Long-Term Impact of an Educational Antimicrobial Stewardship Program on Management of Patients with Hematological Diseases

antibiotics Article Long-Term Impact of an Educational Antimicrobial Stewardship Program on Management of Patients with Hematological Diseases Ana Belén Guisado-Gil 1,2 , Manuela Aguilar-Guisado 1,*, Germán Peñalva 1, JoséAntonio Lepe 1, Ildefonso Espigado 3, Eduardo Rodríguez-Arbolí3, JoséGonzález-Campos 3, Nancy Rodríguez-Torres 3, María Isabel Montero-Cuadrado 3, JoséFrancisco Falantes-González 3, Juan Luis Reguera-Ortega 3, María Victoria Gil-Navarro 2, JoséMolina 1, José-Antonio Pérez-Simón3and JoséMiguel Cisneros 1   Citation: Guisado-Gil, A.B.; Aguilar-Guisado, M.; Peñalva, G.; Lepe, J.A.; Espigado, I.; Rodríguez-Arbolí, E.; González-Campos, J.; Rodríguez-Torres, N.; Montero-Cuadrado, M.I.; Falantes-González, J.F.; et al. Long-Term Impact of an Educational Antimicrobial Stewardship Program on Management of Patients with Hematological Diseases. Antibiotics 2021,10, 136. https://doi.org/ 10.3390/antibiotics10020136 Academic Editors: Albert Figueras and Diane Ashiru-Oredope Received: 16 December 2020 Accepted: 27 January 2021 Published: 30 January 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Copyright: © 2021 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/). 1Department of Infectious Diseases, Microbiology and Preventive Medicine, Infectious Diseases Research Group, Institute of Biomedicine of Seville (IBiS), University of Seville/CSIC/University Hospital Virgen del Rocio, 41013 Seville, Spain; [email protected] (A.B.G.-G.); [email protected] (G.P.); [email protected] (J.A.L.); [email protected] (J.M.); [email protected] (J.M.C.) 2Department of Pharmacy, University Hospital Virgen del Rocio, 41013 Seville, Spain; mariav[email protected] 3 Department of Hematology, Institute of Biomedicine of Seville (IBiS/CSIC/CIBERONC), University Hospital Virgen del Rocio, University of Seville, 41013 Seville, Spain; [email protected] (I.E.); [email protected] (E.R.-A.); [email protected] (J.G.-C.); [email protected] (N.R.-T.); [email protected] (M.I.M.-C.); [email protected] (J.F.F.-G.); [email protected] (J.L.R.-O.); [email protected] (J.-A.P.-S.) *Correspondence: maguilar[email protected]; Tel.: +34-670943816 Abstract: Antimicrobial stewardship programs (ASPs) in hematological patients are especially relevant. However, information about ASPs in this population is scarce. For 11 years, we quarterly assessed antimicrobial consumption and incidence and death rates of multidrug-resistant (MDR) bloodstream infections (BSI) in the hematology Department. Healthcare activity indicators were also monitored yearly. We performed an interrupted time-series analysis. Antimicrobials showed a sustained reduction with a relative effect of − 62.3% (95% CI − 84.5 to − 40.1) nine years after the inception of the ASP, being especially relevant for antifungals (relative effect − 80.4%, − 90.9 to − 69.9), quinolones (relative effect − 85.0%, − 102.0 to − 68.1), and carbapenems (relative effect − 68.8%, − 126.0 to − 10.6). Incidence density of MDR BSI remained low and stable (mean 1.10 vs. 0.82 episodes per 1000 occupied bed days for the pre-intervention and the ASP period, respectively) with a quarterly percentage of change of − 0.3% (95% CI − 2.0 to 1.4). Early and late mortality of MDR BSI presented a steady trend (quarterly percentage of change − 0.7%, 95% CI − 1.7 to 0.3 and − 0.6%, 95% CI − 1.5 to 0.3, respectively). Volume and complexity of healthcare activity increased over the years. The ASP effectively achieved long-term reductions in antimicrobial consumption and improvements in the prescription profile, without increasing the mortality of MDR BSI. Keywords: antimicrobialstewardship; anti-infectiveagents; bacteremia; candidemia; hematologicdiseases 1. Introduction Antimicrobial stewardship programs (ASPs) have been identified as a valuable tool to optimize the antimicrobial use in healthcare centers, improving patient outcomes and reducing adverse events and the selection pressure related to the use of antimicrobial agents [1]. In hematological patients receiving immunosuppressive therapy, collateral damages of antimicrobial consumption, especially