Zaragoza et al. Critical Care (2020) 24:383 https://doi.org/10.1186/s13054-020-03091-2 REVIEW Open Access Update of the treatment of nosocomial pneumonia in the ICU Rafael Zaragoza1,2* , Pablo Vidal-Cortés3, Gerardo Aguilar4, Marcio Borges2,5, Emili Diaz6,7,8, Ricard Ferrer9, Emilio Maseda2,10, Mercedes Nieto11, Francisco Xavier Nuvials9, Paula Ramirez12, Alejandro Rodriguez13, Cruz Soriano14, Javier Veganzones10 and Ignacio Martín-Loeches15 Abstract In accordance with the recommendations of, amongst others, the Surviving Sepsis Campaign and the recently published European treatment guidelines for hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP), in the event of a patient with such infections, empirical antibiotic treatment must be appropriate and administered as early as possible. The aim of this manuscript is to update treatment protocols by reviewing recently published studies on the treatment of nosocomial pneumonia in the critically ill patients that require invasive respiratory support and patients with HAP from hospital wards that require invasive mechanical ventilation. An interdisciplinary group of experts, comprising specialists in anaesthesia and resuscitation and in intensive care medicine, updated the epidemiology and antimicrobial resistance and established clinical management priorities based on patients’ risk factors. Implementation of rapid diagnostic microbiological techniques available and the new antibiotics recently added to the therapeutic arsenal has been reviewed and updated. After analysis of the categories outlined, some recommendations were suggested, and an algorithm to update empirical and targeted treatment in critically ill patients has also been designed. These aspects are key to improve VAP outcomes because of the severity of patients and possible acquisition of multidrug-resistant organisms (MDROs). Keywords: HAP, VAP, Nosocomial pneumonia, Ceftolozane-tazobactam, Ceftazidime-avibactam, Pseudomonas aeruginosa, KPC, PCR Introduction/methodology acquisition of multidrug-resistant organisms (MDROs) In accordance with the recommendations of, amongst which will doubtlessly be related to a higher level of un- others, the Surviving Sepsis Campaign [1] or the latest suitable empirical treatment and, consequently, higher European treatment guidelines for hospital-acquired mortality. As an example, when reviewing the data from pneumonia (HAP) and ventilator-associated pneumonia the National Surveillance Programme of Intensive Care (VAP) [2], in the event of a patient with such infections, Unit (ICU)-Acquired Infection in Europe Link for Infec- empirical antibiotic treatment must be appropriate and tion Control through Surveillance (ENVIN-HELICS) [3], administered as early as possible. Complying with these the likelihood of receiving an inadequate empirical treat- conditions is more important and more complex in pa- ment for a Pseudomonas aeruginosa infection, even with tients being admitted to an intensive care unit (ICU), combination therapy, is approximately 30%. both because of the severity of patient and the potential The development of new antibiotics and their use should be cautious. In the present manuscript, we * Correspondence: zaragoza_raf@gva.es propose different algorithms that allow to implement 1 2 Critical Care Department, Hospital Universitario Dr. Peset, Valencia, Spain empirical and targeted use for potential MDROs. We Fundación Micellium, Valencia, Spain must first and foremost capitalize on their greater Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. 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 in a credit line to the data. Zaragoza et al. Critical Care (2020) 24:383 Page 2 of 13 in vitro activity, lower resistance and suitable efficacy in a patient presents symptoms of infection of the lower re- clinical trials and, secondly, antibiotic diversification and spiratory tract after more than 48 h under MV and does the need for carbapenem-sparing strategies [4, 5]. Anti- not present opacities on chest X-ray, the patient is diag- microbial optimization programmes, such as the US nosed with ventilator-associated tracheobronchitis antimicrobial stewardship programmes (ASP), aim to (VAT). improve the clinical outcomes of patients with nosoco- Respiratory infections are the most prevalent nosoco- mial infections, minimizing adverse effects associated mial infection observed in ICUs [10]. In a broad global with the use of antimicrobials (including the onset and multicentre study, half the patients presented an infec- dissemination of resistance) and guaranteeing the use of tion at the time of the observation, 65% of respiratory cost-effective treatments [6]. In addition, the analysis of origin [11] and HAP and VAP accounted for 22% of all its use and results obtained in patients and microbio- hospital infections in a prevalence study performed in logical resistance result paramount. Avoiding unneces- 183 US hospitals [12]. A total of 10 to 40% of patients sary treatments and reducing the spectrum and duration who underwent MV for more than 