Ventilator-associated pneumonia (VAP) is believed to be the most commonly acquired infection in the intensive care unit (ICU) and is associated with high morbidity and mortality rates (Timsit et al., 2017a; Vandana Kalwaje and Rello, 2018). The incidence of VAP ranges from 10 to 25% of all ICU patients, the VAP-related mortality rate is between 24 and 76%, which is 6–21 times higher in the intubated patients (Dasgupta et al., 2015). VAP usually occurs 48–72 h after mechanical ventilation and is related to the increased incidence of multidrug-resistant (MDR) infections, prolonged mechanical ventilation, increased antibiotic usage, and patient stay in the hospital (Charles et al., 2014). Although prevention efforts may reduce the frequency of these infections, unfortunately, only a few preventive strategies have been demonstrated to be effective in managing VAP, while many others should be further evaluated in large randomized trials before becoming the clinical recommendations (Li Bassi et al., 2017). In addition, it’s very challenging to make the correct diagnosis of VAP in the clinical setting in the absence of a gold standard (Tejerina et al., 2010; Nair and Niederman, 2015; Timsit et al., 2017a).

A prevention policy aiming to reduce VAP remains an important element of the management for patients admitted to ICUs and requiring mechanical ventilation. The current preventive strategies for VAP are mainly directed at colonization and aspiration modification, such as avoiding intubation (Carron et al., 2013), oral care (Nicolosi et al., 2014), assessing for early weaning and mobility (Balas et al., 2014; Klompas et al., 2015), and prophylactic probiotics (Wong et al., 2015). The empiric treatment strategies of VAP should be informed by the local distribution of pathogens and their antimicrobial susceptibilities, because the pathogens responsible for VAP and the drug-resistance situation are varying from region to region (Weber et al., 2007; Chung et al., 2011; Mathai et al., 2016; Awad et al., 2018). VAP is commonly caused by Pseudomonas aeruginosa, Klebsiella pneumonia, and Acinetobacter baumannii globally. It is important that the antimicrobial therapy be right in the first time in VAP patients, because the pathogens associated with inappropriate initial therapy are usually antibiotic-resistant strains of these pathogens, so patients at high risk of infection with these organisms initially needed to receive a combination of agents providing a very broad spectrum of coverage (Weiner et al., 2016; Rhodes et al., 2018). This review aims to summarize the available knowledge on drug prevention and control of VAP, taking profit from the recommendations of several health organization such as the American Thoracic Society with the Infectious Disease Society of America (Kalil et al., 2016), the Centers for Disease Control and Prevention (CDC) (Tablan et al., 2004), the European Task Force on VAP (Torres and Carlet, 2001), the Society for Healthcare Epidemiology of America, and the Institute for Healthcare Improvement (Klompas et al., 2014), as well as the recently major guidelines for the management of VAP (Kalil et al., 2016; Timsit et al., 2017a; Torres et al., 2017), and we hope that our clinicians know more about the initial therapies and treatment strategies of VAP, and we can investigate and focus on the management of the disease in future.

Currently, there is no gold standard and valid definition for VAP, even the most widely used VAP criteria and definitions are neither sensitive nor specific. From 2013, the ventilator-associated event (VAE) was established by CDC based on a novel and multi-tiered algorithm, including definitions for a ventilator-associated condition (VAC), infection-related ventilator-associated complication (IVAC), and possible or probable VAP (PVAP). These definitions were developed in order to better capture infectious and non-infectious events in patients receiving mechanical ventilation (Magill et al., 2013). Unfortunately for the bedside practitioner, the new CDC definition for VAP has been found to have a sensitivity as low as 37% with a negative predictive value of only 84%, suggesting that VAE algorithm might not be intended for use in the clinical management of patients. In 2016, CDC reported a module about the definition of VAP is pneumonia that arises at least 48 h after endotracheal intubation (Erb et al., 2016). As shown in Figure 1, despite lacking a gold standard definition for VAP, they are still based on a combination of radiographic, laboratory, and clinical findings. Clinical suspicion of VAP in a patient is the initial part of the diagnosis, and the recommended standard diagnostic criteria for VAP is as follows: (i) radiographic (such as new or progressive and persistent infiltrates, consolidation or cavitation); (ii) laboratory evidence (such as blood count of white blood cell not more than 4 or at least 12 × 10³ cells/mm³); (iii) clinical evidence (such as temperature <36°C or >38°C, new onset or increase of purulent aspirates, wheezing, rales, rhonchi, or worsening gas exchange) (Grgurich et al., 2013; Timsit et al., 2017a; Torres et al., 2017; Metersky and Kalil, 2018; Vazquez Guillamet and Kollef, 2018).

In addition, microbiologic criteria are also an important element for VAP in a clinical context, such as positive culture results from suctioned sputum, bronchoscopy, blind bronchoalveolar lavage (BAL), or pleural fluid. Although not required to diagnose VAP, serial cultures and microscopic assessments of tracheal aspirate samples during treatment can be useful gauges of the patient’s response to antibiotics (Mariki et al., 2014; Fernandez-Barat et al., 2017). VAP can also be divided into early- and late-onset VAP. VAP developing within 4 days of admission are defined as early-onset VAP, which are usually caused by microorganisms sensitive to antibiotics. VAP occurring more than 4 days after admission are defined as late-onset VAP, which are most commonly associated with MDR pathogens and related to higher mortality than early-onset VAP (Nguile-Makao et al., 2010; Martin-Loeches et al., 2015; Torres et al., 2017).

