Abstract
Ventilator-associated pneumonia (VAP) is one of the most common and serious infections in hospitalized patients. VAP is associated with worse outcomes and significant morbidity and mortality worldwide. Our primary goal in this study was to identify the VAP pathogen with its distribution characteristics, clarify risk factors, prognosis, and outcomes, and help reduce associated morbidity and mortality. This retrospective observational study was conducted between June 2019 and June 2022 in 3 general intensive care units of a training and research hospital. Data on demographic, clinical and laboratory parameters were collected retrospectively from medical cards and electronic records. A total of 204 patients were diagnosed with VAP caused by Gram-negative microorganisms. Chronic renal failure (RF) and neurological diseases were significantly associated with mortality (P = .01, P = .023). The duration of mechanical ventilation before VAP and the duration of mechanical ventilation were significantly longer in survivors compared to non-survivors. The number of patients with early VAP was significantly higher, and the days of VAP were shorter in the non-survivors compared to the survivors (P = .006, P = .016). The number of VAP episodes (P = .0001), the presence of RF, acute respiratory distress syndrome, bacteremia, and sepsis before VAP (<48 hours) were associated with mortality. Intensive care unit and the length of hospital stay were significantly shorter in non-survivors than in survivors (P = .0003, P = .0001). Administration of monotherapy, inadequate empirical antibiotic therapy, inadequate antibiotic therapy (P = .004, P = .002, and P = .0006), persistence of the pathogen (P = .0001), C-reactive protein and procalcitonin levels (P = .002, P = .041) were associated with mortality. The presence of neurological diseases and RF was associated with a greater likelihood of mortality in patients with VAP. As risk factors, early-onset VAP, presence of RF–acute respiratory distress syndrome–bacteremia–sepsis 48 hours before VAP, organ failure, need for hemodialysis, shock and the persistence of the pathogen increased the risk of mortality.
Keywords: Gram-negative microorganisms, mortality, multidrug-resistant pathogens, prognosis, ventilator-associated pneumonia
1. Introduction
Healthcare-associated infections are nosocomially acquired infections that are typically not present or might be incubating at the time of admission. The infections are closely monitored by agencies such as the National Healthcare Safety Network of the Center for Disease Control and Prevention.[1] Over the last few decades, the prevalence of healthcare-associated infections has been linked to a variety of factors, including patient risk factors such as immunosuppression, older age, length of stay (LOS) in the hospital, multiple underlying comorbidities, frequent visits to healthcare facilities, mechanical ventilatory support, recent invasive procedures, indwelling devices, and stay in an intensive care unit (ICU), as well as overuse of antibiotics and multidrug-resistant microorganisms (MDR).[2]
Ventilator-associated pneumonia (VAP) is one of the most common and serious infections occurring in hospitalized patients.[3–5] Based on the guidelines from both the Infectious Disease Society of America and the American Thoracic Society, the definitions of pneumonia have been redefined. According to Infectious Disease Society of America, VAP is defined as “pneumonia that develops more than 48 to 72 hours after endotracheal intubation.”[5]
VAP is linked to poorer outcomes and significant morbidity and mortality worldwide.[6] Data regarding the incidence and prevalence of VAP are variable because of confounding factors related to patient comorbidities. In patients with VAP, there is a 24% to 50% mortality rate, which increases to 76% if infection is caused by MDR pathogens.[7] In different studies, various estimates have proposed that the incidence of VAP is about 2 to 16 episodes per 1000 ventilator days, with an attributable mortality of 3% to 17%.[8] The major concern in treating VAP is the high prevalence of MDR in the implicated organisms isolated from such patients.
MDR pathogens are also a significant cause of infections in hospitals, particularly in the ICU.[9] Infections with MDR organisms are associated with an increase in the LOS, mortality indicators, and increased costs of care.[10] Antibiotic resistance has been particularly problematic among the common bacterial pathogens associated with VAP, particularly Enterobacterales and nonfermenting Gram-negative bacteria (GNB). The mortality rate for VAP ranges between 27% and 76%. Pseudomonas and Acinetobacter pneumonia are associated with higher mortality rates than those associated with other organisms. Studies have consistently shown that a delay in starting appropriate and adequately dosed antibiotic therapy increases the mortality rate.[11] Pathogens that frequently cause VAP in ICUs include potential extremely drug-resistant (XDR) GNB such as Escherichia coli (E coli), Klebsiella pneumoniae (K pneumoniae), Pseudomonas aeruginosa (P aeruginosa), and Acinetobacter baumannii (A baumannii).[12] Moreover, the mortality of VAP caused by XDR-GN pathogens may be higher than 70%[13] and has become more common in recent years.
Our aim in this study was to determine the pathogen of VAP with distribution characteristics, clarify the risk factors, prognosis, and outcomes to help reduce associated morbidity and mortality.