48 h will develop a of treatment together with the reduction of adverse ef- VAP. Marked differences are observed between different fects and/or possible interactions will be the ultimate countries and kinds of ICU [13]. These variations can be aim [7, 8]. accounted for by diagnostic difficulties, differences in This point of view article summarizes the recently the definition used, the diagnostic methods used and the published literature on the management of nosocomial classification of units because the prevalence of VAP is pneumonia in the critically ill patients that require inva- higher in certain populations (patients with adult re- sive respiratory support, both those arising from hospital spiratory distress syndrome (ARDS) [14], with brain wards that ultimately require ICU admission and those damage [15], or patients with veno-arterial extracorpor- associated with mechanical ventilation. Experts were se- eal membrane oxygenation (VA-ECMO) [16]. lected on the basis of their contrasted experience in the If we analyse the density of incidence, significant dif- field of nosocomial infections, including specialists in ferences between European and US ICUs have been re- anaesthesia and in intensive care medicine. An extensive ported. The National Healthcare Safety Network search of the literature was performed by the authors (NHSN) (2013) reported that the average rate of VAP in using the MEDLINE/PubMed and Cochrane library da- the USA was 1–2.5 cases/1000 days of MV [17], substan- tabases, from 2009 to October 2019, aimed to retrieve tially lower than in Europe, 8.9 episodes/1000 days of relevant studies on diagnosis and treatment of nosoco- MV according to the European Centre for Disease Pre- mial pneumonia in ICU patients especially randomized vention and Control (ECDC) [18]. In Spain, according to controlled clinical trials (RCT), systematic reviews, the ENVIN-HELICS 2018 report, the incidence was 5.87 meta-analysis and expert consensus articles. Priorities episodes/1000 days of MV [3]. Both in the USA and in have been established in regard to the management, Europe, the incidence of VAP has gradually reduced agreed by the group and based on risk factors for their [19], probably in relation to preventive measures [20], al- development and prognostic factors. Moreover, the most though a potential bias cannot be ruled out due to not important clinical entities, methods of rapid diagnostics very objective monitoring criteria. in clinical microbiological available and new antibiotic A condition with growing relevance is ventilator- treatments recently added to the therapeutic options associated tracheobronchitis (VAT). In a prospective and have been reviewed and updated. After the analysis of multicentre study, the incidence of VAT and VAP was the priorities outlined, recommendations that can be ap- similar with 10.2 and 8.8 episodes for 1000 days of plied have been included. An algorithm that takes into mechanical ventilation, respectively [21]. Sometimes, it is account the priorities analysed to update empirical and difficult to differentiate VAT and VAP, and in fact, some targeted treatment in ICUs has also been designed. authors advocate that the two entities are a continuum and that VAT patients can evolve towards VAP [22]. Epidemiology These authors report a series of reasons in their ration- The definitions of hospital-acquired pneumonia (HAP) ale: higher incidence of VAP in patients with VAT com- and ventilator-associated pneumonia (VAP) are not pared to those with VAT, post-mortem findings homogeneous and may alter the incidences reported [9]. coexisting in both entities, higher ranges of biomarkers In this document, we will refer to HAP as that which ap- (procalcitonin) or severity scores in VAP compared to pears as of 48 h from hospital admission, in the ICU or VAT and mortality, or a common microbiology [23]. in the hospital ward, whether or not related to mechan- Non-ventilated ICU patients appear to have a lower ical ventilation (MV). We will use the term HAP to talk risk of developing pneumonia, as reported in a recent of that HAP unrelated to MV or intubation, as opposed study, where 40% of cases of pneumonia acquired in the to VAP, which is what appears after 48 h of MV. When ICU occurred in patients who had not been ventilated Zaragoza et al. Critical Care (2020) 24:383 Page 3 of 13 previously [24]. Another study, performed in 400 Ger- the ICU and hospital, in addition to the increased time man ICUs, reports a number of VAP of 5.44/1000 days under mechanical ventilation [41]. The crude mortality MV, as opposed to 1.58/1000 days of non-invasive mech- rates of patients with VAP vary between 24 and 72%, anical ventilation (NIMV) or 1.15/1000 HAP patients with greater mortality in VAP caused by Pseudomonas [25]. The global incidence (including intra- and extra- aeruginosa [42]. The more recent data estimate attribut- ICU) of HAP ranges from 5 to more than 20 cases/1000 able mortality of 13%, higher in patients with intermedi- hospital admissions, being more complex to determine, ate