broad-spectrum antibiotic therapy, include the selection of multidrug-resistant (MDR) microorganisms [ 2 ], an increased propensity to Antibiotics 2021,10, 136. https://doi.org/10.3390/antibiotics10020136 https://www.mdpi.com/journal/antibiotics Antibiotics 2021,10, 136 2 of 13 fungal infections [ 3 ], and microbiota dysbiosis [ 4 ]. Although, due to these reasons the impact of ASPs in patients with hematological diseases might be especially relevant, information regarding the development of antimicrobial stewardship strategies in these patients is scarce [5–7]. An ASP named Institutional Program for the Optimization of Antimicrobial Treatment (PRIOAM) started in our institution in January 2011. Since then, assessments of antimicrobial use, in-hospital bacterial resistance, and mortality rates associated with nosocomial bloodstream infections (BSI) have decreased significantly [ 8 , 9 ]. This program covers the entire hospital and presents specific interventions focused on hematological patients. We hypothesized that a comprehensive ASP in hematological patients could also optimize antimicrobial use, reducing the overall consumption and improving the prescription profile without increasing the incidence and mortality rates of BSI produced by MDR microorganisms. Thus, the objective of the present study was to assess the impact of the PRIOAM on antimicrobial consumption and the incidence and death rates caused by MDR BSI in hospitalized adult patients with hematological diseases. 2. Results Since the inception of the ASP and as part of PRIOAM educative measures (see “Intervention” at the Materials and Methods section), a total number of 218 face-to-face structured educational interviews (EI) were performed (mean 24 ± 19 EI per year). The main reasons for inappropriate antimicrobial therapy were: an incorrect selection of the drug according to the suspected diagnosis (28.4%) or inappropriate duration (28.0%) in the case of empiric treatments, and failing to de-escalate (11.0%) in the case of targeted therapies. Moreover, 18 clinical sessions (two per year) were performed about practical aspects of common infections in hematological malignancy patients and 45 reports were produced, including one per quarter and an additional annual report to the head of the department, on the level of attainment of pre-agreed objectives. 2.1. Antimicrobial Consumption The mean consumption of all antimicrobials decreased from 148.2 ± 16.2 defined daily doses (DDD) per 100 occupied bed days (OBD) in the pre-intervention period to 112.0 ± 21.7 DDD per 100 OBD in the ASP period (p< 0.001). Detailed data from the pre-post analysis are included in the Supplementary material (Table S1). The interrupted time-series (ITS) analysis (Table 1, Figures 1–3) showed a sustained reduction in favor of the intervention with a relative effect of − 62.3% (95% confidence interval [CI] − 84.5 to − 40.1) nine years after the inception of the ASP, when compared with the expected antimicrobial consumption based on the pre-intervention trend. As for antibiotics, a prompt change in the level after the inception of the ASP of − 17.22 DDD per 100 OBD (95% CI − 29.17 to − 5.28) was found. Regarding antifungal consumption, a decreasing trend with a change in slope of − 3.32 DDD per 100 OBD (95% CI − 6.04 to − 0.60) and a relative effect − 80.4% (95% CI − 90.9 to − 69.9) was obtained with the intervention. Quinolones were the agents that showed the highest reduction with a change in the level of − 18.45 DDD per 100 OBD (95% CI − 25.29 to − 11.62) after the start of the intervention that led to a relative effect of − 85.0% (95% CI − 102.0 to − 68.1) at the end of the study period. Broad-spectrum antibiotics such as carbapenems and glycopeptides presented significant relative effects of − 68.8% (95% CI − 126.0 to − 10.6) and − 70.5% (95% CI − 138.9 to − 2.1), respectively, compared with the expected consumption based on the pre-intervention trend. The global trend is described in Table S2. Antibiotics 2021,10, 136 3 of 13 Table 1. Interrupted time-series analysis of changes in trends of antimicrobial consumption. Outcomes Pre-Intervention Trend Change in Level a Change in Trend b Relative Effect c% Total