2. Materials and methods
2.1. Study design
This retrospective observational study was conducted between June 2019 and June 2022 in 3 general ICUs of a training and research hospital. The Institutional Research Ethics Committee approved study protocol number 2022/156.
2.2. Patients
The study included all intubated patients undergoing intensive care follow-up (n = 840). The exclusion criteria were as follows: patients without a diagnosis of VAP (n = 551); patients in whom VAP was caused by pathogens other than GNB (n = 85). At last, 204 patients had been enrolled in the study. Figure 1 shows the flow chart of the study.
Figure 1.
Flow chart of the study. CNS = coagulase-negative staphylococcus, MRSA = methicillin-resistant Staphylococcus aureus, VAP = ventilator-associated pneumonia.
2.3. Data collection
Data on the following demographic, clinical, and laboratory parameters were retrospectively collected from medical cards and electronic records: age, gender, comorbid diseases, severity scores as determined by the Acute Physiology and Chronic Health Evaluation II, Sequential Organ Failure Assessment (SOFA) Score, type of patient and where they were admitted to the ICU, day of intubation and mechanical ventilation (MV) duration, length of ICU and hospital stay, time of diagnosis, pathogens, the presence of colonization for pathogens, resistance patterns of microorganisms, the absence or presence of bacteremia, sepsis, acute respiratory distress syndrome (ARDS), and renal failure (RF) within the 48 hours before and/or after VAP episode diagnosis, antibiotic treatment, microbiological response to antibiotics, and laboratory data on the first day of VAP were collected. The following clinical outcome data were collected: associated organ failures (shock, ARDS, and RF), vasopressor requirement, and 30-day mortality.
Antibiotic therapy was evaluated as empirical, adequate, or inadequate depending on whether the causative pathogens were susceptible or resistant to prescribed antibiotics. We also found empirical antimicrobial therapy inadequate if other co-pathogens were not susceptible to drugs.
2.4. Definitions
In patients who received MV for at least 48 hours, VAP was diagnosed when the following criteria were met: – new or progressive permanent infiltration on chest radiograph; – new-onset fever, purulent endotracheal aspirate, leukocytosis or leukopenia, increased minute ventilation, decreased arterial oxygenation, increased vasopressor infusion requirement (it is difficult to maintain blood pressure when at least 2 of the above criteria are met); – positive quantitative or qualitative culture from broncho-alveolar lavage (BAL), protected distal specimen (PDS), or endotracheal aspirate (ETA).[5]
Early-onset VAP was defined as VAP occurring within the first 4 days of mechanical ventilation.[14]
A “colonization” was defined as a positive bacterial culture on a respiratory sample without any clinical signs of pneumonia or the start of antibiotic treatment.
Antimicrobial resistance was defined according to terminology for antimicrobial-resistant GNB that had been developed by the United States Centers for Disease Control and Prevention, and the European Centre for Disease Prevention and Control. MDR refers to acquired nonsusceptibility to at least 1 agent in 3 different antimicrobial classes. XDR refers to nonsusceptibility to at least 1 agent in all but 2 antimicrobial classes. Pandrug resistance (PDR) refers to nonsusceptibility to all antimicrobial agents that can be used for treatment.[15]
Bacteremia is defined as at least 1 positive blood culture caused by the organism causing pneumonia.
Empirical antibiotic therapy was considered when an antibiotic regimen was given within 24 hours of the sample for VAP diagnosis and before susceptibility was known. Antimicrobial therapy was considered adequate when the microorganism isolate proved susceptible to at least one of the prescribed antimicrobial drugs.[16]
Microbiological outcomes were categorized as follows: (i) eradication: no growth of the pathogen in the final culture of specimens throughout the entire hospitalization; (ii) persistence of pathogen: persistent growth of the relevant pathogen regardless of the clinical outcome of the infection; and (iii) recurrence of the pathogen: regrowth of the same pathogen independent of the clinical outcome of the infection.
The main outcome was in-hospital mortality at day 30 (30-day mortality).
2.5. Statistical analysis
Homogenized distribution was determined by analyzing the data with the Kolmogorov–Smirnov test within the group. Intergroup (independent variable) statistical analysis was performed with chi-square test, and 95% CI and P < .05 were considered statistically significant.
