Clinical characteristics and outcomes of neonates with polymicrobial ventilator-associated pneumonia in the intensive care unit

Ventilator-associated pneumonia (VAP) accounts for one-fifth to one-fourth of healthcare associated infections (HAIs) in the neonatal intensive care unit (NICU), and is very difficult to have the confirmed diagnosis [1, 2]. VAP is confirmed in approximately 15–20% of critically ill/premature neonates who have intubation for more than 48 h [1‐4], and the reported mortality rate was around 9.3–16.4% in recent studies [5‐7]. Although the causative pathogens are associated with the hospital course and duration of mechanical ventilation, gram-negative bacilli account for the majority of VAP in the NICU [6‐9]. VAP is associated with significant morbidity due to prolonged requirement of ventilation and an increased risk of subsequent another episode of HAI [8, 9]. In addition, increased hospital costs and resource use are also noted in neonates with VAP [9‐11].

Previous studies in both adult and pediatric ICUs found 25–40% of all VAP episodes are caused by more than one microorganism [9, 12‐14]. Polymicrobial VAP is supposed to cause therapeutic challenge, especially when neonates have previous broad-spectrum antibiotic exposure or endotracheal colonization of multidrug-resistant (MDR) pathogens [15, 16]. Currently no relevant studies have been conducted to investigate the demographics and clinical outcomes of neonates developing polymicrobial lung infection. In addition, previous studies are limited by retrospective design and sometimes uncertain cases of colonization or true infection [1, 2, 9]. Therefore, to ascertain the epidemiologic aspects and clinical features of polymicrobial VAP in neonates, we conducted a prospective study with consecutive neonates receiving intubation for ≥ 48 h, in whom VAP was confirmed by strict diagnostic criteria of the Centers for Disease Control and Prevention (CDC) [1, 17].

The strict diagnostic criteria of CDC neonatal VAP were applied in this study to investigate the clinical and epidemiological features of polymicrobial VAP in the NICU. We found that 25.4% of neonatal VAP episodes were polymicrobial VAP episodes, which were more likely to occur in neonates with long-term intubation and underlying chronic comorbidities, especially BPD. Most of the clinical characteristics were not statistically different between polymicrobial versus monomicrobial VAP episodes. However, MDR pathogens (particularly Pseudomonas aeruginosa or MRSA) were more likely to be involved in polymicrobial VAP episodes than in monomicrobial VAP episodes, which has never been identified in previous studies [2, 4, 27, 28]. We found that the severity of VAP and underlying chronic comorbidities were independently associated with treatment outcomes.

We found the percentage of MDR pathogens in our series were significantly higher than previous studies [1, 7, 27, 28], especially in polymicrobial VAP cases and neonates with multiple chronic comorbidities. In our cohort, a lot of the E coli and K. pneumonia strains from endotracheal aspirates were MDR pathogens, but most Pseudomonas aeruginosa strains were surprisingly susceptible to gentamicin and/or third-generation cephalosporin. This is in contrast to our previous studies of MDR gram-negative bacteremia in the NICU, but is consistent with previous studies of adult VAP [13, 29, 30]. These antibiotic-resistant pathogens were selected by previous empiric and therapeutic antibiotics, because vancomycin or teicoplanin plus gentamicin or third-generation cephalosporin is frequently prescribed in our NICU for neonatal late-onset sepsis or catheter-related bloodstream infections [31, 32]. Our previous studies have documented that previous antibiotic exposure, especially broad-spectrum antibiotics, is significantly associated with emergence of MDR pathogens [23, 29]. Therefore, MDR gram-negative bacilli and MRSA are more likely to be the long-term colonized pathogen in the endotracheal tube after antibiotic selection and account for the majority of neonatal VAP [33]. Because emergence of MDR pathogens has been the major issue in the ICU, we suggest that NICU surveillance and more epidemiological data may be required for better development of optimized therapeutic strategies, which can be guided by this information and the patient’s risk factors for MDR pathogens [32, 34, 35].

