Introduction

Antibiotic resistance has emerged as one of the most important determinants of outcome in patients with serious infections along with the virulence of the underlying pathogen. More than 700,000 healthcare-associated infections, many caused by antibiotic-resistant bacteria, occur annually in the US with almost half in critically ill patients [1]. In Europe, prevalence of carbapenemase-producing Enterobacteriaceae (CPE), in particular with the rapid spread of carbapenem-hydrolysing oxacillinase-48 (OXA-48) and New Delhi metallo-beta-lactamase (NDM)-producing Enterobacteriaceae is increasing [2]. Escalating rates of antibiotic resistance add substantially to the morbidity, mortality, and costs related to infection in hospitalized patients, especially those in the intensive care unit (ICU) setting [2, 3]. Both Gram-positive organisms, such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE), and Gram-negative bacteria, including Pseudomonas aeruginosa, Acinetobacter species, and CPE have contributed to the escalating rates of multidrug-resistant (MDR), extensively drug-resistant (XDR), and pandrug-resistant (PDR) bacteria causing healthcare-associated infections [3].

The rapid evolution of antibiotic resistance impedes efforts to insure that initial appropriate antibiotic therapy (IAAT) is delivered to critically ill infected patients. IAAT is a key determinant of outcome in severe infection [4, 5], and the Surviving Sepsis Guidelines strongly support initiatives to guarantee that patients receive timely appropriate antibiotic treatment to reduce mortality [6]. Yet, because not all serious infections are due to MDR organisms, clinicians must have a strategy for determining which patients should be treated with broad-spectrum antibiotics. Minimizing the unnecessary use of antibiotics is a fundamental principle of antimicrobial stewardship that should be followed by all intensivists [7]. The challenge is how to best optimize antibiotic decision making in the ICU balancing the need for IAAT, in order to improve patient outcomes, with the need for avoidance of unnecessary antibiotics so as to reduce resistance emergence.

The goal of this research agenda is to concisely describe the current standards of care, major recent advances, areas of uncertainty, and to identify clinical studies/trials that need to be performed over the next decade in regards to the management of MDR bacteria, antibiotic use, and antimicrobial stewardship in the ICU.

Methods

A narrative review based on a systematic analysis of the medical literature was conducted with a timeline from 2006 through 2016 searching PubMed by two authors for each of the three sections using the terms “stewardship, antibiotics, antibiotic resistance and multidrug resistance”. Searches were completed in December 2016. One author (M.H.K.) also manually screened reference lists of articles selected for inclusion to identify additional studies. To identify potential unpublished data, M.H.K. also (1) searched abstracts from the Society of Critical Care Medicine, European Society of Intensive Care Medicine, American Thoracic Society, CHEST, International Symposium on Intensive Care and Emergency Medicine, and Pharmacotherapy from 2006 to 2016, and (2) searched online for clinical trials registration (ClinicalTrials.gov). The selection of articles and topics for inclusion in this research agenda were based on their likely importance for yielding clinically important practice changes over the next decade as determined by the writing committee.

New antibiotics and antibiotic delivery

Standard of care

IAAT for definite infections, such as sepsis, complicated intra-abdominal infection (cIAI), severe community-acquired pneumonia (CAP) and hospital-acquired pneumonia/ventilator-associated pneumonia (HAP/VAP), is a critical aspect of care. Unfortunately, attempts to administer IAAT often lead to the administration of broad-spectrum antibiotics for many non-resistant infections. Rapid provision of appropriate antibiotics is most important in the presence of shock, since delays in therapy are associated with increased mortality [8]. When shock is not present, a more careful approach to the diagnosis of bacterial sepsis is warranted, as administration of broad spectrum antibiotics produces collateral damage and, in the presence of non-bacterial inflammatory conditions, selects for antibiotic-resistant bacteria [9].

Standard dosing regimens are often not adequate for critically ill patients. Two common differences in pharmacokinetic/pharmacodynamic (PK/PD) parameters encountered in the ICU that result in this are an increased volume of distribution and increased renal clearance of antibiotics [10]. Initial antibiotic doses should address the increased volume of distribution of antibiotics (particularly hydrophilic drugs) that often occurs in sepsis with fluid resuscitation [11], such that a large loading dose is required independent of subsequent clearances. Without this, time to achieve optimal bacterial killing is delayed due to under-dosing which also predisposes to the emergence of newly resistant bacterial overgrowth. After empirical broad spectrum and/or combination treatments are prescribed, secondary re-evaluation and focused therapy following documentation of the etiology of infection is strongly recommended. Despite this basic tenet of antibiotic stewardship, conflicting results have been generated on the overall benefits of antimicrobial de-escalation [12, 13].