3. Results
3.1. Patient characteristics
A total of 204 patients were diagnosed with VAP caused by GNB. Patient characteristics at the time of diagnosis are summarized in Table 1. The patients were 61.2% male, with a mean age of 67.7 (15.4). SOFA scores were higher in the death group than in the survivor group (P = .011). 7.3% of the patients were trauma patients. Of the 92.7% of patients without trauma, 76.4% were medical patients, and 16.1% were surgical patients. 53.9% of the patients were admitted to the ICU from the emergency department, 33.8% from the other ICUs, 7.3% from the internal service, and 4.9% from the surgical service. 82.8% of the patients had comorbid diseases. The most frequently encountered comorbidities were cardiac diseases (31.3%), hypertension hypertension (29.9%), diabetes mellitus (29.4%), and neurological diseases (28.9%), respectively. Chronic renal failure (CRF) and neurological diseases were significantly associated with mortality in non-survivors compared to survivors (P = .017, P = .023). The duration of mechanical ventilation before VAP and the duration of mechanical ventilation were significantly longer in survivors compared to non-survivors. The number of patients with early VAP was significantly higher, and the days of VAP were shorter in the non-survivors compared to the survivors (P = .006, P = .016). The number of VAP episodes were associated with mortality (P = .0001). The presence of RF, ARDS, bacteremia, and sepsis before VAP (<48 hours) were associated with mortality.
Table 1.
Demographic and clinical characteristics of patients with VAP.
| Variables | All (n = 204) | Death (n = 125) | Survived (n = 79) | P-value |
|---|---|---|---|---|
| Male (%) | 125 (61.2%) | 79 (63.2%) | 46 (58.2%) | .140 |
| Female (%) | 79 (38.8%) | 46 (36.8%) | 33 (41.7%) | .096 |
| Age in years (SD) | 67.7 (15.4) | 68.0 (14.7) | 67.1 (16.5) | .641 |
| APACHE II (SD) | 36.1 (21.2) | 39.5 (22.1) | 30.6 (18.5) | .091 |
| SOFA | 9.72 (10) | 9.93 (10) | 8.04 (7.5) | .011 |
| Type of patients, n (%) | ||||
| Non-trauma | 189 (92.7%) | 117 (61.9%) | 72 (38.1%) | .084 |
| Medical diseases | 156 (76.4%) | 93 (74.4%) | 63 (79.7%) | .078 |
| Surgical diseases | 33 (16.1) | 24 (19.2%) | 9 (11.3%) | .063 |
| Trauma | 15 (7.3%) | 8 (6.4%) | 7 (8.8%) | .085 |
| Admission to ICU | ||||
| Emergency | 110 (53.9) | 67 (53.6%) | 43 (54.4%) | .104 |
| ICU of another hospital | 69 (33.8%9 | 42 (33.6%) | 27 (34.1%) | .621 |
| Surgical wards | 10 (4.9%) | 6 (4.8%) | 4 (5%) | .361 |
| Internal medicine wards | 15 (7.3%) | 10 (8%) | 5 (6.3%) | .241 |
| Comorbidities, n (%) | 169 (82.8%) | 103 (82.4%) | 66 (83.5%) | |
| Hypertension | 61 (29.9%) | 37 (29.6%) | 24 (30.3%) | .076 |
| Diabetes mellitus | 60 (29.4%) | 33 (26.4%) | 27 (34.1%) | .092 |
| Cardiac diseases | 64 (31.3%) | 39 (31.2%) | 25 (31.6%) | .084 |
| Chronic renal failure | 34 (16.6%) | 27 (21.6%) | 7 (8.8%) | .017 |
| Neurological diseases | 59 (28.9%) | 29 (23.2%) | 30 (37.9%) | .023 |
| COPD | 30 (14.7%) | 22 (17.6%) | 8 (10.1%) | .065 |
| Malignancy | 24 (11.7%) | 18 (14.4%) | 6 (7.5%) | .071 |
| Clinical characteristics | ||||
| Immun deficiency | 9 (4.4%) | 8 (6.4%) | 1 (1.2%) | .082 |
| Malnutrition | 23 (11.2%) | 14 (11.2%) | 9 (11.3%) | .061 |
| LOS before ICU (<48 h) | 119 (58.3%) | 76 (60%) | 43 (55.7%) | .071 |
| LOS before ICU (>48 h) | 85 (41.6%) | 50 (40%) | 35 (44.3%) | .069 |
| Days of intubation (SD) | 4.52 (8.14) | 4.2 (8.1) | 4.9 (8.3) | .076 |
| Intubation times (SD) | 36 (37.2) | 18.2 (14.4) | 64 (44.5) | .0001 |
| Tracheostomy | 57 (27.9%) | 18 (14.4%) | 39 (49.3%) | .0003 |
| Extubation | 24 (11.7%) | 5 (4%) | 19 (24%) | .003 |