severity and in surgical patients [43]. As for VAT, because of the heterogeneity of definitions and the this has been related in different studies to a longer stay methodology used. The European Centre for Disease in ICU and more days of MV. However, to date, there Prevention and Control (ECDC), analysing data from are no randomized controlled trials showing a beneficial 947 hospitals in 30 countries, reports a prevalence of effect for the treatment in VAT. Moreover, higher mor- HAP of 1.3% (95% CI, 1.2 to 1.3%) [26]. However, a US tality in patients presenting this complication has not study reports a frequency of HAP of 1.6% in hospitalized been observed [21, 36, 44]. patients, with a density of incidence of 3.63/1000 patients-day [27]. Moreover, a Spanish multicentre study HAP risk factors [28] that analysed 165 episodes of extra-ICU HAP re- Traditionally, three kinds of risk factors for nosocomial ports an incidence of 3.1 (1.3–5.9) episodes/1000 admis- pneumonia have been considered: patient-related, infec- sions, variable according to hospital and type of patient. tion prevention-related and procedures-related. Patient- In the non-ventilated patient’s group, when cultures related factors are acute or chronic severe disease, coma, are available, the aetiology is similar to VAP [24], with a malnutrition, prolonged hospital length of stay, predominance of P. aeruginosa, S. aureus and Enterobac- hypotension, metabolic acidosis, smoking and comorbid- teriaceae spp. [29]. This also depends on the patient’s se- ities (especially of the central nervous system but also verity, individual risk factors and local epidemiology. chronic obstructive pulmonary disease (COPD), diabetes Table 1 summarizes the studies published from 2010 mellitus, alcoholism, chronic renal failure and respira- to 2019 about the microbiology of ICU-acquired pneu- tory insufficiency). Amongst risk factors related to infec- monia (including HAP, VAP and VAT). tion prevention, those notable are deficient hand hygiene or inappropriate care of respiratory support devices. Fi- Impact on outcome nally, amongst factors related to procedures, administra- According to a case-control study, HAP patients pre- tion of sedatives, corticosteroids and other sented a worse clinical course: higher mortality (19% vs immunosuppressants, prolonged surgical procedures (es- 3.9%), more ICU admissions (56.3% vs 22.8%) and longer pecially at thoracic or abdominal level) and prolonged/ hospital stay (15.9 days vs 4.4 days). Overall, patients inappropriate antibiotic treatment are the most recog- with HAP presented an odds ratio of dying 8.4 times nized factors [13, 38, 45–47]. More recent studies have higher than non-HAP patients [38]. It has traditionally observed an increased risk of nosocomial pneumonia in been considered that VAP-associated mortality is higher patients who receive gastric acid-modifying drugs during than HAP [39]. When ICU-HAP was compared to VAP their admission (OR: 1.3 [1.1–1.4]) [48]. [25], the crude mortality was similar, which suggests that Given that there is no artificial airway, we can con- it is related more to patient-related factors than prior in- sider pneumonia in the patient who undergoes NIMV tubation. Therefore, when analysing data from 10 recent as a subtype of pneumonia in the non-ventilated pa- clinical trials in ICU patients, mortality was greater for tient. A prospective study analysed 520 patients who HAP requiring MV, somewhat lower in VAP and less received NIMV. No statistically significant differences for non-ventilated HAP [40]. The need for intubation in were found in terms of age, sex, severity or gas ex- this population is probably a marker of poor clinical pro- change parameters amongst those patients who pre- gression of pneumonia. Adjusted mortality rates were sented nosocomial pneumonia and complication of similar for VAP and ventilated HAP. In a recent multi- NIMV and those who did not [49]. centre study that includes more than 14,000 patients A physiopathological approach for nosocomial pneu- and investigates the impact of VAP and HAP in the monia has been proposed in Fig. 1. ICU, both were associated with a higher risk of death at 30 days [HR 1.38 (1.24–1.52) for VAP and 1.82 (1.35– 2.45) for HAP] [37]. Prognostic factors Overall, the mortality from HAP of 13% with an in- Pneumonia acquired in the ICU leads to a negative im- crease in hospital stay of 4 to 16 days and increased cost pact in terms of morbidity, prolonged stay and duration of 40,000 dollars per episode has been reported [27]. of MV in case of VAP and a consequent increase in VAP has also been associated with an increased stay in healthcare cost [24]. More controversial is the direct Table 1 Microbiology and main resistance profile of microorganism causing VAP, VAT and HAP in non-ventilated patients treated in ICU (data from studies published from 2010 to 2019) Zaragoza et al. Critical Care Reference Type of infection Microbiology Ferrer et al. [30] HAP S. aureus, 17.7% P. aeruginosa, 17.7% E.coli, 6.5% Enterobacter spp., 4.3% K. pneumoniae, 