Impact of the Audit and Intervention of Infectologists in the Use of Antimicrobials in Intensive Care Units

Background: Antimicrobials are among the most prescribed drugs in ICUs, where the use of these drugs is approximately 10 times greater than that of other wards. Even so, it is observed that between 30 to 60% of antimicrobial prescriptions performed in these units are unnecessary or inadequate. Thus, surveillance of antimicrobial prescription is a rst and essential step to identify potential overuse or misuse, which could be the target of interventions for antimicrobial administration. Methods: This is an observational, analytical, and prospective study conducted in two adult intensive care units (ICU 1 = surgical and ICU 2 = clinic), with 27 beds each. The study period was divided into pre-intervention (January to June 2019) and post-intervention (July to December 2019). Results: Overall, in the pre- and post-intervention period, 91.4% and 90.0%, respectively, of patients received at least one antimicrobial agent. The most frequently prescribed antimicrobial classes were carbapenems (PRE = 26.0% vs POST = 24.9%; p = 0.245) followed by glycopeptides (PRE = 21.0% vs POST = 18.6%; p = 0.056). Overall, there was a signicant reduction in the duration of therapy (PRE = 727 LOT / 1000pd vs POST = 680 LOT / 1000pd; p = 0.028). The highest rates regarding the time of use of antimicrobials were observed for carbapenems, followed by glycopeptides, with signicant reductions in the time of exposure of glycopeptides (PRE = 284 DOT / 1000pd vs POST = 234 DOT / 1000pd; p = 0.014) and polymyxin B (PRE = 121 DOT / 1000pd vs POST = 88 DOT / 1000pd; p = 0.029), and signicant increases for penicillins (PRE = 25 DOT / 1000pd vs POST = 45 DOT / 1000pd; p = 0.009), and tigecycline ( PRE = 3 DOT / 1000pd vs POST = 27 DOT / 1000pd; p = 0.046). Conclusions: In general, the intervention of infectologists in intensive care antimicrobial agents, regardless of the number of drugs. The DOT / LOT ratio reveals the combination of antimicrobial therapy or monotherapy.


Background
Intensive care units (ICUs) can be a critical area for the emergence and dissemination of microbial resistance because it is a complex population, with severe clinical conditions and associated comorbidities, in addition to vulnerability to the large number of invasive procedures, where rates of nosocomial infections vary from 5 to 30% [1].
In this scenario, antimicrobials are among the most prescribed drugs in ICUs, in which the use of these drugs is approximately 10 times greater than that of other wards [1][2][3]. Even so, it is observed that between 30 to 60% of antimicrobial prescriptions performed in these units are unnecessary or inadequate [4].
The excessive and long-term use of antimicrobials has led to an increase in the number of adverse events related to drugs, increased health care costs, and, mainly, exerted selective pressure, contributing to microbial resistance, threatening its therapeutic e cacy [1,4,[5][6][7][8][9].
Monitoring the use of antimicrobials in hospitals has become an instrument of great interest and particular attention in recent years [5]. In ICUs, this monitoring has an even greater need, due to the patient's clinical condition, with higher rates of infections, especially nosocomial, high rates of resistance, and mortality [4]. Thus, surveillance of antimicrobial prescription is a rst and essential step to identify potential overuse or misuse, which could be the target of interventions for antimicrobial administration [3].
The Management of Surveillance and Monitoring in Health Services and General Management of Technology in Health Services through the "National Guideline for the Development of a Management Program for the Use of Antimicrobials in Health Services" has proposed as process measures for the evaluation of the use of antimicrobials the Days of therapy (DOT) and Length of therapy (LOT) indicators [10]. That guideline describes DOT as the number of days a patient receives an antimicrobial agent, regardless of the dose. While the LOT is the number of days that the patient receives antimicrobial agents, The exclusion criteria involved patients with a stay of fewer than 24 hours, and administration of antimicrobials by intramuscular, topical, ophthalmic, inhalation, antiviral, and antiretroviral routes.

Data Source
The review of prescriptions and data extraction were performed by the researcher, using an electronic database created especially for this purpose. The data regarding the use of antimicrobials were obtained from the individual prescriptions of the patients and forms of requests for antimicrobials, under the responsibility of the hospital pharmacy.
Other data were extracted from the records of active search under the surveillance of hospital infections carried out by the Center for Epidemiology, Patient Safety, and Hospital Infection.

