1. IntroductionEarly recognition and proper empirical antimicrobial treatment (EAT) of sepsis to cover carbapenem-resistant Gram-negative bacilli (CR-GNB) are fundamental in changing the current scenario of high mortality rates [1,2]. These are especially important because therapeutic options for the treatment of CR-GNB infection are still limited [3,4]. CR-GNB, such as Acinetobacter baumannii, Pseudomonas aeruginosa, and Klebsiella pneumoniae, are increasingly being reported worldwide, although with some regional and hospital variations [2,3,5]. In the hospital studied, these agents have become the main cause of sepsis in the intensive care units (ICUs) for adults [5], followed by Gram-positive bacteria and fungi, in monomicrobial or polymicrobial infections [2,3,5].Geographic and temporal variations, as well as differences in antimicrobial response, highlight the clinical–epidemiological importance of the carbapenem resistance mechanisms involved [6]. Phenotypic resistance to carbapenems is usually caused by Amber class A, B, and D β-lactamases. Additionally, extended-spectrum β-lactamases and AmpC cephalosporinases, when combined with porin mutation or the overexpression of efflux pumps, can lead to carbapenem resistance [7]. Nonenzymatic carbapenem resistance includes loss of expression or mutations of porin-encoding genes, and the overexpression of genes encoding efflux pumps, particularly in P. aeruginosa [7,8]. Rarely, mutations or other modifications that alter the level of production or affinity of penicillin-binding proteins may also be responsible for resistance to carbapenems [7,9]. Intrinsic resistance to carbapenems is present in some species, such as Stenotrophomonas maltophilia [7]. In addition, the concomitance of resistance to other classes of antimicrobials is common among CR-GNB isolates [7,9]. EAT should be started within the first hour of the presumed diagnosis of sepsis, at a time when the clinical–epidemiological characteristics remain as the only determinants of patient risk [5]. Risk score studies based on clinical–epidemiological parameters with the aim of assisting physicians in choosing the most appropriate EAT for sepsis remain scarce or nonexistent [10,11,12]. One study was conducted in a tertiary-level hospital in the Netherlands, where resistance rates were low and EAT was based on the combination of second- or third-generation cephalosporin associated with aminoglycoside; thus, this did not reflect our reality. Through risk-based strategies, the authors were able to estimate the possibility of reducing carbapenem usage by 83%, associated with a treatment adequacy rate of 96% [11]. In another study, the accuracy of a risk score was evaluated in predicting the first episode of imipenem-resistant GNB bacteremia, predominantly of non-fermenters, among critically ill patients in a tertiary hospital in Taiwan, in 2016 [10]. The obtained predictor model showed good discrimination with an area under the receiver operating characteristic (ROC) curve (AUC) of 0.75 (95% CI: 0.70–0.80) through internal validation.The study design and the concordance of our data with the literature on the risk factors for CR-GNB presented in our previous publication support the utility in developing a predictive score to stratify patients according to the risk of CR-GNB sepsis at the first encounter [5]. In this study, our overall aim was to develop and estimate the performance of a predictive score for sepsis caused by CR-GNB in the entire cohort. Our hypothesis was that a score based on clinical–epidemiological predictors, developed locally, would have sufficient accuracy to identify patients at high risk of CR-GNB sepsis, among adult patients receiving intensive care. In addition, the adequacy of carbapenem and polymyxin therapy, as well as EAT, was investigated, with the aim of determining the proportion of patients in which the score system would effectively improve the EAT. 4. Discussion The prevalence of CR-GNB sepsis is increasing globally, and the rational use of antibiotics is one of the pillars to contain the agents and extend the shelf-life of antibiotics [24,25,26]. Physicians around the world, particularly those in ICUs, need to use effective antimicrobial treatments as quickly as possible to prevent disability and death in patients without indiscriminately prescribing broad-spectrum antibiotics [27]. When to escalate sepsis therapy to cover these microorganisms, as well as how to preserve last-resort antibiotics, particularly newly developed drugs, are frequent impasses. The solution to this problem seems simple, but it is not to prescribe the antibiotic with just the right spectrum. Thus, a clinical score to help decide whether or not