3.2% Esperatti et al. [22] VAP P. aeruginosa, 24% S. aureus, 23% E. coli, 7% Enterobacter spp., 6% H. influenzae, 4% Restrepo et al. [31] VAP S. aureus, 38.7% H. influenzae, 23.4% P. aeruginosa, 14.7% k. pneumoniae, 11.5% E. coli, 11.1% MDR, 30% (2020) 24:383 Quartin et al. [32]* VAP S. aureus, 60.3% P. aeruginosa, 9.4% Acinetobacter spp., 7.3% Klebsiella spp., 6.8% Enterobacter spp., 5.1% Nseir et al. [33] VAT P. aeruginosa, 34.4% S. aureus, 20.5% A. baumanii, 11.5% K. oxytoca, 10.6% Enterobacter spp., 9.8% MDR, 36.8% Martín-Loeches et al. [21] VAT P. aeruginosa, 25% S. aureus, 23% Klebsiella spp., 15% E. coli, 12% Enterobacter spp., 11% MDR, 61% VAP P. aeruginosa, 24% S. aureus, 24% Klebsiella spp., 14% Enterobacter spp., 12% E. coli, 11% MDR, 61% ECDC [18] VAP P. aeruginosa, 20.8% S. aureus, 17.8% Klebsiella spp., 16.1% E. coli, 13.3% Enterobacter spp., 10.3% Koulenti et al. [29] HAP Enterobacteriaceae, 32.9% S. aureus, 24.9% P. aeruginosa, 17.4% A. baumanii, 15.4% ENVIN-HELICS [3] VAP P. aeruginosa, 23.8% S. aureus, 13.5% Klebsiella spp., 10.3% E. coli, 9.1% Enterobacter spp., 8.6% PIP/TAZ R, 34.1% MRSA, 12.7% PIP/TAZ R, 50% PIP/TAZ R, 21.7% Carba R, 37.9% Carba R, 23.5% Carba R, 0% Colistin R, 8.6% 3°G cef R, 37% 3°G cef R, 12.5% Pulido et al. [34] VAP P. aeruginosa, 21.1% A. baumanii, 17.9% K. pneumoniae, 15.6% S. aureus, 13.3% E. coli, 7.8% Huang et al. [35] VAP A. baumanii, 33.9% K. pneumoniae, 23.6% P. aeruginosa, 19.8% S. aureus, 7.1% S. maltophilia, 3.8% Carba R, 76.4% Carba R, 44% Carba R, 59.5% MRSA, 60% Cantón-Bulnes et al. [36] VAT P. aeruginosa, 24.5% H. influenzae, 18.9% E. coli, 9.4% S. aureus, 9.4% K. pneumoniae, 7.5% Ibn Saied et al. [37] VAP P. aeruginosa, 33.5% Enterobacteriaceae, 32.3% S. aureus, 19% S. pneumoniae, 4.9% S. maltophilia, 4.7% carba carbapenem, HAP hospital-acquired pneumonia, MDR multidrug resistant, VAP ventilator-associated pneumonia, VAT ventilator-associated tracheobronchitis, PIP/TAZ piperacillin/tazobactam, R resistance, 3°G cef 3° generation cephalosporin *Trial designed to compare MRSA pneumonia treatment, special effort to include patients with MRSA pneumonia Page 4 of 13 Zaragoza et al. Critical Care (2020) 24:383 Page 5 of 13 Fig. 1 Physiopathological approach of progression of nosocomial pneumonia from wards to ICU. From green to red colour, the progression of the severity of nosocomial pneumonia is described independently of the area of hospital admission. vHAP shows the poorest outcome. HAP, hospital-acquired pneumonia; NV-ICUAP, non-ventilated acquired pneumonia; VAP, ventilator-acquired pneumonia; vHAP, ventilated hospital-acquired pneumonia relationship between the development of nosocomial Therefore, to correctly evaluate the remaining prog- pneumonia and increase in mortality [50, 51]. nostic factors, it is necessary to focus the analysis on Various factors have been associated with a worse those patients who receive a suitable empirical treat- prognosis of pneumonia including the existence of co- ment. As a second step, we must choose between two morbidities, the patient’s performance status, the in- possible clinical scenarios; to consider which factors, pa- fection severity at the time of its development and tient and disease-related are associated with a worse the patient’s response to infection. However, the study final outcome or to perform a more dynamic analysis of these factors is routinely eclipsed when the same and to try to elucidate which clinical course is associated analysis is performed whether or not a suitable em- with a poor response to the treatment and, conse- pirical antibiotic is used [52]. quently, a worse final outcome. Following the first op- The choice of an inappropriate antibiotic treatment, tion, older age, existence of a malignant haematology which is directly related to the existence of MDROs, is disease or clinical onset in the form of septic shock probably the most relevant and, even more important, or severe acute respiratory failure will be associated potentially modifiable prognostic factor. In fact, the like- with higher mortality, but there is not much clinical lihood of death in case of inappropriate treatment sub- application of this association [55]. In the same way, stantially increases mortality in patients with severe it occurs with analytical aspects such as initial lym- infections [53, 54]. phopaenia [56]. Zaragoza et al. Critical Care (2020) 24:383 Page 6 of 13 There is more interest in the evaluation of the response MDROs: the link with colonization to early treatment strategies. Against this backdrop, Esper- MDR Pseudomonas aeruginosa, extended spectrum atti et al. validated a few years ago the association between beta-lactamase-producing enterobacteria (ESBL-E), a series of clinical variables 72 to 96 h from the onset of meticillin-resistant Staphylococcus aureus (MRSA), treatment with the prognosis of 335 patients with nosoco- Acinetobacter baumannii and carbapenemase- mial pneumonia [57]. The absence of improved oxygen- producing Enterobacteriaceae (CPE) are the MDROs ation, the