*Article* **Effectiveness of a Multifaced Antibiotic Stewardship Program: A Pre-Post Study in Seven Italian ICUs**

**Giulia Mandelli 1, Francesca Dore 1,2,\*, Martin Langer 2,3, Elena Garbero 1,2, Laura Alagna 4, Andrea Bianchin 5, Rita Ciceri 2,6, Antonello Di Paolo 7, Tommaso Giani 8,9, Aimone Giugni 2,10, Andrea Gori 4,11,12, Ugo Lefons 13, Antonio Muscatello 4, Carlo Olivieri 2,14, Angelo Pan 15, Matteo Pedeferri 2,16, Marianna Rossi 17, Gian Maria Rossolini 8,9, Emanuele Russo 18, Daniela Silengo 2,19, Bruno Viaggi 2,20, Guido Bertolini <sup>1</sup> and Stefano Finazzi 1,2**


**Abstract:** Multidrug resistance has become a serious threat for health, particularly in hospitalacquired infections. To improve patients' safety and outcomes while maintaining the efficacy of antimicrobials, complex interventions are needed involving infection control and appropriate pharmacological treatments in antibiotic stewardship programs. We conducted a multicenter pre-post study to assess the impact of a stewardship program in seven Italian intensive care units (ICUs). Each ICU was visited by a multidisciplinary team involving clinicians, microbiologists, pharmacologists, infectious disease specialists, and data scientists. Interventions were targeted according to the characteristics of each unit. The effect of the program was measured with a panel of indicators

**Citation:** Mandelli, G.; Dore, F.; Langer, M.; Garbero, E.; Alagna, L.; Bianchin, A.; Ciceri, R.; Di Paolo, A.; Giani, T.; Giugni, A.; et al. Effectiveness of a Multifaced Antibiotic Stewardship Program: A Pre-Post Study in Seven Italian ICUs. *J. Clin. Med.* **2022**, *11*, 4409. https://doi.org/10.3390/ jcm11154409

Academic Editors: Luca Brazzi and Giorgia Montrucchio

Received: 19 May 2022 Accepted: 25 July 2022 Published: 28 July 2022

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**Copyright:** © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

computed with data from the MargheritaTre electronic health record. The median duration of empirical therapy decreased from 5.6 to 4.6 days and the use of quinolones dropped from 15.3% to 6%, both *p* < 0.001. The proportion of multi-drug-resistant bacteria (MDR) in ICU-acquired infections fell from 57.7% to 48.8%. ICU mortality and length of stay remained unchanged, indicating that reducing antibiotic administration did not harm patients' safety. This study shows that our stewardship program successfully improved the management of infections. This suggests that policy makers should tackle multidrug resistance with a multidisciplinary approach based on continuous monitoring and personalised interventions.

**Keywords:** antibiotic stewardship; multidrug resistance; intensive care units; healthcare-associated infections; infection control; electronic health record; education in medicine; appropriateness of antibiotic

#### **1. Introduction**

The efficacy of antimicrobials still saves the vast majority of patients suffering from bacterial or fungal infections. However, their use, overuse and mainly inappropriate use in and outside hospitals, as well as in livestock, favours the emergence of resistance. Resistant bacterial species threaten health and cause related morbidity and even mortality [1]. This has become a general emergency in hospitals and in general medical practice—although with significant geographical differences [2]. However, it is recognised that judicious use of antimicrobials is a cornerstone of the containment of multidrug resistance (MDR) [3].

Antibiotic stewardship programs (ASPs) are accepted worldwide as a must to improve patients' safety and outcomes, while maintaining the efficacy of antimicrobials by withholding the selective pressure driving antibiotic resistance (ABR) [4]. ASP comprises a bundle of interventions to improve several aspects of a complex decision-making process [5] involving organisation, prevention of transmission, diagnosis of infection, handling of microbiological investigations, optimisation of drug prescriptions [6], and duration of treatments.

There is general agreement on the urgent need for effective ASP, the best bundle composition, and the best way to implement these programs and to maintain the benefit over time. Most published stewardship programs, using very different methods, report success in achieving specific goals [7–14]. However, better management of infections calls for the design and achievement of several goals: reduction of the circulation and transmission of MDR [15] microorganisms and more appropriate use of drugs (sparing of carbapenems, limitation of quinolones and other broad-spectrum drugs, and appropriate site, dose, and duration of treatments).

Intensive care units (ICUs) present unique challenges for ASP due to their crucial position in the chain of antibiotic resistance: they admit critical and chronically ill patients frequently colonised by MDR microorganisms, transferred from hospital wards and nursing homes [16]. ICU doctors use antimicrobials generously, and return survivors with a greater or even unit-acquired MDR burden to the hospital and the community [17]. However, ICU personnel, having experienced how difficult it is to treat patients with MDR infections, do frequently pay closer attention to the MDR problem. ASPs have often been optimised in ICUs in recent years, with attempts also to develop the multidisciplinary aspect by including infectious diseases, microbiologists, and pharmacists in the projects.

In 2017 the Italian Group for the valuation of Intervention in Intensive Care Units (GIViTI, giviti@marionegri.it) started a multi-ICU project to control antibiotic resistance through a complex peer-to-peer intervention and extended monitoring with a common electronic health record (EHR), MargheritaTre (M3) [18] as a potential continuous antibioticstewardship tool.

The aim of this before/after project, intended as a pilot study, was to assess the efficacy of an ASP in a multicenter study. Specific goals of the ASP were reduction of the overall antibiotic pressure, sparing of the essential anti-MDR-drugs (e.g., carbapenems, colistin, linezolid), reduction of the use of quinolones, optimisation of drug administration, and improvement of appropriateness of antibiotic treatment. Appropriateness was assessed across several dimensions, focusing on infections with valid diagnostic specimens, microbiological diagnoses and pharmacologic properties as tissue penetration of the prescribed drugs. These actions, together with prevention of transmission, should yield the very ambitious achievement of reducing MDR infections. Considering the complexity of such a project, the ASP intervention was designed by a multidisciplinary team and agreed with the representatives of the participating ICUs.

The performance of each center was evaluated through a set of indicators designed to monitor several dimensions in the management of infections. The ASP interventions were tailored to each ICU on the basis of data collected during the first year of the project (before the intervention) and discussed with a panel of experts at on-site visits. The impact of the ASP over the year of observation was assessed by comparing the values of the indicators before and after the intervention. A further year of observation was planned to verify how long the benefits, if any, lasted.