to expect antimicrobial resistance at the bedside when deciding EAT, especially with easy-to-use components, is of great importance.From an antimicrobial stewardship standpoint, it is recommended that EAT be adjusted to the local data [11], according to the local epidemiology of patients and pathogens. The developed score is a simple tool, because the predictor variables can be easily obtained during initial assessments, at a time when the clinical–epidemiological characteristics remain the only determinants of a patient´s risk. The score aims to guide EAT until a timely antimicrobial de-escalation based on microbiological identification, susceptibility testing, and clinical response is implemented. These are essential strategies to improve the prognoses of septic patients, preserving the effectiveness of existing antimicrobials and preventing the emergence of resistance. In our study, the score represented a valuable option to effectively improve polymyxin coverage in 21% (14–30%) of CR-GNB sepsis cases and may be useful to withdraw unnecessary coverage in 26% (95% CI: 21–31%) of the studied population. To the best of the authors’ knowledge, this is the first study to develop a suitable predictive score to guide EAT for CR-GNB sepsis. Although bacteremia has been widely used as a proxy for sepsis, in our study, bacteremia did not represent all types of infections and was identified in a smaller proportion of cases, mainly catheter related bloodstream infections [5]. Bacteremia has been identified in fewer than 30% of septic cases in ICUs [5,28,29], and blood culture is relatively insensitive for the recovery of agents in VAP [30,31], the predominant infectious source of ICU sepsis [2,29]. In addition, a diversity of GNB species could be the cause of sepsis in monomicrobial and polymicrobial infections as demonstrated, making the score for specific species not useful for targeting therapy. Considering incident cases, all single and recurrent episodes in the cohort, and the variety of infections commonly identified in hospital-acquired sepsis, the estimates are likely to be more representative of what happens in real life. In addition, including episodes with unknown etiology improves our understanding of the complex epidemiological picture, aiming to understand the balance between damages and benefits of novel tool use. Successful longitudinal follow-up of this cohort was essential to achieve the study proposal. Prior infection, mechanical ventilation, carbapenem usage, and hospitalization longer than or equal to 19 days were associated with a higher risk of sepsis due to CR-GNB [5], in agreement with the literature concerning the risk factors for the acquisition of or infection by CR-GNB [32,33,34,35].

Using data from a prospective cohort, we developed a predictive score that allowed us to accurately identify patients at high or low risk of CR-GNB sepsis. The score performance was considered to be satisfactorily estimated when applied to the entire cohort. The best combination of sensitivity (92%, 95% CI: 85–96%) and specificity (65%. 95% CI: 58–71%) was reached when we used three or more points as cutoffs. The best specificity was achieved using four as the cutoff (76%, 95% CI: 70–81%). A score of less than or equal to one showed optimal sensitivity (99%; 95% CI: 95–100%) for the exclusion of CR-GNB sepsis cases. Those exhibiting scores of two had at least 8% (8/96) false negative results, which is high considering the severity of clinical cases. Notably, higher scores (three and four) had 25% and 29% occurrences of inappropriate EAT, respectively, and these patients would benefit with a broader-spectrum EAT if the score were to be applied prospectively. Patients with lower scores (zero and one) used polymyxins unnecessarily, while exerting pressure on antimicrobial resistance and incrementing cost. Sepsis by non-GNB (including Gram-positive bacteria) also had 35% inadequate EAT, although the score would not solve all the issues, because it is designed for CR-GNB.

Additionally, the inhibition of CR-GNB growth in cultures due to polymyxin use could explain false positive or discordant results, because the drug was administered in 40% of these cases within the 3 days preceding the collection of cultures. Therefore, some of the episodes in the control group would have been in the case group if the agent was identified by microbiological tests. Thus, considering the high incidence of CR-GNB sepsis and high consumption of carbapenem and polymyxins, we expect that the score has the potential to benefit a larger number of patients who are misclassified as controls. Consequently, an NNT of two to avoid mismatch in a single case is probably an overestimation.

