Microorganisms and clinical outcomes of early- and late-onset ventilator-associated pneumonia at Srinagarind Hospital, a tertiary center in Northeastern Thailand

Pneumonia is the most common hospital-acquired infection with a prevalence of approximately 22% [1, 2]. Ventilator-associated pneumonia (VAP) is pneumonia developing after 48–72 h of endotracheal intubation [3‐5]. VAP is the most common nosocomial infection, developed in about 5–40% of mechanically ventilated patients [5‐7]. Data from the International Nosocomial Infection Control Consortium (INICC) collected summary data from 50 countries including Southeast Asia during 2010–2015 indicated the VAP rate was 13.1 per 1000 mechanical ventilator (MV) days in the medical and surgical intensive care unit (ICU) [8]. Similar results of Reechaipichitkul et al. who determined that VAP rates in Srinagarind Hospital, Khon Kaen University, a tertiary-care hospital in northeastern Thailand were 13.6 and 12.6 per 1000 MV days in 2008 and 2009. This study also demonstrated that more than half of the costs of nocosomial treatment in 2008 and 2009 were the costs for hospital acquired pneumonia (HAP) and VAP, 16.8 and 17.5 million Baht [9]. Melsen et al. performed a meta-analysis and suggested that overall attributable mortality in mechanical ventilator patients from VAP was 13% [10].

VAP was categorized into early-onset VAP (EOVAP) and late-onset VAP (LOVAP) depending upon when it occurred on which days after hospitalization. The cutoff point of a range 4–7 days onset varied across the studies [11‐16]. Recent guideline for HAP and VAP management from The Infectious Disease Society of America (IDSA)/American Thoracic Society (ATS) and the International ERS/ESICM/ESCMID/ALAT use the cutoff point of 5 days after hospitalization [2, 17, 18]. It is believed that in EOVAP, the causative pathogens are not drug-resistant bacteria such as Streptococcus pneumoniae, Haemophilus influenzae, antibiotic-sensitive enteric gram-negative bacilli or methicillin-sensitive Staphylococcus aureus (MSSA). There is a greater risk that the causative pathogens in LOVAP are multi-drug resistant (MDR) such as Acinetobacter baumannii, Pseudomonas aeruginosa, methicillin-resistant S. aureus (MRSA), extended-spectrum beta-lactamase (ESBL)-producing bacteria and other gram-negative bacilli [5, 17, 19, 20]. The prevalence of MDR pathogens between EOVAP and LOVAP in several studies remained a controversy. Several studies demonstrated that EOVAP had a significantly lower prevalence of MDR pathogens [21‐23]. Subsequent studies, however, did not show a significant difference in MDR pathogens between EOVAP and LOVAP groups [11, 12, 14, 24].

Therefore, this study was conducted and aimed to compare the pathogens, clinical characteristics, treatment outcomes between EOVAP and LOVAP groups, and factors associated with hospital mortality.

A cross-sectional study between 1 January 2015 and 31 December 2017 was conducted at Srinagarind Hospital, Faculty of Medicine, Khon Kaen University, a 1466-bed tertiary care center in Northeast Thailand. In our hospital, patients who underwent mechanical ventilator received VAP bundle care as following: (1) endotracheal tube suctioning every 2 h, (2) sedation keeping Richmond Agitation Sedation Scale (RASS) of 0 to − 1, (3) oral decontamination with 0.2% chlorhexidine, (4) aspiration precaution with head elevation of 30°–45° and (5) hand hygiene either with 4% chlorhexidine soap and water or with alcohol-based hand rub. In a case of VAP development; infection control ward nurses (ICWNs) reported all patients’ data to infectious control (IC) unit system. We retrieved all VAP patient data from these recordings. The study was approved by the Human Research Ethics Committee, Khon Kaen University (approval number HE611281).

The study revealed that the most common pathogens were gram-negative bacteria. A. baumannii, K. pneumoniae, P. aeruginosa were common pathogens in both groups while S. maltophilia was increased in LOVAP. The pathogens from this study did not differ between EOVAP and LOVAP. The results of this study were similar to other tertiary centers in Thailand [27, 28]. Of these, A. baumannii, K. pneumoniae, P. aeruginosa were the common pathogens of VAP. These studies, however, did not address the causative pathogens into EOVAP and LOVAP. Three studies from different tertiary-care centers of India had results similar to our study [14, 15, 29]. A. baumannii, K. pneumonia and P. aeruginosa were common pathogens in both EOVAP and LOVAP. The pathogens of EOVAP from this study differed from pathogens mentioned in the recent guideline [17]. The results supported that empiric antibiotics should be guided by a local distribution of pathogens that are recommended by the Management of Adults with Hospital-acquired and Ventilator-associated Pneumonia in 2016 by IDSA/ATS guideline [2]. Papazian et al. suggested that microbiological confirmation is strongly recommended when considering a diagnosis of VAP and pathogens may vary depending on many factors including the duration of MV, hospital LOS, ICU LOS, previous antibiotics exposure, the occurrence of epidemic phenomena in a given ICU and local distribution of organisms [5].