Both Infectious Diseases Society of America and American Academy of Pediatrics suggest that broad-spectrum antibiotics can be considered only in high risk patients with severe sepsis or septic shock, or in those with a high risk of clinical deterioration or multi-organ failure [36, 37]. In our cohort, initial broad-spectrum antibiotics were prescribed in 75.4% episodes of these VAP episodes because these patients were considered to have high risks of infection caused by MDR pathogens, including long-term hospitalization, previous antibiotic exposure, presence of CVC in situ, and multiple comorbidities. In addition, clinicians cannot take the risk of clinical deterioration or progression to severe sepsis or septic shock since 86 (36.4%) of the VAP episodes occurred in neonates on HFOV treatment and approximately three-fourth of these VAP episodes had a high NTISS score > 25, indicating the high severity of illness. Although we found that inappropriate initial antibiotic therapy did not significantly contribute to worse outcomes, it was only 31.4% of these cases and we cannot underestimate the importance of initial appropriate treatment. Additionally, the influences of MDR pathogens and polymicrobial VAP episodes may also be masked by the high percentage of empirical broad-spectrum antibiotic therapy. Overuse of broad-spectrum antibiotics has now become as an important issue and contributed to emergence of MDR pathogens, which require more prescription of broad-spectrum antibiotics and create a vicious circle [32, 38, 39].

No data are available regarding the clinical characteristics and therapeutic outcomes of neonates with polymicrobial VAP in the literature. Polymicrobial VAP is supposed to cause therapeutic challenge and increased use of antibiotics in the NICU because all isolated microorganisms have to be covered. In this series, only more modification of therapeutic antibiotics was documented. In adult studies of nosocomial VAP, the mortality rate between monomicrobial and polymicrobial VAP episodes were comparable [13, 40]. We found neonatal VAP rarely progressed to systemic bacteremia or have rapid deterioration, even in cases of inappropriate initial antibiotic therapy. This accounts for the lower attributable mortality rate of neonatal VAP when compared with neonatal bacteremia or adult VAP [29, 40]. Therefore, it is worth reconsidering the necessity of using broad-spectrum antibiotics to treat neonates with VAP that without concurrent bacteremia.

The reported incidence rate of neonatal VAP is 2.7–10.9 cases/1000 mechanical ventilation days in developed countries and 32–37.2 cases/1000 ventilator days in developing countries [1‐3, 7]. The incidence rate of VAP in this cohort was underestimate because we did not count the repeated episodes or recurrent episodes of VAP. In this study, nonquantitative cultures of the endotracheal aspirate were used for diagnoses of neonatal VAP, which is commonly used in clinical practice in the NICU because quantitative culture of the BAL fluid is often unavailable in extremely preterm or low birth weight neonates [41]. The incidence rate of VAP in our cohort was comparable with previous studies and most of them applied similar diagnostic criteria for neonatal VAP [1, 3, 7]. Therefore, it is clinically applicable to consider all potential microorganisms regardless of the number of CFU per milliliter as the causative pathogens of VAP [1, 9].

There are some limitations in this study. Although we applied the updated and strict diagnostic criteria and prospectively followed these cases, this was an observational, non-interventional study and we cannot conclude whether therapeutic policies will affect the outcomes or not. Therefore, a future randomized controlled trial is required to reach clear conclusion regarding this issue. A high proportion of VAP cases were treated with broad-spectrum antibiotics in our tertiary level NICUS, which may be due to higher illness severity and more chronic comorbidities in our cohort. Therefore, we cannot find significant impacts of MDR pathogens or polymicrobial VAP on the outcomes. This is a single center study from tertiary level medical center and these results are less applicable to nonteaching hospitals. In addition, the sample size of this study is only moderate and we did not enroll the repeated or recurrent episodes of VAP for analysis. However, the prospective study design, strict and uniform criteria of neonatal VAP, close observation and complete follow-up of all cases without any missing data are the major strengths of this study.

In conclusion, polymicrobial VAP is not uncommon in the NICU, and commonly occurred in extremely preterm neonates with prolonged ventilation and underlying bronchopulmonary dysplasia. Although the therapeutic responses and outcomes were not significantly worse when compared with monomicrobial VAP, polymicrobial VAP episodes were more often associated with MDR pathogens and requirement of antibiotic modification. Overuse of broad-spectrum antibiotics has emerged as an important issue in the NICU, so it is urgently needed to consider antibiotic stewardship programs for neonatal VAP. Although neonatal VAP is not associated with a high attributable mortality rate, significant morbidity is noted in neonates with VAP, especially those with concurrent bacteremia, higher severity of illness and underlying neurological sequelae.