The optimal duration of antibiotic therapy remains controversial but has significantly decreased over the past two decades. In VAP, a shorter treatment course of 7–8 days has been validated, even though for some specific pathogens or clinical situations a longer treatment course may still be recommended [14, 15]. For cIAI, a treatment course of 4 days may also be acceptable when septic shock is not present [16]. Serial biomarkers such as procalcitonin can also help to accurately identify patients appropriate for shorter courses of antibiotics [17].

Major recent advances

When compared to the twentieth century, few new antibiotics have been recently marketed or even developed. Because of the importance of both antibiotic resistance and emerging infectious diseases, the scientific community and national governments have decided to support both discovery and research in the anti-infective field. Therefore, both large pharmaceutical and smaller biotech companies have re-invested in this endeavor.

Accordingly, a few antibiotics with some ICU indications (especially HAP/VAP and cIAI) have recently been approved and others should become available in the near future. Potentially interesting new options include broad-spectrum antibiotics covering both resistant Gram-negative bacteria and MRSA which could be used as first-line empiric therapy in clinical situations where a high risk of antibiotic resistance is suspected or confirmed, especially with mixed infections. Additionally, options to cover MDR pathogens including CPE and NDM-producing Enterobacteriaceae have recently been approved or are forthcoming, including novel β-lactamase inhibitors (Table 1). The concern with these new antibiotics is that they may be utilized indiscriminately, especially in locations with suboptimal infection control and antimicrobial stewardship practices, thereby allowing resistance to rapidly arise.

Table 1 Recently approved antibiotics and drugs in development
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Ceftolozane/tazobactam is a recently approved antibiotic that is especially active against Pseudomonas aeruginosa (from the intrinsic activity of ceftolozane), while the addition of tazobactam confers activity against most extended-spectrum β-lactamase (ESBL) producers. It is currently approved for the treatment of complicated urinary tract infection (cUTI) and cIAI [18]. Avibactam is a novel β-lactamase inhibitor that inactivates class A [including Klebsiella pneumoniae carbapenemase (KPC)], class C (AmpC), and some class D (OXA) β-lactamases. It is licensed in combination with ceftazidime and approved for cUTI and cIAI. The REPROVE trial (NCT01808092) has assessed the efficacy of ceftazidime-avibactam compared to meropenem for the treatment of HAP/VAP. The results have not yet been published but preliminary data confirm that the primary objective of statistical non-inferiority, employed by regulatory agencies for drug approval, has been reached with crude mortality rates at day 28 being similar for both groups [19].

While developing new antimicrobials is an essential task, emphasizing the importance of proper antibiotic dosing in order to optimize cures and prevent resistance is also paramount. Several studies have shown that sub-therapeutic antibiotic concentrations are often achieved in critically ill patients when standard dosage regimens are administered, particularly when dealing with difficult-to-treat pathogens [20, 21]. β-Lactam antibiotics have a large therapeutic ratio (i.e., toxicity is rare in usual therapeutic doses). However, β-lactam efficacy is now being questioned, with possible under-dosing in difficult-to-treat groups including ICU patients [22]. To improve PK/PD target attainment in critically ill patients, higher doses than those currently accepted by the regulatory agencies may be required. This may include the use of continuous or extended infusions with front-loading doses, as opposed to traditional intermittent bolus doses, for time-dependent antibiotics (e.g., β-lactams). For concentration-dependent antibiotics (e.g., aminoglycosides), once daily dosing to achieve high peak antibiotic concentrations is now accepted as the standard of care [23]. Increased awareness of these issues suggests the need for clinical trials of routine therapeutic dose monitoring (TDM) for β-lactams and other antibiotic classes to assess whether clinical and microbiologic outcomes can be improved.

Common beliefs contradicted by recent trials

ICU patients are often considered as primarily having renal impairment requiring dose reduction of antibiotics especially with more severe renal dysfunction. Nevertheless, recent clinical studies have shown that supranormal renal clearances, especially in young patients, are associated with suboptimal plasma concentrations of antibiotics and treatment failures [10, 14, 22].