Gram-positive bacteria were identified in only 2.6% and most of them were MRSA. The prevalence of drug-resistance gram-positive bacteria in this study was markedly lower as compared to the study of the pathogens of VAP in Thailand by Chittawatanarat et al., Inchai et al. and Werarak et al. [27, 28, 30]. Reechaipichitkul et al. conducted a study of the causative organisms of VAP in the same center during 2008–2009. The study indicated MRSA was responsible for 6–7% of the total causative pathogens [9]. The majority of S. aureus colonization in the respiratory tract is in the nares and throat. Chlorhexidine is a topical antiseptic, which is most active against gram-positive bacteria [31]. Our center has applied selective oral decontamination (SOD) with chlorhexidine since 2011. This might have reduced the incidence of VAP due to MRSA.

Inappropriate and delayed empiric antibiotics are associated with higher mortality in VAP patients [32‐34]. In our center, the empiric antibiotic was based on the previous local study in 2008 [9]. The study demonstrated that gram-negative bacteria were the majority of VAP causative pathogen. The three most common pathogens were A. baumannii, P. aeruginosa and K. pneumoniae. A. Baumannii mostly resisted carbapenems, cefoperazone/sulbactam, piperacillin/tazobactam but were still susceptible to colistin. P. aeruginosa resisted mostly to carbapenems but were still susceptible to ceftazidime, piperacillin/tazobactam and levofloxacin. Forty-seven percent of K. pneumoniae was ESBL producer. The carbapenems had activity against ESBL producing K. pneumoniae [9]. The purpose of differentiation of VAP into EOVAP and LOVAP was to guide empiric antibiotic treatment to cover MDR bacteria. The study found that LOVAP had a significantly higher proportion of MDR pathogens than EOVAP (p = 0.007). The results endorsed the Management of Adults with Hospital-acquired and Ventilator-associated Pneumonia in 2016 by IDSA/ATS suggested that VAP developed after 5 days of hospitalization had a greater risk of MDR pathogen presence than VAP developed earlier [2]. Therefore empiric broad-spectrum antibiotics against MDR pathogens were recommended for LOVAP.

Furthermore, this current study demonstrated that LOVAP had significantly longer MV days, ICU LOS, and hospital LOS than EOVAP. The hospital mortality was significantly greater in LOVAP (35.1% vs 16.7%, p = 0.02). These worse outcomes of LOVAP were also observed by Khan et al. [24]. The implementation of VAP prevention might reduce the cost of hospitalization and unnecessary mortality, especially in LOVAP [35].

A meta-analysis from Melsen et al. suggested that overall attributable mortality from VAP was 13% and the higher mortality were found in surgical patients, acute physiology and chronic health evaluation (APACHE) score of 20–29 and SAPS II score of 35–58 [10]. Bekaert et al.revealed the SAPS II score of 28–40 was significantly greatest associated with ICU death per additional day since the onset VAP [36]. Similar to our study, on stepwise backward multivariate analysis, a SAPII score ≥ 40 was significantly associated with hospital mortality of VAP patients.

The strengths of this study were that the recorded data were complete because VAP was under regular surveillance of our institute by ICWNs and confirmed by the IC unit.

This study had some limitations. First, the sample size is small, especially in EOVAP. This affected the statistical power. Second, this was a retrospective study, some data might be difficult to determine such as previous antibiotic exposure within 90 days, prior hospitalization preceding 90 days. These factors are associated with MDR pathogen infections [2, 37]. Third, the results of this study were unable to be applied to VAP in immunocompromised patients. Fourth, this study was from a single tertiary center, which had some limitations for the application in general hospitals. Pathogens and resistance patterns could vary between hospitals, regions and countries [2]. The local pathogens and pattern resistance of each hospital were the crucial factors for the selection of initial empiric antibiotics.

In conclusion, LOVAP was significantly higher MDR pathogens, MV days, ICU LOS, hospital LOS and hospital mortality than EOVAP. A broad-spectrum antibiotic to cover MDR pathogens should be considered in LOVAP. The factor associated with hospital mortality of VAP was a SAPII score ≥ 40.