Outcome measures
Primary outcomes were represented by the percentage of patients using antimicrobials and antimicrobial prescriptions, by class and agent, routes of administration, and diagnostic indications. Secondary outcomes included analyzes of pre-and post-intervention periods in the use of antimicrobials, expressed as DOT and LOT per 1000 patient days, the average length of stay in the units, and overall mortality.

Statistical analysis
The variables were expressed as percentages, mean ± standard deviation (SD), or median with interquartile range (IQR: 25-75 percentile). The normality of data distribution was veri ed and compared using Student's t test or Wilcoxon rank-sum tests, as appropriate. The level of statistical signi cance was set at 0.05.

Results
During the study period, 981 patients were followed, 510 in ICU 1 and 471 in ICU 2, represented by 19,550 patient-days, with a median age of 54 years (IQR: 37-67) and 51 years (IQR: 33-65 ), respectively. Overall, in the pre-and post-intervention period, 91.4% and 90.0%, respectively, of patients received at least one antimicrobial agent. Slight reductions, but not statistically signi cant, were observed both individually in the ICU and globally after the intervention. Intravenous administration was present in 97.9% of pre-intervention prescriptions and 97.5% post-intervention, with a reduction, although not signi cant, globally, linked to the reduction of this route in ICU 1 prescriptions ( Table 1).
Regarding the duration of therapy, although its reduction was not signi cant in the units in isolation, overall, this data was signi cant (PRE = 727 LOT / 1000pd vs POST = 680 LOT / 1000pd; p = 0.028). Each patient received an average of 1.8 ± 0.2 antimicrobials during their stay in the units, with a signi cant reduction globally (PRE = 1.9 DOT / LOT vs POST = 1.7 DOT / LOT; p = 0.046) linked to a reduction in ICU 2 (PRE = 1.9 DOT / LOT vs POST = 1.7 DOT / LOT; p = 0.007) ( Table 2). Overall, the highest rates regarding the time of use of antimicrobials were observed for carbapenems, followed by glycopeptides,  Table 2).
The diagnostic indications for the use of antimicrobials, in each unit re ecting globally, were predominantly related to respiratory infections and septic shock.
The only difference observed after intervention was the reduction in indications for surgical site infections in ICU 2 (PRE = 4.3% vs POST = 1.4%; p = 0.032) ( Table 3). Regarding clinical outcomes, the median length of hospital stay was 14 days (IQR: 13-14). The overall mortality was 25.0% ± 3%. There were no signi cant differences regarding these data after the intervention (p > 0.005) ( Table 4).  [3], when conducting a study for four years in an ICU at the University Hospital in Ghent, observed that 84% of patients, with a stay > 48 h, were exposed to at least one class of antibiotics. Álvarez-intervention, reductions in the indication of these pathways, although not signi cant, were observed globally linked to reductions in the ICU 1. One of the factors that may have contributed to this de-escalation, especially in this unit, was the participation in a project to improve patient safety, with a round-trip and multidisciplinary visit, requiring from this unit more active monitoring of the rational use of antimicrobials. The predilection of the parenteral route may be related, among others, to the necessary immediacy of the results, also, the options for the oral route are limited. The switch from parenteral to enteral in ICUs is a very controversial subject. Changing the route may bring some important results, such as early discharge, less risk of bacteremia, less use of venous access, and incidence of thrombophlebitis, and lower cost of treatment [12].
The most prescribed antimicrobial classes, individually in units with global re ex, were related to carbapenems, followed by glycopeptides. In addition to those described, studies also show signi cant values for cephalosporin and beta-lactam prescriptions (piperacillin + tazobactam) in intensive care units [2,1,8,12]. The data reveal that the most recurrent antimicrobial therapy involves agents of a broad spectrum and that it is often performed empirically, during the uncertainty of the diagnosis, not always representing the appropriate therapy [2,4]. That is why it is important to send cultures before starting antimicrobials, making it possible to verify the response to treatment more quickly. Empirical therapy should be guided by accurate and recent antibiograms, in addition to having standardized approaches that take into account the susceptibility pattern of bacteria commonly isolated in the units [4].
The mean duration of antimicrobial therapy was 703 LOT / 1000pd, with a signi cant reduction globally. The literature is scarce regarding the use of this indicator in ICUs. In Brazil, Marcelino FAB [2], found a rate slightly above the nding (median = 844 LOT / 1000pd). These high rates re ect the complexity of infections acquired by patients in intensive care units. Also, the age group of the population observed, in this study requires a longer time for recovery, enabling the acquisition of secondary infections. Each patient received an average of 1.8 ± 0.2 antimicrobials during their stay in the units, indicating that the combination of antimicrobial therapy is common in hospital ICUs. There was a signi cant reduction in this data when observed globally, linked to a reduction in the number of antimicrobials prescribed in the ICU2.
Similar to the number of prescriptions, the highest rates related to the time of use of antimicrobials have been described for carbapenems followed by glycopeptides. These ndings re ect the main diagnostic indications observed in this study, which referred to respiratory infections and septic shock. This data corroborates with several studies that point out the respiratory system as the most affected in ICUs [3,2,12,4]. When comparing the data from this study with others, it was found that the rate regarding the time spent using carbapenems was higher than the ndings by De Bus L et al. [3] (236 DOT / 1000pd) and Candeloro CL et al. [1] (196 DOT / 1000pd), a higher rate about glycopeptides (187 DOT / 1000pd); and lower when compared to the study by Rupali P et al. [7] (426 DOT / 1000pd). Studies still demonstrate a relevance to the time of use of beta-lactams in ICUs, in which the rates ranged from 116 DOT / 1000pd to 296 DOT / 1000pd [3,7,6,1].
Overall The median length of stay, overall, in the units, was 14 days. The literature describes, for intensive care units, one remained ranging from 6 to 18 days [2,7,11,12]. These observed variations can be explained due to the characteristics of the patients seen at each institution.
As for the percentage of general mortality, this study found an average of 25.0% ± 3%. Similar data were observed by Rupali P et al. [7] in which in the preintervention phase mortality was 22.4% and in the intervention phase 27.6%. Higher percentages were found by Marcelino FAB [2] (33.0%) and lower ones as described by De Bus L et al. [3] (10.7%), Gasparetto J et al. [12] (12.6%), and Álvarez-Lerma F et al. [11], this reports that in the previous year the intervention the mortality percentage was 13.7% and in the following year after the intervention is reduced to 11.1%.
Although intervention in the present study slightly decreased the use of antimicrobials, there were no changes in the length of stay and survival of patients.
The strengths of this study include the prospective design with comparison before and after interventions of a team of infectologists in the rationalization of the use of antimicrobials in intensive care units, the direct investigation of the prescriptions enabling a greater precision of the analysis regarding the use of antimicrobials and the use of the DOT and LOT indicators according to the new recommendations for monitoring the use of antimicrobials. However, some limitations were noted: First, the study was conducted at a single center. Second, comorbidities have not been evaluated. Third, the adequacy of the prescriptions was not addressed. Fourth, no data were obtained on the prevalence of bacterial pathogens and their susceptibility patterns.