In mechanically ventilated patients, antibiotic concentrations in the airways can be 100-fold higher when given through the aerosol route. Several studies have demonstrated a reduction of bacterial load and an interesting safety profile with both aerosolized colistin and aminoglycosides [24]. Accordingly, aerosolized antibiotics are now widely used, especially in Gram-negative VAP and more specifically with MDR pathogens. Despite the overall findings of the recent negative randomized trial of adjunctive aerosolized fosfomycin:amikacin for VAP, subgroup analysis suggested that patients infected with PDR Acinetobacter might still benefit from aerosolized antibiotics [25].

In severe sepsis, because of their time-dependent activity, continuous or prolonged β-lactam infusion could improve outcome due to better PK/PD target attainment, and many physicians are using this approach as their standard of care. Nevertheless, in two large multicenter prospective trials, clinical outcomes were not different by type of infusion [14, 26]. However, a significant increase in clinical cure with prolonged antibiotic infusions in a recent trial keeps this as an open question [27, 28].

Remaining areas of uncertainty

Despite several improvements in the use of antibiotics in the ICU, numerous scientific questions remain to be addressed. The optimal duration of antibiotic therapy remains uncertain and, aside from 7–8 days therapy in HAP/VAP and 4 days therapy in cIAI, little is known, and “one duration size” may not fit all indications.

The need for combination antibiotic therapy in critically ill patients remains highly debated, and is often prescribed based on patient severity without taking into account other important factors including pathogen virulence and resistance.

Nebulized antibiotics are currently used in critically ill patients with VAP and ventilator-associated tracheobronchitis (VAT) due to the low penetration of systemic antibiotics into the lung compartment [29]. Nebulized antibiotics aim to increase antibiotic efficacy by delivering higher drug concentrations to the distal areas of the lung in order to reduce systemic drug toxicity and to minimize the risk of resistance. Several factors can influence the delivery of aerosolized antibiotics to the lungs, although aerosol particle size seems to be the most important factor [30]. Currently available nebulizers include jet, ultrasonic and vibrating mesh devices whose antibiotic delivery efficiency to the lung parenchyma ranges from 15 to 60% across this continuum of devices [31]. To date, the efficacy and safety of aerosolized antibiotics for VAP has been examined in heterogeneous studies and meta-analyses yielding conflicting results [24, 25, 32].

Evolution of high-efficiency vibrating mesh nebulizers including the Pulmonary Drug Delivery System (PDDS) (NKTR-061) and the PARI eFlow® Inline rapid nebulizer are under development and could improve overall drug delivery to the lung. The PDDS system employs a new formulation of Amikacin Inhalation Solution (BAY41-6551) and provides antibiotic delivery of up to 60% of the administered dose [33]. The PARI eFlow® system is a single-patient, multiple-use device developed to deliver uniform small particles of an amikacin:fosfomycin formulation over a short time of nebulization. The observed mean values of tracheal concentrations with this system are 12,985 and 9000 µg/g, respectively, for amikacin and fosfomycin [34]. Unfortunately, a phase 2 study of aerosolized amikacin:fosfomycin delivered via the eFlow® Inline system in mechanically ventilated patients with Gram-negative bacterial pneumonia (IASIS study, NCT01969799) demonstrated no overall outcome benefit compared to optimal standard of care parenteral antibiotic therapy [24].

Mdr bacteria

Standard of care

MDR bacteria are now prevalent all over the world, with XDR and PDR pathogens also being increasingly encountered [1, 2]. Emergence of antimicrobial resistance is largely attributed to the indiscriminate and often abusive use of antimicrobials, including inadequate dosages and prolonged durations, both within hospitals and other healthcare settings such as nursing homes and the community. Moreover, there is also increasing spread of resistance genes between bacteria and of resistant bacteria between humans and the environment including waterborne and agricultural sources. Even in areas hitherto known for having relatively minor resistance problems, 5–10% of hospitalized patients on a given day have been found to harbor ESBL-producing Enterobacteriaceae in their gut flora, as seen in a French ICU study [35].