J01+J02 1.83 (−2.14 to 5.80) −13.98 (−35.65 to 7.69) −3.52 (−7.57 to 0.52) −62.3 (−84.5 to −40.1) Total antibiotics (J01) −0.65 (−2.84 to 1.54) −17.22 (−29.17 to −5.28) −0.27 (−2.49 to 1.95) −32.4 (−99.2 to 34.5) Total antifungals (J02) 2.54 (−0.12 to 5.20) 3.31 (−11.12 to 17.74) −3.32 (−6.04 to −0.60) −80.4 (−90.9 to −69.9) Carbapenems −0.01 (−0.69 to 0.66) −0.67 (−4.33 to 2.99) −0.20 (−0.89 to 0.49) −68.8 (−126.0 to −10.6) Piperacillintazobactam 0.63 (−0.25 to 1.51) 7.78 (3.30 to 12.27) −0.86 (−1.78 to 0.07) −67.3 (−96.9 to −38.6) Antipseudomonal cephalosporins −0.55 (−1.57 to 0.47) −10.79 (−16.18 to −5.41) 0.77 (−0.29 to 1.82) 105.1 (−195.6 to 405.8) Quinolones 0.16 (−1.16 to 1.47) −18.45 (−25.29 to −11.62) −0.45 (−1.82 to 0.93) −85.0 (−102.0 to −68.1) Amikacin −0.03 (−0.46 to 0.39) 1.68 (−0.51 to 3.87) −0.05 (−0.48 to 0.39) 0.1 (−410.8 to 413.6) Glycopeptides 0.01 (−0.55 to 0.56) 0.68 (−2.27 to 3.62) −0.17 (−0.74 to 0.40) −70.5 (−138.9 to −2.1) Data are presented as quarterly defined daily doses per 100 occupied bed days with a 95% confidence interval, unless otherwise specified. a Increase or decrease in the first quarter after the start of the antimicrobial stewardship program (ASP) period with respect to the expected value. b Change in slope for the ASP period. c Percentage difference between the expected value according to the pre-intervention trend and the trend nine years after the start of the ASP. Antibiotics 2021, 10, x 3 of 14 Table 1. Interrupted time-series analysis of changes in trends of antimicrobial consumption. Outcomes Pre-Intervention Trend Change in Level a Change in Trend b Relative Effect c % Total J01+J02 1.83 (−2.14 to 5.80) −13.98 (−35.65 to 7.69) −3.52 (−7.57 to 0.52) −62.3 (−84.5 to −40.1) Total antibiotics (J01) −0.65 (−2.84 to 1.54) −17.22 (−29.17 to −5.28) −0.27 (−2.49 to 1.95) −32.4 (−99.2 to 34.5) Total antifungals (J02) 2.54 (−0.12 to 5.20) 3.31 (−11.12 to 17.74) −3.32 (−6.04 to −0.60) −80.4 (−90.9 to −69.9) Carbapenems −0.01 (−0.69 to 0.66) −0.67 (−4.33 to 2.99) −0.20 (−0.89 to 0.49) −68.8 (−126.0 to −10.6) Piperacillin-tazobactam 0.63 (−0.25 to 1.51) 7.78 (3.30 to 12.27) −0.86 (−1.78 to 0.07) −67.3 (−96.9 to −38.6) Antipseudomonal cephalosporins −0.55 (−1.57 to 0.47) −10.79 (−16.18 to −5.41) 0.77 (−0.29 to 1.82) 105.1 (−195.6 to 405.8) Quinolones 0.16 (−1.16 to 1.47) −18.45 (−25.29 to −11.62) −0.45 (−1.82 to 0.93) −85.0 (−102.0 to −68.1) Amikacin −0.03 (−0.46 to 0.39) 1.68 (−0.51 to 3.87) −0.05 (−0.48 to 0.39) 0.1 (−410.8 to 413.6) Glycopeptides 0.01 (−0.55 to 0.56) 0.68 (−2.27 to 3.62) −0.17 (−0.74 to 0.40) −70.5 (−138.9 to −2.1) Data are presented as quarterly defined daily doses per 100 occupied bed days with a 95% confidence interval, unless otherwise specified. a Increase or decrease in the first quarter after the start of the antimicrobial stewardship program (ASP) period with respect to the expected value. b Change in slope for the ASP period. c Percentage difference between the expected value according to the pre-intervention trend and the trend nine years after the start of the ASP. Figure 1. Interrupted time-series analysis of the trends in antimicrobial consumption (antibacterials for systemic use and antifungals) observed before and after the implementation of the antimicrobial stewardship program. Solid lines show the observed trend during the pre-intervention and intervention periods. Dashed lines show the expected trend after the intervention according to the pre-intervention values. DDD, defined daily doses. OBD, occupied bed days. Q, quarter. Figure 1. Interrupted time-series analysis of the trends in antimicrobial consumption (antibacterials for systemic use and antifungals) observed before and after the implementation of the antimicrobial stewardship program. Solid lines show the observed trend during the pre-intervention and intervention periods. Dashed lines show the expected trend after the intervention according to the pre-intervention values. DDD, defined daily doses. OBD, occupied bed days. Q, quarter. Antibiotics 2021,10, 136 4 of 13 Antibiotics 2021, 10, x 4 of 14 Figure 2. Interrupted time-series analysis of the trends in consumption for antibacterials for systemic use (J01) and antifungals (J02) observed before and after the implementation of the antimicrobial stewardship program. Solid lines show the observed trend during the pre-intervention and intervention periods. Dashed lines show the expected trend after the intervention according to the pre-intervention values. DDD, defined daily doses. OBD, occupied bed days. Q, quarter. Figure 2. Interrupted time-series analysis of the trends in consumption for antibacterials for systemic use ( J01 ) and antifungals ( J02 ) observed before and after the implementation of the antimicrobial stewardship program. Solid lines show the observed trend during the pre-intervention and intervention periods. Dashed lines show the expected trend after the intervention according to the pre-intervention values. DDD, defined daily doses. OBD, occupied bed days. Q, quarter. Antibiotics 2021,10, 136 5 of 13 Antibiotics 2021, 10, x 5 of 14 Figure 3. Interrupted time-series analysis of the trends in consumption for carbapenems and quinolones observed before and after the implementation of the antimicrobial stewardship program. Solid lines show the observed trend during the pre-intervention and intervention periods. Dashed lines show the expected trend after the intervention according to the pre-intervention values. DDD, defined daily doses. OBD, occupied bed days. Q, quarter. Figure 3. Interrupted time-series analysis of the trends in consumption for carbapenems and quinolones observed before and after the implementation of the antimicrobial stewardship program. Solid lines show the observed trend during the pre-intervention and intervention periods. Dashed lines show the expected trend after the intervention according to the pre-intervention values. DDD, defined daily doses. OBD, occupied bed days. Q, quarter. Antibiotics 2021,10, 136 6 of 13 2.2. Clinical Outcomes For the entire study period, the most common gram-negative microorganism causing BSI was non-extended-spectrum beta-lactamase (ESBL) producing Escherichia coli (48.1%). MDR gram-negative bacteria and Candida spp. caused 14.4% and 5.6% of BSI that were monitored, respectively (Table S3). BSI produced by MDR Pseudomonas aeruginosa and Candida spp. were responsible for the highest values of early and late mortality rates (Table S4). For incidence density (ID) and mortality rate, the ITS analysis is shown in Table 2. The pre-post analysis and the trend analysis can be found in Tables S5 and S6, respectively. Table 2. Interrupted time-series analysis of changes in trends of incidence and mortality rate of multidrug-resistant bloodstream infections. Outcomes Pre-Intervention Trend Change in Level a Change in Trend b Relative Effect c% Incidence density −0.09 (−0.25 to 0.07) −0.11 (−1.00 to 0.77) 0.10 (−0.06 to 0.26) 98.9 (−301.4 to 499.2) Early mortality 0.009 (−0.03 to 0.05) 0.06 (−0.14 to 0.26) −0.01 (−0.05 to 0.03) −72.1 (−147.8 to 3.5) Late mortality 0.01 (−0.06 to 0.08) −0.03 (−0.42 to 0.36) −0.005 (−0.08 to 0.07) −35.55 (−346.9 to 275.8) Data are presented as quarterly incidence density and all-cause crude death rate per 1000 occupied bed days with a 95% confidence interval, unless otherwise specified. a Increase or decrease in the first quarter after the start of the antimicrobial stewardship program (ASP) period with respect to the expected value. b Change in slope for the ASP period. c Percentage difference between the expected value according to the pre-intervention trend and the trend nine years after the start of the ASP. The ID of BSI caused by MDR organisms, which kept low during the entire study period, remained stable (mean incidence 1.11 episodes per 1000 OBD for the pre-intervention period and 0.82 episodes per 1000 OBD for the ASP period) with a quarterly percentage change (QPC) of − 0.3% (95% CI − 2.0 to 1.4, p= 0.709). Early and late mortality of MDR BSI presented a steady trend with a QPC of − 0.7% (95% CI − 1.7 to 0.3, p= 0.154) and − 0.6% (95% CI −1.5 to 0.3, p= 0.201), respectively. 