| ICU LOS (SD) | 41.5 (38.8) | 22.5 (16.8) | 71.4 (44.7) | .0003 |
| Hospital LOS (SD) | 49.1 (41.9) | 28.8 (22.4) | 81.3 (45.5) | .0001 |
| Culture negativity before ICU | 176 (86.2%) | 109 (87.2%) | 67 (84.8%) | .097 |
| MV times without VAP (SD) | 11.1 (10.3) | 10.2 (10.5) | 12.7 (9.8) | .008 |
| Early VAP | 64 (31.3%) | 48 (38.4%) | 16 (20.2%) | .006 |
| Days of VAP (SD) | 15.1 (12.7) | 13.9 (13.8) | 16.7 (10.5) | .016 |
| Number of attacks of VAP (SD) | 1.4 (0.9) | 1.1 (0.2) | 2 (1.1) | .0001 |
| CRF before VAP (<48 h) | 69 (33.8%) | 51 (40.8%) | 18 (22.7%) | .007 |
| ARDS before VAP (<48 h) | 19 (9.3%) | 17 (13.6%) | 2 (2.5%) | .008 |
| Bacteremia before VAP (<48 h) | 50 (24.5%) | 38 (30.4%) | 12 (15.1%) | .013 |
| Sepsis before VAP (<48 h) | 121 (59.3%) | 82 (65.6%) | 39 (49.3%) | .021 |
| Use of vasopressor | 161 (78.9%) | 107 (85.6%) | 54 (68.3%) | .003 |
| Dialysis | 55 (26.9%) | 40 (32%) | 15 (18.9%) | .087 |
| Shock | 116 (56.8%) | 83 (66.4%) | 33 (41.7%) | .0005 |
| ARDS | 26 (12.7%) | 23 (18.4%) | 3 (3.8%) | .0002 |
| Organ failure | 82 (40.2%) | 59 (47.2%) | 23 (29.1%) | .010 |
| Type of bacterium | ||||
| Acinetobacter baumannii | 125 (61.2%) | 82 (65.6%) | 43 (54.4%) | .085 |
| Klebsiella pneumoniae | 30 (14.7%) | 16 (12.8%) | 14 (17.7%) | .104 |
| Pseudomonas aeruginosa | 8 (3.9%) | 5 (4%) | 3 (3.8%) | .098 |
| Escherichia coli | 15 (7.3%) | 9 (7.2%) | 6 (7.5%) | .083 |
| Polymicrobial | 17 (8.3%) | 10 (8%) | 7 (8.8%) | .091 |
| Monomicrobial | 187 (91.7%) | 115 (56,4%) | 72 (35,2%) | .075 |
| Others | 9 (4.4%) | 3 (2.4%) | 6 (7.5%) | .078 |
| Antibiotic susceptibility, n (%) | ||||
| Sensitive | 14 (6.8%) | 11 (8.8%) | 3 (3.8%) | .085 |
| MDR | 40 (19.6%) | 20 (16%) | 20 (25.3%) | .093 |
| XDR | 150 (73.5%) | 94 (75.2%) | 56 (70.8%) | .087 |
| Antibiotic treatment | ||||
| Sole antibiotic | 62 (30.3%) | 47 (37.6%) | 15 (18.9%) | .004 |
| Combined antibiotic | 142 (69.7%) | 78 (62.4) | 64 (81%) | .091 |
| Empirical antibiotic | 51 (25%) | 26 (20.8%) | 25 (31.6%) | .081 |
| Empirical + insufficient antibiotic | 26 (12.8%) | 23 (18.4%) | 3 (3.8%) | .002 |
| Insufficient antibiotic | 11 (5.3%) | 11 (8.8%) | 0 (0%) | .0006 |
| Causative + insufficient antibiotic | 7 (3.4%) | 5 (4%) | 2 (2.5%) | .087 |
| Antibiotic for the causative | 109 (53.5%) | 60 (48%) | 49 (62%) | .050 |
| Response to treatment | ||||
| Persistent | 164 (80.3%) | 121 (96.8%) | 43 (54.4%) | .0001 |
| Eradication | 40 (19.6%) | 4 (3.2%) | 36 (45.5%) | .093 |
Statistically significant values are indicated in bold.
APACHE II = Acute Physiology And Chronic Health Evaluation II, ARDS = acute respiratory distress syndrome, COPD = chronic obstructive pulmonary disease, ICU = intensive care unit, LOS = length of stay, MDR = multidrug-resistant, MV = mechanically ventilation, RF = renal failure, SOFA = Sequential Organ Failure Assessment Score, VAP = ventilator-associated pneumonia, XDR = extensively drug-resistant.
3.2. Patient outcomes
Vasopressor requirements, shock, ARDS, and organ failure were more common in the non-survivors than in the survivors. ICU and hospital stay (LOS) were significantly shorter in non-survivors than in survivors (P = .0003, P = .0001).
3.3. Pathogens of VAP
Of the GNB, the first 3 most common organisms were A baumannii (61.2% of all VAP and mortality, 65.6%), K pneumonia (14.2% of all VAP/mortality 12.8%), and E coli (7.3% of all VAP/mortality 7.2%). No differences were observed by the microorganisms and antibiotic susceptibility of microorganisms between survivors and non-survivors. Figure 2 demonstrates the proportion of drug susceptibility patterns for each organism.