need for mechanical ventilation in case of HAP, most commonly involved in HAP. Knowledge of the persistence of fever or hypothermia together with local epidemiology is essential because there are sig- purulent respiratory secretions, radiological worsening in nificant differences in the local prevalence of each more than 50% of the lung area or the development of MDRO [59]. septic shock or multi-organ failure after the onset of anti- The ENVIN-HELICS report does quantify the resist- biotic treatment were more common in patients with a ance of the most important microorganisms to different worse clinical course (in terms of ICU and hospital length antibiotics, which enables an overall vision of expected of stay, duration of mechanical ventilation and mortality). resistance rates in the case of nosocomial pneumonia in Amongst all of these aforementioned factors, the ab- Spanish ICU [3]. sence of improved oxygenation was significantly asso- The ENVIN-HELICS data also reveal an increased re- ciated with greater mortality (OR 2.18 [1.24–3.84] p = sistance of Klebsiella to carbapenems. The grade of re- 0.007). In regard to both the original figure and sistance to antibiotics in the remaining bacteria has course at 72–96 h of scales such as the CPIS or bio- remained stable in the last few years. Table 1 shows the markers such as C-reactive protein or procalcitonin, most important microorganisms that cause VAP and the most studies agree over its prognostic use and follow- percentage resistance to some of the main antibiotics up of infection [58]. used for these infections. Table 2 Principal variables associated with resistance for main MDROs causing NP MDRO Risk factors References MRSA ⇒ Age [61–63] ⇒ NP appearance > 6 days after admittance ⇒ NP development excluding summers ⇒ Respiratory diseases ⇒ Multilobar involvement ⇒ Respiratory infection/colonization caused by MRSA in the previous year ⇒ Hospitalization in the previous 90 days ⇒ Recent nursing home or hospital stay ⇒ Recent exposure to fluoroquinolone or antibiotics treating Gram-positive organisms Pseudomonas aeruginosa ⇒ Prior airway colonization by P. aeruginosa [64, 65] ⇒ Previous antibiotic treatment ⇒ Solid cancer ⇒ Shock ⇒ Alcohol abuse ⇒ Pleural effusion ⇒ Chronic liver disease independently predicted MDR amongst Pa-ICUAP ⇒ Prior use of carbapenems ⇒ Prior use of fluoroquinolones ⇒ Duration of therapy ⇒ APACHE II score KPC ⇒ Admission to ICU, antimicrobial use [66–69] ⇒ Prior carbapenem ⇒ Invasive operation ⇒ Previous non-KPC-Kp infections ⇒ Duration of previous antibiotic therapy before KPC colonization Enterobacteriaceae ⇒ Male sex [68, 70] ⇒ Admission from another health care facility ⇒ Ventilation at any point before culture during the index hospitalization ⇒ Receipt of any carbapenem in the prior 30 days ⇒ Receipt of any anti-MRSA agent in the prior 30 days Acinetobacter baumannii ⇒ APACHE II score at admission [5, 71, 72] ⇒ Systemic illnesses (chronic respiratory disease and cerebrovascular accident) ⇒ Presence of excess non-invasive or invasive devices (mechanical ventilation) ⇒ Ever used antibiotics within 28 days (carbapenem and cefepime) KPC Klebsiella pneumoniae carbapenemase, MRSA meticillin-resistant Staphylococcus aureus, MDRO multidrug-resistant organism, NP nosocomial pneumonia Zaragoza et al. Critical Care (2020) 24:383 Page 7 of 13 When evaluating the risk of development of nosoco- about epidemiology (Table 1), antimicrobial resistances mial pneumonia in the ICU by a MDRO, we must first (Table 2), rapid microbiological test and risk factors for evaluate the risk factors for these pathogens. The Euro- HAP. pean guidelines for nosocomial pneumonia [2] include Some new antibiotics have been recommended over risk factors for MDRO: septic shock, hospital ecology old ones based on their potential advantages shown in with high levels of MDROs, prior use of antibiotics, re- pivotal studies (Table 3), observational studies and in vi- cent hospitalization (> 5 days) and prior colonization by tro data. However, the use of other families of antibiotics MDROs. Risk factors are in general common to all has been also warranted. MDRO; to discriminate different MDROs, we mainly Various experts recommend using these new anti- base ourselves on local epidemiology and prior biotics according to the site of infection, clinical se- colonization of the patient [60]. The importance of verity, existence of risk factors for MDRO colonization as a risk factor for suffering pneumonia by acquisition, existence of comorbidities and existing the colonizing microorganism varies according to the MDROs in each unit/hospital as suggested in the al- type of MDRO and location of the colonization. Table 2 gorithm [4, 5, 85–87]. describes the principal variables associated with resist- The onset of two antibiotics such as ceftolozane/tazo- ance for the main MDROs causing NP. bactam (CFT-TAZ) and ceftazidime/avibactam (CAZ/ AVI) has broadened the treatment options for patients Current and future solutions with suspected MDRO infection. Both antibiotics offer In