The number of different mechanisms by which bacteria can become resistant to an antimicrobial agent is increasing, as is the variety of encountered resistance genes, the number of clones within a species which carry resistance, and the number of different species harboring resistance genes. This all contributes to accelerating antibiotic resistance development with spread of antibiotic-resistant pathogens leading to life-threatening diseases [36]. Local outbreaks of antibiotic resistant infections have been reported with MRSA, Escherichia coli, K. pneumoniae, Acinetobacter baumannii, P. aeruginosa and Enterococcus faecalis or faecium (the latter species being difficult to treat when glycopeptide resistance is present). These outbreaks have typically occurred in highly specialized healthcare settings such as neonatal wards, ICUs, transplant units and hematology/oncology areas. The rising incidence of MDR bacteria results in two important consequences: increase of initial inappropriate antibiotic therapy (IIAT) and greater overall consumption of broad-spectrum antibiotics [36]. Since no truly new antimicrobial classes have been approved recently for the treatment of resistant bacteria, interest in “rediscovered” older antimicrobials has also increased [37]. At present, the best current option for optimizing antibiotic use and minimizing further resistance is to select antibiotic regimens with the highest level of effectiveness for the infection, while also minimizing collateral damage in the form of colonization with resistant clones (Fig. 1).

Fig. 1
figure 1

Schematic representing the essential factors needing to be considered in order to optimize antibiotic treatment and outcomes in critically ill patients. PK pharmacokinetic; PD pharmacodynamics; MIC minimum inhibitory concentration

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Major recent advances

Several rapid microbiological identification methods are currently being developed for clinical use, such as PCR, PNA FISH, and mass spectrometry. Some of these techniques can potentially be brought “to the bedside”, with microbiological results being available within a few hours. This could completely change the landscape of bacterial species and susceptibility documentation, especially in bacteremia and VAP [38], and could even be considered as a companion diagnostic for specific targeted therapies such as anti-infective monoclonal antibodies (mAbs).

Anti-infective mAbs represent a promising class of infectious disease drugs in the ICU, with a very innovative mechanism of action via one or several specific virulence targets. Several ICU studies have found encouraging preliminary results, especially when targeting P. aeruginosa [39]. With the current technological progress and the increasing need for alternative therapeutic options to standard antibiotics in critically ill infected patients, numerous anti-infective mAbs are being developed targeting the most frequent ICU pathogens including S. aureus, P. aeruginosa, K. pneumoniae, A. baumannii and E. coli [40].

Similarly, there has been growing interest in the use of bacterial viruses (i.e., bacteriophage therapy) to treat infections by MDR bacteria. Bacteriophage lysins are classified as peptidoglycan hydrolases, being able to cleave a variety of bonds in the bacterial peptidoglycan. Preliminary in vitro and in vivo studies suggest high efficiency of such peptides to kill A. baumannii, supporting further clinical development [41].

Common beliefs contradicted by recent trials

In the recent era, characterized by the lack of novel antibiotic class development, several clinical trials have yielded frustrating results. New antimicrobials targeting antibiotic-resistant pathogens (i.e. doripenem, tigecycline, ceftobiprole) have unfortunately failed to demonstrate non-inferiority for the primary endpoint of clinical cure in patients with VAP [14, 42, 43]. The presence of young adults with augmented creatinine clearance enrolled in these studies combined with antibiotic under dosing, resulting in reduced antibiotic plasma concentrations, may partly explain these negative study results [44].

Remaining areas of uncertainty

Improved accuracy and timeliness to detect drug susceptibility, including the ability to detect heteroresistance, inducible enzymes, and highly resistant subpopulations, is increasingly being desired to improve overall antibiotic therapy and outcomes. While PCR is now widely used in the ICU, and thus allows for a more rapid detection of antibiotic resistance genes, additional efforts are required to develop patient profiles with the use of these technologies in order to optimize antimicrobial stewardship in the ICU. Similarly, the development of a toolkit to accurately and objectively detect successful versus unsuccessful therapy in MDR/XDR/PDR infections, is clearly needed.

As suggested above, experiences with rapid diagnostics for the evaluation of blood culture specimens suggests that rapid diagnostics may play an important role in enhancing antimicrobial prescribing practices in hospitalized patients [45]. The benefits to this can be numerous, including optimizing clinical outcomes, reducing toxicity, and facilitating clinical trials for new anti-infective agents by stratifying patients eligible for the trial at the earliest possible opportunity. However, it is also important to understand the limitations of these new technologies, including that they cannot differentiate colonization from infection, which could be highly problematic in mechanically ventilated patients, nor give us the true susceptibility patterns of the responsible pathogens. The latter is true with the exception of a few specific mechanisms of resistance provided by molecular techniques and automated microscopy which has the potential to provide real-time susceptibility data [46].