Figure 2.
Percentage of drug susceptibility patterns for each organism. Numbers represent the number of patients; susceptible means susceptible to all antimicrobial agents in 4 patients infected with Serratia (2), Proteus mirabilis (1), Enterobacter (1); multidrug-resistant in 4 patient infected with Serratia (2), Proteus mirabilis (1), Enterobacter (1), Aeromanas (1) and extensively drug-resistant in 1 patients infected with Pantoea. (1). MDR = multidrug-resistant; XDR = extensively drug-resistant.
3.4. Antibiotic treatment
Administration of monotherapy, inadequate empirical antibiotic therapy, inadequate antibiotic therapy was associated with mortality (P = .004, P = .002, P = .0006). Persistence of the pathogen was associated with mortality (P = .0001).
3.5. Prognostic factors
Table 2 shows the laboratory findings of the patients with VAP. C-reactive protein and procalcitonin levels were associated with mortality (P = .002, P = .041).
Table 2.
Laboratory findings of the patients with VAP.
| Laboratory characteristics | All | Death | Survived | P-value |
|---|---|---|---|---|
| (n = 204) | (n = 125) | (n = 79) | ||
| WBC | 4.48 (1.1–42.6) | 4.52 (2.4–42.6) | 4.12 (1.1–8.84) | .126 |
| Nötrofil | 4.73 (0–32.4) | 4.87 (4.1–32.4) | 3.65 (0–6.23) | .072 |
| Lenfosit | 0.61 (0–12.4) | 0.64 (0–12.4) | 0.59 (0.14–9.6) | .984 |
| Monosit | 0.48 (0–10.1) | 0.52 (0–9.6) | 0.56 (0.2–10.1) | .863 |
| CRP | 162 (2–413) | 167 (2–413) | 158.6 (11–321) | .002 |
| PCT | 2.47 (0.02–14) | 2.43 (0.3–14) | 1.62 (0.02–1.93) | .041 |
| AST | 71.4 (8–160) | 76.2 (20–160) | 65.2 (8–103) | 1.234 |
| ALT | 66.5 (2–260) | 71.9 (6.2–260) | 49.6 (2–143) | .931 |
| Total bilüribin | 1.0 (0.06–5.8) | 1.0 (0.08–5.8) | 0.96 (0.06–4.86) | .887 |
| PLT | 222.7 (7–674) | 215.7 (140–674) | 268.4 (7–581) | 1.024 |
| BUN | 84.6 (2–194) | 89.5 (6–194) | 76.5 (2–185) | .976 |
| CRE | 1.03 (0.02–8) | 1.07 (0.04–8) | 1.06 (0.02–3.62) | 1.341 |
| GFR | 71.3 (5–285) | 69.3 (5–265) | 86.5 (30–285) | 1.003 |
| Na | 141.7 (123–165) | 141.1 (126–165) | 143.2 (123–158) | .962 |
| K | 4.09 (2.29–5.54) | 4.56 (2.36–5.54) | 4.82 (2.29–5.01) | .879 |
| pH | 7.44 (7.30–7.69) | 7.01 (7.30–7.51) | 7.38 (7.33–7.69) | .065 |
| pCO2 | 42.7 (20–99) | 51.2 (36–99) | 40.6 (20–83) | .939 |
| pO2 | 79.4 (51–122) | 75.2 (51–103) | 83.2 (70.4–122) | .782 |
| SO2 | 94.3 (85–99) | 88.6 (85–93) | 95.2 (93–99) | .795 |
| HCO3 | 28 (11–42) | 26.4 (16–42) | 27.5 (11–40) | .692 |
| Laktat | 2.69 (0.7–20) | 2.81 (0.9–20) | 2.74 (0.7–19.4) | .871 |
Statistically significant values are indicated in bold.
BUN = blood urea nitrogen, eGFR = estimated glomerular filtration rate, HCO3 = bicarbonate, PCO2 = partial pressure of carbon dioxide, Ph = potential of hydrogen, PO2 = partial pressure of oxygen, SpO2 = oxygen saturation, WBC = white blood cell count.
For the risk factor analysis in Table 3, the significantly increased hazard ratio (HR) parameters were CRF (HR 2.83; P = .01), neurological diseases (HR 1.49; P = .02), hemodialysis requirement (HR 2.01; P = .04), shock (HR 2.75; P = .0005), organ failure (HR 2.17; P = .01), early-onset VAP (HR 2.45; P = .006), renal failure before VAP (<48 hours) (HR 2.33; P = .008), ARDS before VAP (<48 hours) (HR 6.06; P = .008), bacteremia before VAP (<48 hours) (HR 2.43; P = .01), sepsis before VAP (<48 hours) (HR 1.95; P = .04), persistence of pathogen (HR 24.3; P = .0001). Immunodeficiency (HR 5.33; P = .08) trended toward a significant increase in HR. In contrast the significantly decreased HR parameter was colonization before VAP (HR 0.40; P = .01). The other microorganisms (Serratia, Proteus mirabilis, Enterobacter, Aeromanas, and Pantoea) (HR 0.29; P = .07) had a trend toward decreased HR.