Conclusion
In general, the intervention of infectologists in intensive care units had a limited impact on the results evaluated. This may be due to the short period analyzed.
Although the difference in the percentage of patients using antimicrobials, after the intervention, was not signi cant, a small decline in data was observed, signi cantly interfering with the time of exposure to certain broad-spectrum agents. Therefore, it is important to monitor the impact of these changes in the long term, drawing a more accurate assessment of the effectiveness of an intervention, with the implementation of active feedback.
The hospital does not have a management program for the use of antimicrobials, nor does it have a basic structure or adequate resources for its development, but these initiatives, although immature, can gradually interfere signi cantly in the care of patients.

Abbreviations
Page 8/9 DOT -Days of Therapy 3.518.197 and by the Institutional Teaching and Research Center. A waiver of informed consent was obtained due to the non-interventional nature of this study and the complete anonymity of patient data.
Consent for publication.
Not applicable.
Availability of data and materials.
All data generated or analyzed during this study are included in this published article [and its supplementary information les].
The authors declare that they have no competing interests. Funding.
Coordination for the Improvement of Higher Education Personnel (CIHEP) Authors' contributions.
RMRS collected, analyzed, and interpreted the data and wrote the work. ACBC, EKCVK, WBS, and IMFL contributed to the conception of the work and substantially revised it. All authors read and approved the nal manuscript.