The potential role of rapid diagnostics in improving antimicrobial therapy and outcome when embedded in a well-organized antimicrobial stewardship program (ASP) is illustrated by the study by Huang et al. from the University of Michigan [47]. These investigators performed a study to analyze the impact of MALDI-TOF MS in conjunction with an ASP in patients with bloodstream infections. The ASP provided antibiotic recommendations after receiving real-time notification following blood culture Gram stain, organism identification, and antimicrobial susceptibilities using conventional microbiology methods in the before-period and MALDI-TOF MS in the after-period. Use of MALDI-TOF MS significantly decreased time to organism identification, and improved time to optimal directed antibiotic therapy. Similarly, the PCR-based GeneXpert MRSA/SA diagnostic platform (Cepheid, Sunnyvale, CA, USA) for MRSA bacteremia has been shown to reduce the mean time to initiation of appropriate therapy and the duration of unnecessary MRSA drug therapy [48]. A recent systematic review also demonstrated that rapid diagnostic testing was associated with decreases in mortality risk in the presence of an ASP [49].

The use of rapid diagnostics may hold the key for achieving a proper balance between the need to provide timely appropriate antibiotic therapy while minimizing the unnecessary use of antibiotics in the ICU. There is an urgent need for clinical studies aimed at understanding how to best integrate the use of antibiotics in critically ill patients with the emerging rapid diagnostic technologies in a way that is cost-effective and sustainable for the long run [50].

Antibiotic stewardship

Standard of care

Antimicrobial stewardship involves a multifaceted and multidisciplinary approach to achieving the following goals: (1) combating antimicrobial resistance, (2) improving clinical outcomes, and (3) controlling costs by improving antimicrobial use. As one of the largest consumers of antibiotics in the hospital, ICUs are well situated to reap benefit from an effective ASP. Recent guidelines provide evidence-based criteria for implementation and self-evaluation of such a program [51]. ASPs are necessary and effective in critical care settings, resulting in reductions in drug-resistant pathogen infections, reduced broad-spectrum antimicrobial use, and reduced antimicrobial costs, all without increases in mortality [52, 53].

All ASPs in ICUs should include prospective audit and feedback of antimicrobial prescriptions, therapeutic drug monitoring, formulary restrictions, use of local antibiograms, and partnership with infection prevention services when available. Underlining the importance of a multidisciplinary approach to antimicrobial stewardship, a recent study showed the importance of infectious disease (ID) fellowship programs, full-time ID physicians, and clinical pharmacists with ID training in reducing antimicrobial use [54].

A recently performed systematic review found that the quality of evidence supporting specific antimicrobial stewardship interventions was low, but did recommend audit and feedback, guideline implementation, and decision support [55]. Additional strategies for ASPs have been tested in studies with poorly defined outcomes, resulting in low-quality evidence for their efficacy. Unfortunately, this poor-quality evidence limits knowledge of the advantages and disadvantages of individual stewardship strategiesthough ASP implementation does not seem to result in harm. Table 2 provides some strategies of plausible benefit in an ASP.

Table 2 Components to be considered for inclusion into Antimicrobial Stewardship Programs (ASPs) in the intensive care unit (ICU) (stratified by likelihood of efficacy)
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Major recent advances

Advances in molecular biology have paved the way for imminent revolutions in antimicrobial stewardship. Though not uniformly ready for routine clinical use, rapid diagnostics have the potential to dramatically alter the field of antimicrobial stewardship [56]. Rapid diagnostic tools have the potential to identify bacterial, fungal, and viral causes of sepsis at a much earlier stage than traditional culture methods, which should reduce time to appropriate therapy, a known determinant of sepsis mortality [4, 5, 57].