Table 3.
Hazard ratio of mortality following VAP.
| Multivariate data analysis | Hazard ratio | P-value |
|---|---|---|
| (95% CI) | ||
| Male | 1.23 (0.69–2.19) | .47 |
| Age | 1.02 (0.76–1.41) | .32 |
| Comorbidity | 0.92 (0.43–1.95) | .83 |
| Hypertension | 0.96 (0.52–1.78) | .90 |
| Diabetes mellitus | 0.69 (0.37–1.27) | .23 |
| Cardiac diseases | 0.98 (0.53–1.79) | .94 |
| Chronic renal failure | 2.83 (1.16–6.86) | .01 |
| Neurological diseases | 0.49 (0.26–0.91) | .02 |
| COPD | 1.89 (0.79–4.49) | .14 |
| Malignancy | 2.04 (0.77–5.40) | .14 |
| Immun deficiency | 5.33 (0.65–43.4) | .08 |
| Malnutrition | 0.98 (0.40–2.38) | .96 |
| Secondary infection | 1.60 (0.30–8.47) | .57 |
| Dialysis | 2.01 (1.02–3.94) | .04 |
| Shock | 2.75 (1.54–4.92) | .0005 |
| Organ failure | 2.17 (1.19–3.96) | .01 |
| LOS before ICU (<48 h) | 1.19 (0.67–2.11) | .54 |
| LOS before ICU (>48 h) | 0.83 (0.47–1.48) | .56 |
| Colony before VAP | 0.40 (0.19–0.83) | .01 |
| Early VAP | 2.45 (1.27–4.73) | .006 |
| CRF before VAP (<48 h) | 2.33 (1.23–4.40) | .008 |
| ARDS before VAP (<48 h) | 6.06 (1.36–26.9) | .008 |
| Bacteremia before VAP (<48 h) | 2.43 (1.18–5.02) | .01 |
| Sepsis before VAP (<48 h) | 1.95 (1.10–3.47) | .02 |
| Type of bacterium | ||
| Acinetobacter baumannii | 1.59 (0.89–2.84) | .11 |
| Klebsiella pneumoniae | 0.68 (0.31–1.48) | .33 |
| Pseudomonas aeruginosa | 1.05 (0.24–4.54) | .94 |
| Escherichia coli | 0.94 (0.32–2.76) | .91 |
| Polymicrobial | 0.89 (0.32–2.45) | .82 |
| Others | 0.29 (0.07–1.23) | .07 |
| Sensitive | 2.44 (0.66–9.05) | .16 |
| MDR | 0.56 (0.28–1.12) | .10 |
| XDR | 1.24 (0.66–2.34) | .49 |
| Response to treatment | ||
| Persistent | 24.3 (8.51–75.3) | .0001 |
| Eradication | 0.03 (0.01–0.11) | .12 |
Statistically significant values are indicated in bold.
ARDS = acute respiratory distress syndrome, COPD = chronic obstructive pulmonary disease, ICU = intensive care unit, LOS = length of stay, MDR = multidrug-resistant, RF = renal failure, VAP = ventilator-associated pneumonia, XDR = extensively drug-resistant.
4. Discussion
VAP is a common cause of increased morbidity and mortality in patients hospitalized in the ICU.[17] The total cost of VAP infections in developing countries is about 5 times higher than for other diseases.[18] This study aimed to identify the pathogen of VAP with distribution characteristics, risk factors, prognosis, and outcomes of VAP patients in general ICUs in Turkey.
Of 204 VAP patients in ICU included in the study. Previous studies have found the incidence of VAP cases to be quite significant in male patients compared to females, or the majority of males among patients with suspected VAP.[18,19] Similarly to previous studies, males composed of the majority of VAP patients in our study as well. Majumdar and Padiglione have shown in their studies that elderly patients have a higher risk of developing VAP, whereas Shah et al found that younger age is an independent predictor for the development of VAP in MV patients.[20,21] In our study, the elderly were the majority in VAP patients, and the mean age was 67.7 years. We think that the reason for the difference in these findings in the studies may be related to the etiology of hospitalization of the patients. Young patients are intubated for surgical reasons (trauma or elective surgeries) rather than medical reasons. 2010 Cook et al showed that the probability of VAP development was 4 times higher in trauma patients than in non-trauma patients (OR 3.68, 95% CI 2.26–5.99, P = .001), and the prevalence of younger patients was higher in trauma patients.[22] In our study, the reason for the admission of the majority of VAP cases was medical problems, 92.7% of the patients were admitted to the ICU due to non-trauma and 76.4% of them due to medical illness, as in previous studies.[23] In previous studies it was shown that comorbidities, such as neurological, renal, hepatic diseases, malignancy, and immuno compromised hosts were prognostic factors of mortality.[22,24,25] Similarly, we found in our study that neurological disease and CRF were associated with mortality.