2.3. Changes in Healthcare during the Study Period Activity indicators related to the volume and complexity of the hematology department such as the number of blood cultures per 1000 OBD, total admissions, OBD, and the number of allogeneic hematopoietic stem-cell transplantation (HSCT) increased during the study period. Other indicators of the department’s activity remained stable (Table 3). Antibiotics 2021,10, 136 7 of 13 Table 3. Indicators related to the volume and complexity of the activity at the hematology department. Outcomes 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019 APC (95% CI) Blood cultures per 1000 OBD 72 71 59 71 100 121 92 100 100 133 102 6.014 (2.348 to 9.811) AML 21 33 35 47 35 37 35 29 43 35 37 4.400 (−6.186 to 16.279) Admissions 1005 1055 1081 946 1052 1148 1169 1120 1133 1290 1265 2.336 (1.253 to 3.430) OBD 8966 9128 10,616 10,463 10,343 10,620 10,840 11,135 11,753 11,719 14,463 3.540 (2.358 to 4.735) Length of stay, mean 16 15 18 17 17 16 16 16 17 14 16 −0.843 (−1.908 to 0.235) Allogeneic HSCT 19 20 33 40 47 55 56 58 44 43 47 8.609 (4.436 to 12.948) HSCT−related mortality, % 5.3 5.0 0 0 6.4 1.8 7.1 1.7 0 2.3 2.1 −7.007 (−16.347 to 3.376) For each year, data are presented as the number of events, unless otherwise specified. In the last column, the annual percentage of change (APC) obtained from joinpoint regression analysis with a 95% confidence interval (CI) is included. OBD, occupied bed days. AML, acute myeloid leukemia. HSCT-related mortality, hematopoietic stem-cell transplantation (HSCT)-related mortality within the first 100 days after allogeneic HSCT from human leukocyte antigen (HLA)-identical siblings. 3. Discussion The results of our study show that an education-based ASP in the hematology department was able to achieve long-term reductions in overall antimicrobial consumption and improvements in the prescription profile, especially relevant in broad-spectrum antibiotics such as carbapenems, quinolones, and antifungals, without increasing the mortality rates and maintaining a low incidence of MDR BSI. This positive impact was observed in a tertiary care hospital where infectious diseases consultation (IDC) was performed for more than 25 years and up to the PRIOAM implementation. To the best of our knowledge, this is the first study proving nine years’ data on the benefits of ASPs in the setting of hematological patients. Very few previous studies have evaluated the effect of ASPs on antimicrobial consumption in hematological patients with most of them limited by sample size, study period (<2 years before or after intervention), and the absence of data about specific groups of antibiotics. One of the most rigorous is the study performed by So et al. [ 10 ] in leukemia units with audit and feedback as the core measures of the ASP. In contrast to our results, the intervention was associated with a significant decrease in antibiotic use ( − 35.1 DDD per 100 patient-days), but no significant trend in antifungal prescription was observed during a two-year period ( − 4.0 DDD per 100 patient-days). Two other research works with a one-year evaluation time and including solid and hematological malignancy patients showed favorable results after the beginning of antimicrobial stewardship strategies in terms of global antibiotic consumption [11] and meropenem prescription [7]. The increase of infections caused by MDR bacteria is a major health problem worldwide [ 12 ]. This challenge also affects hematological patients [ 13 – 15 ]. However, the percentage of MDR bacteria in our center was lower than previously reported by others [ 15 – 18 ], and notably, remained stable throughout the study period. The low prevalence of ESBL producing E. coli and MDR P. aeruginosa and, particularly, the absence of carbapenemaseproducing Enterobacteriaceae was especially important. The sustained reduction of the use of all-class antibiotics associated with the intervention has likely contributed to preventing the generalized increase in MDR infections described in other centers. In our study, the early and late mortality rates from MDR BSI remained stable during the intervention, showing the absence of deleterious effects for reducing antimicrobial use in these patients. Death rates were higher for BSI caused by MDR organisms as Antibiotics 2021,10, 136 8 of 13 described before [ 12 , 18 ]. Late mortality for ESBL producing Enterobacteriaceae was inferior to the 21-day mortality rate reported