Advances in Antibiotic Therapy in the Critically Ill Jean-Louis Vincent1*, Matteo Bassetti2, Bruno François3, George Karam4, Jean Chastre5, Antoni Torres6, Jason A
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Vincent et al. Critical Care (2016) 20:133 DOI 10.1186/s13054-016-1285-6 REVIEW Open Access Advances in antibiotic therapy in the critically ill Jean-Louis Vincent1*, Matteo Bassetti2, Bruno François3, George Karam4, Jean Chastre5, Antoni Torres6, Jason A. Roberts7, Fabio S. Taccone1, Jordi Rello8, Thierry Calandra9, Daniel De Backer10, Tobias Welte11 and Massimo Antonelli12 In this review, we briefly highlight the importance of Abstract early infection diagnosis before discussing some of the Infections occur frequently in critically ill patients and key issues related to antibiotic management, including their management can be challenging for various problems associated with timing, duration, and dosing. reasons, including delayed diagnosis, difficulties We also briefly consider ventilator-associated pneumonia identifying causative microorganisms, and the high (VAP), the use of inhaled antibiotics, and new antibiotic prevalence of antibiotic-resistant strains. In this and adjunct strategies for the future. We focus on bacter- review, we briefly discuss the importance of early ial infections and issues associated with multi-drug resist- infection diagnosis, before considering in more detail ance will not be covered. some of the key issues related to antibiotic management in these patients, including controversies surrounding use of combination or monotherapy, duration of therapy, Diagnosis and de-escalation. Antibiotic pharmacodynamics and The diagnosis of infection in critically ill patients and pharmacokinetics, notably volumes of distribution and identification of causative microorganisms and their anti- clearance, can be altered by critical illness and can biotic susceptibilities can be a challenge and yet early, influence dosing regimens. Dosing decisions in different appropriate antibiotic therapy is associated with improved subgroups of patients, e.g., the obese, are also covered. outcomes [1], so accurate, rapid diagnosis is important. We also briefly consider ventilator-associated pneumonia Typical clinical signs of infection, such as fever or raised and the role of inhaled antibiotics. Finally, we mention white blood cell count, are non-specific and can occur in antibiotics that are currently being developed and show many other conditions in the critically ill population. Simi- promiseforthefuture. larly, although many biomarkers, e.g., C-reactive protein and procalcitonin (PCT) to name just two [2], have been suggested to help diagnosis or to rule out infection, none Background is specific for infection and all can be altered in other Intensive care unit (ICU) patients are particularly likely to conditions that commonly affect ICU patients. Diagnosis have or develop infection, in part because infection is a of infection still relies largely on culture-based techniques, reason for admission and in part because of immunosup- which can take several days for a positive result to be pression associated with critical illness and the large num- available. Moreover, in patients already receiving antibi- ber of invasive devices used in these patients. Correct and otics, cultures may be negative. adequate antibiotic coverage is essential but can be com- In response to this problem, more rapid microbiological plex as a result of delayed identification of microorganisms, identification methods are being developed, including the impact of critical illness and therapy on pharmacokin- polymerase chain reaction (PCR) and mass spectrometry etics (PK) and pharmacodynamics (PD) of antibiotics, and with or without electrospray ionization [3–6]. These tests, the high prevalence of antibiotic-resistant strains. particularly when associated with an antimicrobial therapy team or pharmacist trained in infectious diseases, may * Correspondence: [email protected] result in shorter times to effective therapy, shorter lengths 1Department of Intensive Care, Erasme Hospital, Université libre de Bruxelles, of hospital stay, and reduced hospital costs [3, 4] and are 1070 Brussels, Belgium likely to become more widely used in the near future [7]. Full list of author information is available at the end of the article © 2016 Vincent et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Vincent et al. Critical Care (2016) 20:133 Page 2 of 13 Antibiotic therapy with macrolides was associated with better outcomes Empiric treatment compared with monotherapy in mechanically ventilated It is generally accepted that antibiotics should be admin- patients with community-acquired pneumonia (CAP) istered as soon as possible once infection is identified [16]. However, not all studies have demonstrated an ad- [8], although randomized data to support this notion are vantage of combined therapy over monotherapy [17–20]. lacking in humans for obvious ethical reasons, and most Importantly, all these studies have compared different data are from observational studies. antibiotic regimens in different patient populations, mak- There has been and still is considerable debate re- ing it difficult to generalize the results. In addition, sever- garding the potential benefits of combination versus ity of illness can play an important role when comparing monotherapy in the empiric management of infection mono- and combination therapy. In a meta-regression in critically ill patients. Combination therapy has ad- analysis, Kumar et al. [21] reported that although there vantages and disadvantages (Table 1). A first potential was no overall mortality/clinical response benefit with advantage is in vitro synergy between two drugs result- combination therapy for the 50 studies included, when ing in improved bacterial killing. For example, a colistin– studies were stratified according to baseline mortality glycopeptide (vancomycin or teicoplanin) combination risk, combination therapy was consistently associated was shown in vitro to be synergistic against multidrug- with benefit in the more severely ill patients. Moreover, resistant (MDR) Gram-negative bacteria, especially Acine- the benefits of antibiotic therapy, whether combined or tobacter baumannii [9, 10]. Nevertheless, clinical studies monotherapy, are related to the activity of the chosen have been unable to demonstrate an effect of synergy on antibiotics against the infecting organisms and adequacy outcomes [11, 12], calling into question the importance has rarely been assessed in these studies. of synergy with the potent antibacterial agents used as In current guidelines, combination therapy is suggested monotherapy today. Another potential advantage is that for neutropenic patients with sepsis, patients with infec- combination regimens may provide a greater overall tions caused by MDR pathogens and patients with severe spectrum of activity. respiratory infections and septic shock [8, 22]. In general, One of the most important potential disadvantages of decisions regarding the use of combination or monother- combination therapy is increased drug toxicity, particu- apy should be made on an individual basis according to larly when aminoglycosides are used [13]. Although this the severity of the disease, likely causative microorgan- increased risk may be acceptable in a critically ill popu- ism(s), concomitant diseases, and local microbiological lation with a high risk of MDR organisms, it is likely less and resistance patterns. acceptable in more stable patient populations or where the risk of β-lactam resistance is lower. Risk of super- infection with resistant bacteria or fungal infections De-escalation? represents another potential disadvantage [14]. Another Decisions regarding empiric antibiotic therapy are based frequently cited disadvantage of combination therapy is on two approaches: (1) a judgment that the likely agent increased cost. However, although drug costs will almost has “normal antibiotic susceptibility” and can therefore certainly be higher with combination therapy, this in- be treated as such with possible need for “escalation” to creased cost may be acceptable if compensated for by second-line drugs after microbiological identification; shorter hospital stays and improved patient outcomes. (2) a judgment, based on local microbiology patterns In a cohort of patients with septic shock, combination and clinical presentation, that the infecting microorgan- therapy of a β-lactam with other antibiotics was associ- ism may be MDR and should be treated as such, with ated with a decrease in 28-day mortality compared with possible “de-escalation” to a simpler antibiotic regimen β-lactam monotherapy [15]. And, in a prospective, multi- after identification and antibiotic susceptibilities of the center European observational study, combination therapy causative microorganism are known. More frequently the latter approach is used in the ICU to ensure that all Table 1 Some potential advantages and disadvantages of using possible causative organisms are initially covered. In- combination empiric therapy versus monotherapy deed, only about 30 % of all antibiotics are used for Advantages