In studies conducted in India and Egypt, the most common GNB species was Klebsiella spp.[23,26] A baumani was the most frequently isolated microorganism in 2 separate studies in Korea and Vietnam.[27,28] A recent study showed that in the VAP incidence of mixed medical–surgical ICUs in Thailand, GNB were the most common organisms particularly A baumannii (25%–50%), P aeruginosa (18%–35%), and K pneumoniae (7%–25%).[29] Similarly, in our study, the most common cause of VAP in our mixed medical-SICUs was A baumani (61.2%), the GNB. This was followed by K pneumonia (14.7%) and E coli (7.3%). Differences in study results may be explained by geographical differences, differences in the hospital environment, invasive procedures and patient characteristics. Vo et al reported that in their study isolation rates of multiresistant GNB were 10.6% MDR, 63.6% XDR, and 25.8% PDR.[28] Ninh V.D. reported 22.9% MDR, 77.1% XDR, and 0% PDR in his study in 2014.[30] In our study antibiotic susceptibility of microorganisms were 6.8% susceptible, 19.6% MDR, 73.5% XDR, 0% PDR. Similar to Ninh V.D. reported, we did not have PDR and most of them were XDR. The incidence of XDR Acinetobacteria strains is increasing, and Kaweesak et al reported that more than 80% of A baumanii were resistant to the usual GN antimicrobial agents, and more than 90% of them were XDR.[31] Our results support the literature, and 98.4% of A baumanii, which constitutes the majority, were XDR strains. As Combes et al and Blot et al reported in their study, no association was found between antimicrobial resistance and mortality in our study.[32,33]
Although previous studies have described late-onset VAP to be associated with drug-resistant organisms, increased MV days, ICU LOS, hospital LOS, and hospital mortality,[34] recent studies found that there were no significant differences in the prevalence and resistance patterns of MDR pathogens associated with early-onset and late-onset VAPs.[35] Unlike these studies, we found that early-onset VAP is associated with mortality. And also, the duration of MV before VAP was statistically significantly shorter in those who died. We think that these results may be related to accompanying underlying factors such as presence of septic shock, ARDS, renal replacement therapy before the early-onset VAP.
Juthamas and Ranes et al showed that the presence of septic shock[24] and bacteriemia[36] at VAP onset was a risk factor of death. Gursel et al in their study which they investigate the incidence of acute renal failure (ARF) among patients with VAP, they showed that patients with VAP were at high risk for the development of ARF during their ICU stay and MDR microorganisms, sepsis and severity of admission disease increase risk of ARF.[37] Forel et al showed in their study that in those with severe ARDS, patients ventilated according to a standardized lung-protective strategy, the development of VAP was associated with a higher risk for dying in the ICU. However, no relation to ICU death was found after adjustment.[38] Nunez et al performed a retrospective analysis of VAP patients and showed use of vasoactive agents was associated with increased mortality.[39] Consistent with the studies, we found that the presence of RF, sepsis, bacteremia and ARDS 48 hours before the development of VAP and vasopressor requirement were associated with mortality. And also, in our study, we found that shock, ARDS and organ failure that developed after VAP detection were associated with mortality in patients with VAP.
In many studies in the literature, it has been shown that VAP is associated with both the duration of MV and the prolongation of the duration of intensive care and hospital LOS.[40] Contrary to the results of these studies, MV duration, ICU and hospital LOS durations were significantly shorter in those who died in our study. Nowadays, VAP caused by MDR or PDR-GNB is growing more common and negative effect on patient outcomes. This supports us and explains early deaths in our study that are associated with more serious diseases, increased XDR microorganisms and, consequently, shorter MV duration, ICU and hospital LOS durations.
Several studies have already shown that CRP and PCT can be helpful in diagnosing VAP.[41–43] Similarly, in our study, we found that high CRP and PCT levels were associated with mortality.
Antibiotics are the treatment of choice for VAP, and the antibiotic chosen depends on the nature of the VAP, the microorganism, the individual’s immune status, and many other factors. The ongoing spread of antimicrobial resistance in VAP cases has made empirically treating MDR or PDR-GNB difficult. As a result, it is critical to quickly identify the bacterial species involved and their susceptibility to antibiotics for decision of antimicrobial therapy variety. In many studies it was showed that the administration of adequate empirical antibiotics could help improve patients’ prognosis,[27] appropriate antibiotic therapy is the key factor to improved outcomes for VAP patients, inappropriate initial antimicrobial therapy was associated with high mortality.[24,43] Our study confirmed that inadequate empirical antibiotic therapy and inadequate antibiotic therapy associated with mortality. Combination therapy is currently preferred for severe infections caused by GN MDR organisms.[4] Combination antibiotic treatment was found to be superior to monotherapy in 3 studies with severely ill patients (mainly ICU patients).[44–46] In support of these studies, monotherapy was found to be associated with increased mortality in our study. Additionally, the persistence of the microorganism was found to be associated with mortality.