Emerging diagnostics can produce susceptibility results more rapidly than traditional methods [46]. Accelerated susceptibility testing will allow for appropriate antimicrobial choices to occur much earlier in the course of infection, with the potential for improvements in mortality, other clinical outcomes, and reduced usage of broad spectrum antimicrobials. Reduced broad spectrum antimicrobial use will likely result in fewer Clostridium difficile infections, fewer gut microbiome disturbances, fewer MDR infections, and the preservation of the remaining antibiotics in our armamentarium for antibiotic-resistant infections. Similarly to local antibiograms, it is likely that rapid diagnostics will need to be tailored to each institution's needs, as local prevalence of organisms varies [58]. For example, a rapid diagnostic aimed at detecting MRSA would likely be of little value in an area of low MRSA prevalence such as northern Europe.

Another growing area of research that could transform empiric antimicrobial decision making is host gene expression analysis. Host transcriptome analyses were able to differentiate non-infectious inflammatory syndromes from sepsis with modest sensitivity and specificity [59, 60]. After distinguishing non-infectious inflammatory syndromes from sepsis, bacterial and viral infections were also differentiated using transcriptome analysis [60]. Host gene expression analysis requires clinical trial verification of predictive validity, further research on the host transcriptome profiles in mixed infections, fungal infections, mycobacterial infections, and more robust recognition of when infections are not present. Though not ready for clinical use, it is a promising area of research that will likely be more feasible as molecular technology continues to advance and become more affordable.

Common beliefs contradicted by recent trials

Physicians may continue to feel that ASPs are too intrusive and interfere with autonomy [61]. Yet, ASPs may result in reduced mortality [62, 63]. With continuously mounting evidence in support of improved patient outcomes due to ASPs, physicians can be further convinced of the benefit of a multidisciplinary approach to antimicrobial stewardship.

Despite guidelines that place nominal emphasis on the importance of education in antimicrobial stewardship [51], there is still clearly a great need for education among providers who treat infections, as evidenced by several recent studies [64, 65].

Remaining areas of uncertainty

Due to the low quality of evidence in trials of antimicrobial stewardship, many areas of uncertainty remain. It is clear that ASPs do not result in harm and likely improve patient outcomes. However, which individual components of ASPs provide the greatest benefits is less clear. Some ASP strategies also have potential harm, such as requiring ASP team approval for certain antibiotics for hypotensive patients at risk for MDR pathogens. These higher risk interventions should be prospectively studied. Funding limitations and variability in resources for ASPs at different institutions make it unlikely that each component of an ASP will be systematically studied in a clinical trial.

For ICUs looking to implement ASPs, one major area of uncertainty is the concept of antimicrobial de-escalation. Further research must be done to determine what defines antimicrobial de-escalation, when it is appropriate, when to “re-escalate,” and how to transition antimicrobial decision making when patients move from the ICU to the hospital ward. Antimicrobial de-escalation is also uncertain in pathogen-negative sepsis, particularly whether it is safe to de-escalate and the optimal duration of antimicrobials. With improving culture methods and rapid diagnostics, it is possible that the proportion of patients with pathogen-negative sepsis will diminish over time, resulting in fewer uncertainties.

Other areas of uncertainty include outpatient antimicrobial stewardship, stewardship in immunocompromised patients, and agricultural stewardship. Stewardship in these areas will reduce the global burden of antimicrobial use with subsequent reductions in antimicrobial resistance. With global reductions in antimicrobial resistance, patients will be at lower risk for IIAT when admitted to ICUs.

Limitations

Although this narrative review is based on a systematic analysis of the medical literature, the research agenda presented reflects the inherent biases of the writing committee. Moreover, this document does not reflect all possible novel interventions that could or should be explored over the next decade [66,67,68]. We attempted to layout the most compelling areas of future investigation based on the available literature and the experience of the writing committee. Certainly, as new clinical trial information becomes available, modification in the priorities and direction of this research agenda should be considered.

Conclusion

Important fundamental studies examining questions regarding the development and use of new antibiotics, novel strategies for the treatment and prevention of MDR/XDR/PDR bacterial infections, and optimizing antimicrobial stewardship in the ICU, as outlined in this document, should be carried out over the next decade (Table 3). The development of sustainable clinical trial networks represents an important operational goal to successfully carry out these investigations [69]. Moreover, advances in the design of clinical trials, biostatistics, electronic data collection, and randomization tools will enhance our ability to carry out such trials, as illustrated by recent antibiotic studies [25, 69]. The rising prevalence of infections due to MDR/XDR/PDR bacteria in the ICU emphasizes the urgent need to advance this research agenda over the next decade [70, 71].

Table 3 Top trials to be done in the future
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