by Trecarichi et al. [ 18 ] for non-susceptible strains (26.2%) and comparable for MDR P. aeruginosa (42.4%). Despite the differences in study design, population and antimicrobial utilization due to different local treatment protocols and colonization rates by MDR bacteria, preceding results, similar to ours, illustrated the potential benefits of antimicrobial stewardship approaches. The adherence to ASP recommendation has demonstrated to be an effective and safe strategy with a 64% relative risk reduction in 28-day mortality [ 19 ] and a significant decrease in the fatality rate (from 30% to 11%) [ 5 ] both in patients with febrile neutropenia and hematological or solid tumors. In patients with hematological diseases and HSCT recipients, stopping antimicrobial therapy early did not significantly increase the incidence of fever relapse and positive blood cultures or the mortality rate, with the advantage of the reduction in the use of antibiotics [20–22]. The results of the current study are even more remarkable if it is taken into consideration that most indicators related to the volume and complexity of the activity at the hematology department increased considerably during the study period. A fact that, in general, is related to a higher frequency of infectious complications and, as a consequence, higher consumption of antibiotics. Only the number of patients diagnosed with acute myeloid leukemia (AML), the length of hospital stay, and the transplant-related mortality within the first 100 days after allogeneic HSCT from human leukocyte antigen (HLA)- identical siblings remained stable. The monitoring of changes in healthcare as an internal control as well as the largest period of study, spanning 11 years in total, are some of the strengths of this work. Additionally, the employment of ITS analyses, the preferential method to assess the impact of health interventions over time [ 23 ], and the consistent results throughout the variables evaluated, support a potential causality relation between the ASP implementation and the progressive reduction in the antimicrobial pressure. The stable trend in the mortality by MDR BSI supports the safety of the intervention. PRIOAM’s methods diverge from those ASP performed previously in patients with onco-hematological diseases in which educational initiatives were not incorporated as the core element of the program [ 11 ], or they were based on a sole recommendation (deescalation, discontinuation, antibiotic cycling, etc.) [ 6 , 20 , 21 ] and/or a specific diagnosis [ 10 ], commonly febrile neutropenia [ 17 , 19 – 21 ]. The educational nature combined with real-time intervention(s) and the inclusion of patients with all types of hematological diseases comprise a differentiating feature of this work. In patients with hematological diseases, post-chemotherapy febrile neutropenia was one of the most frequent infectious syndromes requiring antimicrobial courses. In this sense, the contribution of the results of the How Long clinical trial [ 24 ], led by investigators from our institution, to change the clinical practice and to decrease antibiotic overpressure in hematological patients was considerable. According to the main findings, in high-risk patients with hematological malignancies and febrile neutropenia, empirical antimicrobial therapy can be safely discontinued after 72 h of apyrexia and clinical recovery irrespective of their neutrophil count. It reinforced the previously published recommendation from the 4th European Conference on Infections in Leukaemia (ECIL-4) about empirical treatment of febrile neutropenia [25]. In our center, quinolones were agents commonly selected as an empirical combination therapy in patients with febrile neutropenia, especially in those with a suspected respiratory infection. Quinolones showed the highest reduction after the start of the intervention and the greatest decrease in the relative effect at the end of the study period. It could be explained by the fact that the ASP guidelines highly recommended the withdrawal of combination therapy 48 h after the start if an infection was not confirmed, or if it was presented and narrower spectrum antibiotics could be employed instead of