The 30-day mortality day in our study was 61.3%. Mortality rates vary in studies; while Gursel et al found a high mortality rate of 76% in their study,[37] Thu Pham Minh et al found a mortality rate of 54.5% similar to our study,[28] while Karakuzu et al found a low mortality rate of 25.1%.[47] The reason for this difference can be explained by the underlying diseases, risk factors and prognosis of VAP, differences in patient characteristics, antibiotic protocols applied and variability in microorganisms.
The strength of this study was the 3-year surveillance data, which included demographic, detailed clinical and laboratory data of patients, determining pathogen distribution and resistance characteristics. This provides a comprehensive overview of VAP and associated mortality. The major strength of the present study is the large-scale cohort.
Our study had some limitations. The most important was its retrospective nature. Since the data were scanned retrospectively, disease scores were used on the day of admission to the ICU, not on the day of diagnosis of VAP. And scoring in response to treatment could not be made with available data. Some patient data were also not available, such as ARDS severity. Another important limitation of the study was that it was a single-center study and the number of patients, although we believe our patients were similar to those receiving tertiary treatment.
5. Conclusion
Despite advances in antimicrobial therapy and supportive care, VAP remains a major cause of morbidity and mortality in critically ill patients. Especially, when a patient has a number of comorbidities, VAP is associated with a higher mortality rate. In this study, we found that the presence of neurological diseases and renal failure was associated with a greater likelihood of mortality in patients with VAP. As risk factors, early-onset VAP, presence of RF–ARDS–bacteremia–sepsis 48 hours before VAP, organ failure, need for hemodialysis, shock, persistence of the pathogen increased the risk of mortality.
In all patients with VAP, empirical therapy (monotherapy or combination therapy) should be started as soon as possible according to necessitates the consideration of numerous variables ranging from local epidemiological data to the patient’s personal history, including prior or current antibiotic therapy, the severity of clinical disease, length of intubation and hospitalization. Following culture data and clinical and radiographic findings, treatment should be narrowed.
Safe, effective therapeutic, and preventative strategies with multidisciplinary collaboration are fundamental in VAP. Further research into VAP in the ICU would be informative for clinicians and developers.
Author contributions
Conceptualization: Sinem Bayrakçi, Selda Aslan.
Data curation: Sinem Bayrakçi, Ahmet Şahin.
Formal analysis: Sinem Bayrakçi, Ahmet Şahin, Onur Bayrakçi, Selda Aslan.
Funding acquisition: Sinem Bayrakçi, Onur Bayrakçi.
Investigation: Sinem Bayrakçi, Ahmet Şahin, Onur Bayrakçi, Selda Aslan.
Methodology: Sinem Bayrakçi, Ahmet Şahin, Onur Bayrakçi, Selda Aslan.
Supervision: Sinem Bayrakçi, Ahmet Şahin, Onur Bayrakçi.
Writing – original draft: Sinem Bayrakçi, Selda Aslan.
Writing – review & editing: Sinem Bayrakçi, Ahmet Şahin, Onur Bayrakçi, Selda Aslan.
Abbreviations:
- ARF
- acute renal failure
- ARDS
- acute respiratory distress syndrome
- CRF
- chronic renal failure
- GNB
- Gram-negative bacteria
- ICU
- intensive care unit
- LOS
- length of stay
- MDR
- multidrug-resistant microorganisms
- MV
- mechanical ventilation
- PDR
- pandrug resistance
- RF
- renal failure
- VAP
- ventilator-associated pneumonia
- XDR
- extremely drug-resistant
Gaziantep Islam Science and Technology University Ethics Committee approved the study protocol (number 2022/156).
The authors have no funding and conflicts of interest to disclose.
All data generated or analyzed during this study are included in this published article [and its supplementary information files].
How to cite this article: Bayrakçi S, Şahin A, Bayrakçi O, Aslan S. Characteristics of ventilator-associated pneumonia due to Gram-negative bacteria in the intensive care unit: A single-center experience. Medicine 2025;104:26(e42946).
This article has not been presented at any congresses or scientific meetings. It has not been sent to any scientific journal other than this journal. All authors have read and agreed to the published version of the manuscript.
Contributor Information
Ahmet Şahin, Email: ahmet27sahin@hotmail.com.
Onur Bayrakçi, Email: dronurbayrakci@gmail.com.
Selda Aslan, Email: Selda.aslan27@gmail.com.
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