Taking everything in account, our findings indicate that episodes with scores of three or four should be treated with the best drugs available to cover CR-GNB sepsis, knowing that we may need to treat two patients to adequately cover one. For those exhibiting scores of zero and one, the drugs can be preserved. However, episodes presenting a score of two should be handled on a case-by-case basis. Considering that 77% (144/186) of the episodes with scores of three or four had an etiology later determined by conventional cultures, and a higher proportion would be achieved if molecular tests were incorporated into the diagnosis of sepsis [36], broad-spectrum EAT initially guided by the new score with subsequent adjustment of therapy, according to the microbiological results, contributes to its incorporation into clinical practice. Compared with standard therapy (clinical practice), we estimated an increase in the adequacy rate, considering the use of empiric polymyxins as a proxy for adequate CR-GNB cover, in 22% (95% CI: 17–28%) of study episodes using the CR-GNB sepsis score. A more in-depth analysis, however, of our results is still under evaluation to indicate the best strategy for the applicability of the score in future studies. In fact, in this scenario of a high prevalence of CR-GNB sepsis, as we demonstrated, high intakes of both carbapenems and polymyxins are expected, because these drugs remain the most widely used drugs in double or triple combinations for the treatment of CR-GNB sepsis, especially in hospitals with restricted access to novel therapeutic options. EAT with different combinations of broad-spectrum antibiotics, generally using the old drugs polymyxins, tigecycline, amikacin, and/or meropenem, is the standard treatment regimen for hospital-acquired septic patients in public Brazilian ICUs, despite the reports of increased resistance [37]. The emergence of resistance to newer agents, such as ceftazidime–avibactam, is critical and further intensifies this problem [38]; therefore, using a bedside tool to preserve the administration of expensive wide-spectrum antibiotics in critically ill patients with a low score (≤1), limiting the use to those with high scores (≥3), indicates the importance of the developed tool and its potential.The main limitations include the single-center nature of the study, which warrants caution for any generalization of our findings. Internal validation is required before implementation, and external, multicentric validations in hospitals with a similar size, profile, and prevalence rates of CR-GNB sepsis are important before extrapolating these results beyond our cohort. The adaptation of management strategies to the local epidemiological data is a general recommendation for hospital infection, which indicates locally cyclic evaluations. The performance of microbiological methods and the use of antimicrobials, which may have inhibited microbial growth in cultures, could also have influenced our estimates. Nonfermenting CR-GNB were more frequent than Enterobacterales CR-GNB in this cohort, whereas carbapenemase production was previously estimated in 76% of CR-GNB isolates [5]. These factors should be taken into consideration depending on the sepsis microbiology profiles across institutions, as well as the types of microbiological monitoring, once VAP is likely less represented by bacteremia [30,31]. 5. Conclusions

Developing a predictive score for empirical sepsis therapy based on local microbiological and clinical data, and estimating NNT CR-GNB sepsis to avoid inadequate EAT and overtreatment in a patient are feasible approaches. Such a score was proposed in this study, and its overall adequacy rate in not only indicating the correct treatment of CR-GNB, but also in avoiding the overtreatment of such pathogens, sparing antibiotics such as polymyxins, is promising. However, defining strategies for the EAT of sepsis is very ambitious, considering limitations in the drug arsenal, costs, drug–drug interactions, and adverse events, as well as the clinical severity of cases. This also comprises moral principles, because decisions of when and how to use EAT affects current patients, as well as future generations. The emergence of resistance to novel drugs is a serious issue; therefore, more clinical studies are needed to determine the ideal approach for EAT, especially in the high-incidence setting of CR-GNB sepsis (33%), as well as for patients with severe sepsis and septic shock, such as the majority of our cases.