the event of sepsis in a critically ill patient, there is an some advantages: apart from the demonstrated efficacy urgent need to commence an empirical antibiotic treat- in clinical trials for approval, they present a better ment that is suitable, appropriate and early [1, 2] with in vitro activity and less resistance and can also be used the risk of resistance to multiple antibiotics, which hin- within the scope of an antibiotic policy aimed to reserve ders complying with the premises mentioned. carbapenems [4, 5]. The future use of rapid diagnostics is promising and Because of its specific features, all authors included will undoubtedly change our approaches to diagnosis in this point of view manuscript coincided in the and treatment of NP optimizing empiric antibiotic treat- choice of CFT/TAZ to treat P. aeruginosa [85, 86] in- ment. New tests have been developed such as multiplex fections and CAZ/AVI for infections caused by KPC- polymerase chain reaction (MPCR), exhalome analysis like carbapenemase-producing Enterobacteriaceae [87]. and chromogenic tests [73]. However, they acknowledged that both antibiotics MPCR has reported a sensitivity of 89.2% and a speci- have never been compared head to head. ficity of 97.1%, using BAL samples, and 71.8% sensitivity CFT/TAZ presents greater in vitro activity against and 96.6% (range, 95.4–97.5%) using endotracheal aspi- P. aeruginosa, with less resistance than the remaining rates (ETA) [74]. current anti-pseudomonal agents in global terms [88]. In the MAGIC-BULLET study, Filmarray® showed a CFT/TAZ also exhibits the lowest mutant prevention sensitivity of 78.6%, an specificity of 98.1%, a positive concentration (MPC) against P. aeruginosa, as well as predictive value of 78.6% and a negative predictive colistin and quinolones (2 mg/L) [85]. The clinical value of 96.6% in respiratory samples. Furthermore, trial ASPECT-NP [83] reveals a favourable result for Filmarray® provided results within only 1 h directly patients who suffer from HAP that require invasive from respiratory samples with minimal sample pro- MV treated with CFT/TAZ (mortality at 28 days, cessing times [34]. 24.2% vs 37%) and also in those patients in whom A new score (CarbaSCORE) was recently published; its initial antibiotic treatment failed (mortality at 28 days, aim is to identify those critically ill patients who will 22.6% vs 45%). In patients with bacteraemia, a trend need to be treated with a carbapenem with the intention towards a higher rate of clinical cure (10.5% vs 36%), of using these antibiotics more selectively [75]. This con- without statistical significance, was observed in CFT/ sideration is appropriate, however, ascertaining some of TAZ-treated patients. In this clinical trial, higher the variables necessary, such as the existence of bacter- levels of microbiological cure in pneumonia caused by aemia or colonization by MDROs involves a delay, which P. aeruginosa were also observed in patients who re- cannot be assumed in the septic patient. ceived CFT/TAZ. An algorithm that includes the priorities analysed to On the other hand, CAZ/AVI was associated with update empirical and targeted treatment in critically ill better survival rates in patients with bacteraemia who patients has been designed (Fig. 2) after reviewing the required rescue treatment in infections caused by major randomized, controlled clinical trials of antimicro- KPC-producing Enterobacteriaceae [89]. In case of in- bial agents actually available for NP in the last 10 years fection caused by a CAZ/AVI-susceptible OXA-48 [76–84] (Table 3) and the considerations made before strain, CAZ/AVI could be an option to treat it [90]. Zaragoza et al. Critical Care (2020) 24:383 Page 8 of 13 Fig. 2 PANNUCI algorithm. From empirical to targeted treatment on nosocomial pneumonia in ICU. After analyzing the onset, the previous use of antimicrobials or clinical condition (vHAP or VAP), empirical antimicrobial therapy is chosen based on risk factors, previous colonization, local flora and/or use of rapid techniques. Therefore, targeted therapy is selected depending on the type of microorganism isolated and the possible advantages of one antimicrobial over others. AT, antimicrobial therapy; vHAP, ventilated hospital-acquired pneumonia; VAP, ventilator-associated pneumonia; MDR, multidrug-resistant; PCR, polymerase chain reaction; CFT/TAZ, ceftolozane/tazobactam; CAZ/AVI, ceftazidime/avibactam; PIP/ TAZ, piperacillin/tazobactam; AMG, aminoglycoside; AZT, aztreonam; EAT, empirical antimicrobial treatment; TAT, targeted antimicrobial treatment; OXA-48, OXA-48 carbapenemase; KPC, Klebsiella pneumoniae carbapenemase; R, resistance. *If Oxa-48 susceptible to CAZ/AVI Data extracted from an in vitro study suggest that Colistin is really a non-effective drug to consider CAZ/AVI plus aztreonam could be an option to treat for HAP unless aerosolized. The Magic Bullet trial infections caused by metallo-β-lactamase-producing failed to demonstrate non-inferiority of colistin com- Enterobacteriaceae [91]. pared with meropenem, both combined