The interventions were delivered in both formal (monthly meetings) and informal (bedside review) formats. Monthly educational sessions for ICU physicians and staff on rational antimicrobial use, since education is considered one of the most basic and effective tools to influence prescriber behavior [14].
The stewardship committee developed hospital protocol for MRSA management align with IDSA guidelines, WHO recommendations and hospital local antibiogram to measure percentage of adherence to MRSA indication and appropriateness use of Linezolid. Incorporating a simplified format to promote and evaluate adherence to the timeout process, this process is guided by Gram stain results provided by the laboratory microbiologist, aiding physicians in determining the appropriate duration of anti-MRSA therapy [19]. Additionally, the protocol supports adherence to the prospective audit and feedback process [8, 16], daily prospective audit and feedback conducted by the ASP team during ICU rounds.
A standardized prescription form was developed by selecting the approved indication for which Linezolid was prescribed [18], adhering to preauthorization process for Linezolid use, requiring approval by an infectious diseases’ consultant [9]. Regular updates of local antibiograms and treatment guidelines shared with clinical teams. The ASP team was multidisciplinary, comprising an infectious diseases consultant, two clinical pharmacists, a clinical microbiologist, and an ICU physician.
A report on the DDD/100 patient-days for previously mentioned anti-MRSA drugs, as a metric tool standardized by WHO, utilized to assess and compare the consumption before and after ASP implementation [20].
Post ASP
From 01.10. 2023 to 31.03. 2024, Linezolid was prescribed after pre-authorization form signed by ICU consultant and clinical pharmacist with written justification of the indication of prescription [11]. The susceptibility of MRSA to Linezolid improves following the implementation of a pre-authorization process [13].
Adherence to hospital protocol for MRSA management and time-out process has demonstrated improvements [8]. DDD per 100 patient-days for the previously mentioned anti-MRSA agents was calculated as described above, based on a total of 2,518 patient-days during the post-ASP period.
Definitions
DDD: is the assumed average maintenance dose per day for a drug used for its main indication in adults.
Standardized antibiotic consumption: total amount of the antibiotic used, adjusted by the WHO DDD.
Total patient-days: is calculated as the number of patients multiplied by the average length of stay.
Timeout: A structured reassessment of ongoing antibiotic therapy, this typically occurs after 48 to 72 h after the initiation of antibiotics to evaluate whether continued use is appropriate.
Prospective audit and feedback: An antimicrobial stewardship strategy where antibiotic use is reviewed by experts after prescription, clinicians receive feedback and recommendations on optimizing therapy.
Preauthorization process: A Core Element in ASP Implementation used to regulate and optimize antimicrobial use, it involves requiring approval before certain antimicrobials can be prescribed or dispensed.
Sample size calculation
A retrospective cohort study detected the change in mean linezolid consumption measured by defined daily doses (DDD) pre and post intervention as a primary outcome. Assuming that the mean linezolid DDD/100 patient-days per month was 7.63 ± 4.82 pre-intervention vs. 2.73 ± 3.03 post-intervention with a pooled standard deviation 4.03 from (Papan et al. 2021) [22] estimated from median defined daily doses and interquartile range as demonstrated in (Wan et al. 2014) [23]. For a resulted effect size (Cohen’s d) of 1.22, that calculated from the formula: Cohen’s d = (M2 – M1) ⁄ Spooled; where: Spooled = √ ((SD12 + SD22) ⁄ 2), at 5% level of significance to achieve 90% power of the study, the minimum total sample size required was 16 patients/group. After adding a 20% increase to account for the incomplete patients ’records, a total of 40 patients (20 patients per group) were required for the study. Calculated using the “pwr” package in R statistical software version 4.2.2.
Statistical analysis
In compliance with the study protocol, all demographic data and clinical characteristics for ICU admitted patients were collected and verified. Tracking patients’ antibiotic consumption during their hospital stay prior to and after ASP implementation was demonstrated accordingly. Descriptive analysis for the collected data was performed as mean, standard deviation (SD), and range for quantitative data. While for qualitative variables, count and percentage were applied instead.
Analytical statistics were applied for patients adhered to the ASP implementation in comparison to those prior to implementation regarding the total antibiotic consumption in grams, adherence to MRSA indication and adherence to timeout process (gram stain results). The comparative analyses were performed using Permutation Welch Two Sample t-test that doesn’t rely on the normality assumptions for the continuous measures, while Chi-squared test or Fisher’s exact test were applied for categorical outcomes according to their assumption’s availability. A two-tailed p value ≤ 0.05 was considered the threshold of significance. The standardized effect sizes were estimated using Cohen’s D for the antibiotic’s consumptions; where Cohen’s D = (M2 – M1) ⁄ Spooled; and Spooled = √ ((SD12 + SD22) ⁄ 2) and the mean square contingency coefficient Phi (φ) applied for chi-squared test; where φ = √(χ²/N).