quinolones. The implementation of this recommendation through the ASP has likely contributed to achieving this result. Antibiotics 2021,10, 136 9 of 13 However, for this study, some limitations should be noted. First, the study design is not exempt from the possibility of ecologic bias, and, consequently, we could not unequivocally associate the results of incidence and mortality of MDR organisms to the ASP implementation. Although the volume and complexity of the activity in the hematology department were monitored, other potential confounding factors such as those related to patients and the center could possibly interfere with the outcomes. In addition, the single-center design limits the external validity of our results and makes it necessary to confirm the reproducibility of the findings in different settings. Second, the close relationship between the IDC in the pre-intervention period and the ASP made it difficult to elucidate the precise weight of each one on the outcomes achieved. Nonetheless, regarding the use of antimicrobials, the stable trends during the pre-intervention period suggest that the implementation of the ASP was necessary to achieve the goals. The sole IDC was insufficient to promote a change in the entire department, as reported in previous studies [ 26 ]. Finally, non-MDR BSI, invasive candidiasis (other than candidemia) and aspergillosis have not been examined in this study. The decreasing trend in overall antimicrobial consumption, including voriconazole and liposomal amphotericin B as common treatments for invasive infections caused by molds [27], suggests, at least, a steady frequency of these infections. 4. Materials and Methods 4.1. Study Design and Period A quasi-experimental before-after study of ITS was performed. The PRIOAM implementation started in January 2011, and, since then, data were prospectively registered for a nine-year period. For the ITS analyses, the study period spanned 44 quarters (11 years) from January 2009 to December 2019. 4.2. Setting The program was performed at the 39-bed hematology department of the University Hospital Virgen del Rocio (Seville, Spain), which is a teaching hospital providing a tertiarycare service in Southwest Spain. The hospital, with 1177 beds and 72 intensive care unit beds, is a referral-center for solid-organ and HSCT. Adult patients (aged ≥ 18 years) receiving treatment for hematological malignancies or undergoing HSCT are treated in this unit. Throughout the last nine years, the hematology department has admitted a mean number of 1134 adult patients per year and has performed a mean of 108 autologous and allogeneic HSCT per year in adults. 4.3. Intervention The PRIOAM’s methods and global outcomes have already been published [ 8 , 9 ]. In brief, it comprises a bundle of educational strategies performed by a multidisciplinary team including infectious diseases physicians, microbiologists, pharmacists, intensive care physicians, pediatricians, and preventivists. The core elements of PRIOAM are summarized in the Supplementary material (Figure S1). Because most EI were performed when a potentially inappropriate prescription was detected (i.e., use of carbapenems or combination therapy for >48 h, antibiotic duration >7 days or targeted therapies), the main messages tackled in EI were: early identification and management of severe infections, interpretation of microbiologic results, de-escalation and sequential oral treatments whenever possible, diversification of antimicrobial prescriptions, and training in the optimal duration of antimicrobial courses. The form employed for EI is included as Figure S2. No other interventions concerning antimicrobial use (i.e., antimicrobial policies, restrictions, etc.) were performed during the study period. The infection control program in the hematology ward consisted of the isolation in high-efficiency particulate air (HEPA) filters conditioned rooms of neutropenic and HSCT patients, and contact isolation of patients with MDR bacteria or respiratory viruses recovered from clinical samples. Local guidelines for antifungal prophylaxis did not change substantially during the intervention period. No additional measures were implemented regarding