with levoflox- The MERINO Trial [92] randomized patients hospi- acin, in terms of efficacy in the empirical treatment talized with bacteraemia caused by enterobacteria re- of late VAP but showed the greater nephrotoxicity of sistant to ceftriaxone to receive antibiotic treatment colistin [84]. However, sometimes, especially in VAP with meropenem or piperacillin/tazobactam. The clin- caused by MDR Acinetobacter baumannii, no other ical outcomes were unfavourable for the group of pa- options are available. Other antimicrobials such as tients that received piperacillin/tazobactam, which ceftobiprole or tigecycline have not been considered cuts down the treatment options for these infections. due to the failure to demonstrate non-inferiority in In published clinical trials, both CFT/TAZ and CAZ/ some of the trials reviewed (Table 3). AVI [82, 83] antibiotics demonstrated appropriate ac- The use of aerosolized therapy for VAP is still tivity and clinical efficacy to ESBL-E, whereby they controversial. Two recent multicenter, randomized, arise as a new alternative and may be included in double-blinded, placebo-controlled trials of adjunct- carbapenem-spare regimens. ive nebulized antibiotics for VAP patients with sus- Cefiderocol recently received US Food and Drug pected MDR Gram-negative pneumonia were Administration’s (FDA) approval for the treatment negative to achieve their primary endpoints [94, 95]. of complicated urinary tract infections, including For this reason, their use as an adjunctive therapy pyelonephritis, and is currently being evaluated in cannot be supported. Rescue therapy for MDROs phase III trials for treating nosocomial pneumonia might be considered when systemic therapy failed and infections caused by carbapenem-resistant [96]. Gram-negative pathogens including Acinetobacter Antibiotic stewardship and duration of antibiotic spp. [93]. therapy also deserve our attention. The clinical Table 3 List of major randomized, controlled clinical trials of systemic antimicrobial agents actually available for treating NP in the last 10 years Author, year, name Antimicrobial tested Phase, Microorganism Subject Primary outcome Results of Mortality Comments of the trial and comparator blinded, primary outcome design Freire, 2010 [76] Tigecycline (T) III, yes, All pathogens HAP + VAP Clinical response in c-mITT: T, 62.7%; I, T, 14.1% T was non-inferior to I for c- Imipenem (I) NI CE and c-mITT 67.6% I, 12.2% mITT but not the CE popula populations at TOC CE: T, 67.9%; tion due to the results in VAP. Zaragoza et al. Critical Care I, 78.2% FDA warning against T use for VAP. Rubinstein, 2011, Telavancin (Te) III, yes, Gram-positive HAP Clinical response at AT: Te, 58.9%; Te, 21.5% Increases in serum creatinine ATTAIN 1 and 2 [60] Vancomycin (V) NI FU/TOC V, 59.5% V, 16.6% level were more common in CE: Te, 82.4%; the telavancin group. V, 80.7% (2020) 24:383 Kollef, 2012 [78] Doripenem (D), 7 days IV, yes, All pathogens VAP Clinical cure at EOT D, 45.6% D, 21.5% Non-inferiority of a fixed 7-day Imipenem (I), 10 days NI (day 10) in the MITT I, 56.8% I, 14.8% treatment with D was no achieved FDA warning against D use for VAP. Wunderink, 2012, Linezolid (L) IV, yes, Meticillin-resistant HAP + VAP Clinical outcome at L, 57.6% L, 15.7% Nephrotoxicity occurred more ZEPHIR [79] Vancomycin (V) NI Staphylococcus EOS in PP patients V, 46.5% V, 17% frequently with V. aureus Ramirez, 2013 [80] Tigecycline low dose II, yes, All pathogens HAP + VAP Clinical response at THD, 85% – THD could be necessary to (TLD) NI EOT TLD, 69.6 treat HAP/VAP. Tigecycline high dose I, 75% (THD) Imipenem Awad, 2014 [81] Ceftobiprole medocaril (C) III, yes, All pathogens HAP + VAP Clinical cure at the ITT: C, 49.9%; C, 16.7% Non-inferiority of C compared Ceftazidime + Linezolid NI TOC CAZ/L, 52.8% CAZ/L, 18% (CAZ/L) CE: C, 69.3%; with CAZ/L was not CAZ/L, 71.3% demonstrated in VAP patients. Torres, 2018, Ceftazidime/avibactam III, yes, All pathogens HAP + VAP Clinical cure at the c-mITT: CAZ/AVI, CAZ/AVI, 8.1% CAZ/AVI could be a potential REPROVE [82] (CAZ/AVI) NI TOC 68.8%; M, 73% M, 6.8% alternative to carbapenems in Meropenem (M) CE: CAZ/AVI, 77.4%; HAP/VAP patients. M, 78.1% Kollef 2019, Ceftolozane/tazobactam III, yes, All pathogens HAP + VAP, 28-day all-cause mor CFT-TAZ, 24% CFT-TAZ, 24% In HAP and in those in whom ASPECT-NP [83] (CFT-TAZ) NI only tality in ITT M, 25.3% M, 25.3% previous antibacterial therapy Meropenem patients on was unsuccessful, CFT-TAZ MV showed lower mortality. Cisneros, 2019, Colistin (Co) IV, no, All pathogens Late VAP Mortality at 28 days Co, 23.2% Co, 23.2% The study was interrupted after the interim Magic-Bullet [84] Meropenen (M) NI after randomization M, 25.3% M, 25.3% analysis due to excessive nephrotoxicity in the in mMITT colistin group (33:3% vs 18.8%). AT all treated patients, CAZ/AVI ceftazidime/avibactam, CE clinically evaluable population, CFT-TAZ ceftolozane/tazobactam, Co colistin, c-mITT clinical modified intent-to-treat population, D doripenem, EOS end of study, EOT end of treatment, FU