A lot of microbes were detected as a causative agent of VAP, the common pathogens of VAP include Gram-negative bacteria such as P. aeruginosa, Escherichia coli, Acinetobacter species, and K. pneumoniae, and Gram-positive bacteria such as Staphylococcus aureus (Chi et al., 2012; Ding et al., 2016). For fungal VAP, because the Candida species are commonly cultured in respiratory samples, it is rarely an etiology of VAP, rarely causes invasive disease, and it is not recommended to use the routine administration of antifungal therapy when Candida species are found in the pulmonary secretions of mechanical ventilation patients (Kalil et al., 2016). Two groups of risk factors for VAP have been identified, including host-related factors and ventilation-related factors. For example, medical history, gender, age, neurological disorders and comorbidities such as acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD), ulcer disease, organ failure, and immunosuppression are particularly important causes of VAP. In addition, ventilation-related factors usually include duration of the mechanical ventilation, reintubation, absence of subglottic secretion drainage, nasogastric tubes, tracheostomy, intracuff pressure of less than 20 cm H₂O, and prior intravenous antibiotic use within 90 days. The causative pathogens and risk factors for VAP are listed in Table 1 (Lau et al., 2015; Kalil et al., 2016; Gupta et al., 2017; Schreiber and Shorr, 2017; Timsit et al., 2017a,b; Kidd et al., 2018; Vandana Kalwaje and Rello, 2018).

Multiple international guidelines regarding the prevention of VAP are available, and the current preventive strategies for VAP are mainly directed at colonization and aspiration modification (Table 2).

It is important to note that once VAP is considered likely for a patient, the selection of initial empiric antimicrobials may have great variability among clinical scenarios. However, currently, evidence supporting a standardized approach to the exact initial selection of antimicrobials is lacking. Antibiotic resistance has exponentially increased over the last decade, and the isolation of MDR pathogen has been identified as an independent predictor of initial inadequate antibiotic therapy and increased mortality (Vardakas et al., 2013), and the risk of MDR is based on the local ecological data, previous colonization, and previous antibiotic therapy received by the patients. Moreover, there are lots of attempts to control VAP, such as novel antibacterial agents, inhaled antibiotics and monoclonal antibodies. We summarized the reference approaches adapted from recent recommendations or studies for the management of VAP (Palmer, 2015; Kalil et al., 2016; Gupta et al., 2017; Schreiber and Shorr, 2017; Timsit et al., 2017a; Bassetti et al., 2018; Kidd et al., 2018; Vandana Kalwaje and Rello, 2018), details were shown in Table 3.

In the coming decade, VAP will continue to be a major infection in the ICU. We anticipate the need for better epidemiologic and diagnostic tools that will inform us about the true incidence of these infections and the impact of specific prevention and treatment strategies. For prevention, a VAP care bundle, nursing care and education are recommended; these strategies have been shown to decrease the health care costs and antimicrobials use, length of ICU stay, and the need of mechanical ventilation therapy (Aiken et al., 2014; Okgun Alcan et al., 2016; Nogueira et al., 2017; Jansson et al., 2019). In addition, a recent study has suggested that N-acetyl-cysteine (NAC) is safe and effective to prevent and delay the development of VAP (Sharafkhah and Abdolrazaghnejad, 2018). It’s also very important to use new diagnostic methods (such as next-generation sequencing technology, phase contrast X-ray imaging, lung ultrasonography (Bouhemad et al., 2018), and the electronic nose) and/or new biomarkers (such as phosphatidylinositol 3-kinase regulatory subunit and sarcoplasmic reticulum calcium transporting ATPase) (Jamaati et al., 2018), to find the bacteriology and its frequency of MDR pathogens and to guide more accurate and focused initial antibiotic therapy. Moreover, it is very urgent to develop new drugs for MDR pathogens because of increasing antimicrobial resistance. There will also be further exploration of optimized antibiotic pharmacokinetics (PK) and pharmacodynamics (PD), which will allow us to improve the effectiveness of the treatments of pneumonia caused by MDR organisms as well as to achieve a lower rate of adverse effects. We believe that with focus on VAP epidemiology, diagnostic methods, bacteriology, prevention, and therapy, we will see further improvement in the outcomes of our patients.

Ventilator-associated pneumonia is an important cause of morbidity and mortality in mechanically ventilated patients, and many strategies have been proposed for the prevention and treatment of this disease. Successful prevention of VAP can save on total costs and is possible using a multidisciplinary clinical and administrative approach. In addition, the early appropriate antimicrobial therapy is critical to improving clinical outcomes for patients with VAP. Unfortunately, clinician failure is common, with about 70% of patients receiving inadequate initial empiric therapy for VAP. Some new antibiotics such as tedizolid, meropenem–vaborbactam, imipenem–relebactam, ceftazidime–avibactam, ceftolozane–tazobactam, and plazomicin, are being developed for VAP to combat our increasingly resistant infecting organisms. Meanwhile, some new options and choices for the management of VAP are also being developed, including inhaled antibiotics and monoclonal antibodies. Future studies are necessary to evaluate these therapeutic strategies in the management of VAP. We hope that the present overview contributes to the prevention and control of VAP.

ML and XX conceived the general idea. XX and ML wrote the first draft. TH, JL, and ML revised the manuscript. All authors read and approved the final manuscript.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.