Serious Infections in the ICU: Evolving Concepts in Management and Prevention

Jean Chastre, MD

Charles-Edouard Luyt, MD, PhD

Michel Wolff, MD

Patients admitted to intensive care units (ICUs) are particularly susceptible to secondary hospital-acquired infections (HAIs), which are often severe, representing a major health concern worldwide. In 2017, the European Center for Disease Prevention and Control estimated that more than 2.5 million cases of HAIs occur annually in Europe, accounting for a substantial proportion of disability and premature death, not to mention the cost they represent for the health care system. In the United States, HAIs account for almost 100,000 deaths annually. Unfortunately, most of these infections are caused by difficult-to-treat pathogens, frequently resistant to many antibiotics, arguing for a continued reassessment of our current modalities of therapy and definition of better protocols. More active as well as less toxic antibacterial agents are still needed, as well as a better use of already available antimicrobial agents.

This issue of Seminars in Respiratory and Critical Care Medicine includes contributions from world-renowned experts in the field of ICU-acquired infections, who have provided state-of-the-art information on important aspects of the clinical management of these dreadful diseases. The first article by Strich and Kadri includes a detailed and up-to-date review of the global epidemiology, burden, risk factors, and treatment of highly resistant gram-negative infections as they apply to the ICU population. Obviously, better knowledge of microbial etiologies of these infections, as well as an in-depth understanding of resistance mechanisms and risk factors, might allow better identification of patients at high risk of infection caused by problematic pathogens, such as multidrug-resistant (MDR) non-fermenting gram-negative bacilli (GNB), and extended spectrum β-lactamase (ESBL)-producing Enterobacteriaceae (including carbapenemase-producing GNB), and consequently, better selection of antibiotics, which often still entails use of antibiotics with suboptimal efficacy and/or toxicity profiles.

Optimal antimicrobial antibiotic use is crucial in the ICU setting, especially in an era of rising antibiotic resistance and lack of new antimicrobial development. Study results indicate that 30 to 60% of antibiotics prescribed in ICUs are unnecessary, inappropriate, or suboptimal, highlighting the potential benefit of implementing antibiotic stewardship programs (ASPs). As rightly pointed out by Fierens and De Waele in second article, a team approach and the use of clinical decision support systems are important adjuncts helping clinicians to implement a strict ASP in ICU patients with severe infection.

The next three articles deal with important topics that have plagued clinicians in the ICU for many years: Should we immediately start antibiotics in every patient with a clinical suspicion of sepsis? What is the role of emerging diagnostic technologies? And should we use biomarkers of bacterial infection to improve detection and treatment of infections in the ICU? While guidelines recommend prompt (i.e., within 1 hour of triage) antibiotic administration for sepsis and septic shock, the level of evidence is not as obvious as one might think in ICU patients having no signs of hemodynamic deterioration. Based on an in-depth literature review, Guery and Calandra in third article conclude that most data favor a link between the timing of the first dose of antibiotic and survival, but the advantages of early treatment must always be balanced by integrating the potential collateral damage associated with excessive use of antibiotics. As indicated by Vazquez Guillamet, Burnham, and Kollef in fourth article, new biomolecular techniques give us the possibility of rapidly detecting the causative pathogen(s) in case of infection and thus offer the potential for providing timely administration of appropriate antimicrobial therapy as well as minimizing the use of broad-spectrum antibiotics when they are not justified. However, advantages and limitations of rapid diagnostic techniques should be well understood prior to their introduction in the diagnostic workflow. Several studies have clearly shown that clinically relevant benefits are obtained only in the presence of an ASP, but not in its absence. While some biomarkers, such as procalcitonin, are well established and showed positive effects in regard to utilization of antibiotics and clinical outcomes in interventional trials, many other markers have not been appropriately studied. Thus, the final proof of an added value to clinical judgment is still lacking (see fifth article by Heilmann, Gregoriano, and Schuetz for a detailed review).

Several articles in this issue provide up-to-date and very useful information regarding how to improve treatment of infections caused by difficult-to-treat microorganisms in the ICU setting. Optimizing the dosing of β-lactams in ICU patients in terms of target concentration attainment and clinical outcomes remains a challenge at the bedside, due to the altered pharmacokinetic parameters often observed in this cohort of patients. As indicated by Williams and colleagues (sixth article), alternative β-lactam dosing strategies that include prolonged infusions, guideline-based dosing, therapeutic drug monitoring, and the utilization of dose optimization software are required in many patients for ensuring optimal therapy and avoiding the emergence of resistant strains. In the seventh article, Martin-Loeches and colleagues review the epidemiology, pathophysiology, and treatment of the most serious forms of influenza infections, as well as other emerging viral infections, namely herpes simplex virus type 1 (HSV-1), Epstein–Barr virus (EBV), and cytomegalovirus (CMV). Unfortunately, our armamentarium against these viruses, although improving, is still limited. Bassetti and colleagues (tenth article), in a very thoughtful and up-to-date article, are proposing a new strategy for the empiric and targeted treatment of candidemia in the ICU, integrating the benefits of the newly available diagnostic tests and antifungal agents. The two articles by Azoulay and colleagues (articles 8 and 11) are devoted to the management of bacterial pulmonary infections in immunosuppressed patients and to invasive aspergillus infection in critically ill patients without traditional risk factors (a less well-recognized complication of influenza infection and prolonged admission to ICU), respectively. In the ninth article, Buetti and Timsit summarize current evidence regarding diagnosis, management, and prevention of central venous catheter-related infections, the most frequent cause of hospital-acquired bacteremia in the ICU, and also the most readily accessible to prevention if rigorous policies are implemented. As emphasized by the two authors, key elements of prevention include hand hygiene, avoidance of insertion of unnecessary catheters, full sterile barrier precautions at insertion, preferential use of the subclavian venous insertion site, cutaneous antisepsis with 2% chlorhexidine (CHX) alcoholic preparation, use of CHX-impregnated dressings, immediate replacement of moistened or detached catheter dressings, and removal of catheters as soon as possible.

The two last articles of this issue present a very detailed and comprehensive discussion of HAI prevention. In the 12tharticle, Klompas rightly pointed out that there is still a great deal of uncertainty about what really works to prevent ICU-acquired pneumonia because of the difficulties inherent in its diagnosis and therefore the high risk of bias in the study results. Avoiding intubation, minimizing sedation, implementing early extubation strategies, and mobilizing patients do appear to improve clinically relevant outcomes in addition to pneumonia, such as mechanical ventilation duration or mortality, and therefore should certainly be implemented. Many of other assumptions about how best to prevent ICU-acquired pneumonia, however, have recently been challenged, including subglottic secretion drainage, oral care with CHX, elevating the head of the bed, and selective digestive decontamination. Extensive efforts have also been devoted in reducing MDR microorganism diffusion in ICU patients through various preventive measures, as thoroughly discussed in the 12th article by Kerneis and Lucet. Whatever the recommended measures, the way in which health workers adhere to them is of crucial importance, requiring a behavioral approach to implement them, with a deep involvement of all the ICU staff.

We sincerely thank each of the authors who have contributed to this issue of Seminars in Respiratory and Critical Care Medicine dedicated to controversies and evolving concepts in serious infections in the ICU. We believe that the current state-of-the art reviews presented here by an internationally recognized group of experts in the field will serve as a valuable resource for clinicians providing care for patients with severe infection in the ICU.