follow-up, I imipenem, ITT intention-to-treat population, M meropenem, MITT modified intent-to-treat population, mMITT microbiologically modified intention-to-treat population, MV mechanical ventilation, NI non-inferiority, T tigecycline, Te telavancin, TOC test of cure, THD tigecycline high dose, TLD tigecycline low dose, PP evaluable per-protocol, V vancomycin Page 9 of 13 Zaragoza et al. Critical Care (2020) 24:383 Page 10 of 13 severity of a suspected VAP makes intensivists start Authors’ contributions as soon as possible broad-spectrum antimicrobial RZ, PV and IML searched the scientific literature, drafted the manuscript and contributed to the conception and design. AR, GA, RF, MB, ED, EM, FN and therapy when, in fact, many patients treated do not PR also contributed to the conception and design. All authors read, critically have NP. Clinical scores, such as Clinical Pulmonary reviewed and approved the final manuscript. Infection Score (CPIS), or non-specific biomarkers Funding such procalcitonin (PCT) and C-reactive protein No funding related to this manuscript was received. (CRP) must be applied to begin or to stop antibiotic treatment as previously discussed [73]. Availability of data and materials Not applicable. Prolonged courses of antimicrobial therapy promote more resistance. European guidelines recommend anti- Ethics approval and consent to participate biotic treatment for HAP no longer than 7 days [2]. How- Not applicable. ever, the duration of therapy for MDROs is not clearly Consent for publication established. A new trial (iDIAPASON) is trying to demon- Not applicable strate that a shorter therapy strategy in Pseudomonas aer- uginosa-VAP treatment is safe and not associated with an Competing interests RZ received financial support for speaking at meetings organized on behalf increased mortality or recurrence rate [97]. This strategy of Merck Sharp and Dohme (MSD), Pfizer and Shionogui. PV received could lead to decreased antibiotic exposure during financial support for speaking at meetings organized on behalf of Merck hospitalization in the ICU and in turn reduce the acquisi- Sharp and Dohme (MSD), Pfizer and Shionogui. FN received financial support for speaking at meetings organized on behalf of Merck Sharp and Dohme tion and the spread of MDROs. (MSD), Pfizer, Astellas and Pfizer as well as honoraria for advisory from Shionogui. GA received financial support for speaking at meetings organized on behalf of Astellas, Gilead, Merck Sharp and Dohme (MSD), and Pfizer, as Conclusions well as unrestricted research grants from MSD and Pfizer. IML received Determining the risk factor for nosocomial pneumonia financial support for speaking at meetings organized on behalf of Merck Sharp and Dohme (MSD) and Gilead. is one of the pillars for the antibiotic selection. There AR, RF, MB, ED, EM, JV, MN, PR and CS declare that they have no competing are different risk factors: patient-related (prolonged hos- interests. pital length of stay and comorbidities, use of prior anti- Author details biotics and septic shock), procedure-related (deficient 1 Critical Care Department, Hospital Universitario Dr. Peset, Valencia, Spain. hand hygiene or inappropriate care of respiratory sup- 2 Fundación Micellium, Valencia, Spain. 3ICU, Hospital Universitario Ourense, port devices) and intervention-related (immunosuppres- Ourense, Spain. 4SICU, Hospital Clínico Universitario Valencia, Valencia, Spain. 5 ICU, Hospital Universitario Son Llázter, Palma de Mallorca, Spain. sants and prolonged/inappropriate antibiotic treatment). 6 Department of Medicine, Universitat Autònoma de Barcelona (UAB), Antibiotic treatment (including new ones) must be ad- Barcelona, Spain. 7Critical Care Department, Corporació Sanitària Parc Taulí, ministered early and be appropriate. These aspects are Sabadell, Barcelona, Spain. 8CIBERES Ciber de Enfermedades Respiratorias, Madrid, Spain. 9ICU, Hospital Vall d’Hebrón, Barcelona, Spain. 10SICU, Hospital key to VAP outcomes because of the severity of patients Universitario La Paz, Madrid, Spain. 11ICU, Hospital Clínico Universitario San and the possible onset of MDROs. Carlos, Madrid, Spain. 12ICU, Hospital Universitari I Politecnic La Fe, Valencia, Spain. 13ICU, Hospital Universitari Joan XXIII, Tarragona, Spain. 14ICU, Hospital Universitario Ramón y Cajal, Madrid, Spain. 15ICU, Trinity Centre for Health Abbreviations Science HRB-Wellcome Trust, St James’s Hospital, Dublin, Ireland. 3°G cef: 3° generation cephalosporin; AT: Antimicrobial therapy; AMG: Aminoglycoside; ARDS: Acute respiratory distress syndrome; Received: 2 March 2020 Accepted: 12 June 2020 ASP: Antimicrobial stewardship programmes; AZT: Aztreonam; CPE: Carbapenemase-producing Enterobacteriaceae; CAZ/AVI: Ceftazidime/ avibactam; CFT/TAZ: Ceftolozane/tazobactam; COPD: Chronic obstructive pulmonary disease; CRP: C-reactive protein; EAT: Empirical antimicrobial References treatment; ECDC: European Centre for Disease Prevention and Control; 1. Levy MM, Evans LE, Rhodes A. 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