DOI: https://doi.org/10.21203/rs.3.rs-225795/v1
Background: Acinetobacter baumannii is one of the most often isolated opportunistic pathogens in intensive care units (ICUs). Extensively drug-resistant A. baumannii (XDR-AB) strains lack susceptibility to almost all antibiotics and pose a heavy burden on healthcare institutions. In this study, we evaluated the impact of XDR-AB colonization on both the short-term and long-term survival of critically ill patients.
Methods: We prospectively enrolled patients from two adult ICUs in Qilu Hospital of Shandong University from April 2018 through December 2018. Using nasopharyngeal and perirectal swabs, we evaluated the presence of XDR-AB colonization. Participants were followed up for six months. Primary endpoints were 28-day and six-month mortality after ICU admission. For survival analysis, we used the Kaplan-Meier curve. We identified risk factors associated with 28-day and six-month mortality using the logistic regression model and Cox proportional-hazards survival regression model, respectively.
Results: Out of 431 patients, 77 were colonized with XDR-AB. Based on the Kaplan-Meier curve results, the survival before 28 days did not differ by colonization status; however, a significant lower survival rate was obtained at six months in colonized patients. Univariate and multivariate results confirmed that XDR-AB colonization was not associated with 28-day mortality, but was an independent risk factor of lower survival days at six months, resulting in a 1.97 times higher risk of death at six months.
Conclusions: XDR-AB colonization has no effect on short-term mortality but is associated with lower long-term survival in critically ill patients.
Acinetobacter baumannii is one of the most important opportunistic pathogen in intensive care units (ICUs) and a major cause of hospital infections such as hospital-acquired pneumonia, peritonitis, and bacteremia [1–3]. Characterized by its environmental resilience, communicability, and wide range of drug-resistance determinants, the infection and dissemination of A. baumannii in critical patients can pose a heavy burden on healthcare institutions [4–6].
Increased antimicrobial resistance of A. baumannii has become a worldwide challenge in the care of hospitalized patients. Extensively drug-resistant A. baumannii (XDR-AB) refers to strains that lack susceptibility to almost all antimicrobial agents except for one or two (e.g., polymyxin and tigecycline) [7]. According to data obtained from a nationwide survey in United States, more than 50% of A. baumannii strains isolated from ICUs are carbapenem-resistant in the enrolled hospitals [8]. In Europe, A. baumannii susceptible to imipenem was reported in less than 11% of all A. baumannii strains [9]. In China, a national investigation program on the microbial resistance reported that in 2004–2014 the prevalence of XDR-AB strains increased from 11.1–60.4% [10]. By 2018, among the Acinetobacter spp. strains isolated by China Antimicrobial Surveillance Network (CHINET), 78.1% and 77.1% were resistant to meropenem and imipenem, respectively [11]. Due to limited efficient treatments, XDR-AB infections contribute to extended hospitalizations and increased mortality rates [12, 13], which can reach 70% in critical patients with bacteremia [12].
Apart from symptomatic infections, A. baumannii colonizes hospitals and is commonly isolated from inpatient sites [11, 14]. Due to the extraordinary environmental persistence and prevalence of extensive drug resistance, it is difficult to eradicate XDR-AB strains. Colonization may precede infections in severely ill patients and lead to poor prognoses. However, the effect of XDR-AB colonization in critically ill patients, especially on long-term prognosis, is not clear. The aim of this study was to evaluate the impact of XDR-AB colonization on both short-term and long-term mortality of critical patients.
We conducted a prospective observational study in two mixed adult ICUs of Qilu Hospital of Shandong University from April 2018 through December 2018. Participants were followed up for six months after ICU admission. The study was approved by the Ethics Committee at Qilu Hospital. We obtained waivers for informed consents.
Patients admitted to ICUs were considered for the study. Patients were excluded if they 1) had a length of ICU stay < 72 h; 2) were < 18 years of age; 3) were lost to follow-up or had insufficient information; or 4) were assumed to have colonization prior to ICU admission. We recorded essential information of the patients (e.g., age, sex, diagnosis on admission, previous medical history, and comorbidities) upon ICU admission. We calculated the Charlson Comorbidity Index (CCI) to evaluate the mortality risk associated with comorbidities [15, 16]. We used the Acute Physiology and Chronic Health Evaluation II (APACHE II) score [17] to assess the severity of illness. Applications of vasoactive drugs and mechanical ventilation were documented.
Nasopharyngeal and perirectal swabs were collected within two days after ICU admission for microbial culture and twice a week thereafter until the occurrence of a positive XDR-AB culture. If the patient stayed for more than three weeks, culture frequency was reduced to once a week. All samples were analyzed at the hospital’s laboratories according to standard operating procedures. We performed strain identification and drug sensitivity test using the VITEK2 COMPACT automatic microbial analysis system (bioMérieux, Marcy-l'Étoile, France). The susceptibility test breakpoints were based on the standards established by the American Clinical and Laboratory Standards Institute (CLSI) [18]. A. baumannii (genospecies 2) was identified through 16S–23S ribosomal RNA gene intergenic spacer region [19].
We defined variables according to guidelines obtained from the US Centers for Disease Control and Prevention and World Health Organization (WHO) [7]. Colonization with XDR-AB was defined as a positive XDR-AB culture during the stay at the ICU. If the first culture of XDR-AB is positive, it is assumed that the patients has been colonized before ICU admission. Colonization is assumed acquired if there is a negative culture before a positive one [20].
We used SPSS 16.0 (SPSS Inc, IL, USA) and R software v3.0 for data analysis. The primary endpoints were 28-day and six-month mortality after ICU admission. Quantitative data with normal distributions were expressed as mean ± standard deviations and compared using Student t test. Non-normally distributed data were analyzed using Wilcoxon’s rank sum test. Categorical variables were expressed as frequency (percentage) and compared using Chi-square or Fisher’s exact test (two-tailed). Survival analysis was performed with the Kaplan-Meier curve and log-rank test. The multivariate analysis for 28-day mortality was conducted with the logistic regression model. The Cox proportional-hazards survival regression model was used for analyzing variables associated with mortality at six months. Variables identified in univariate analysis with P values < 0.1 and XDR-AB colonization were validated in multivariate models. P < 0.05 was considered statistically significant in multivariate analysis. We performed subgroup analysis to assess the consistency of colonization effect on survival by the baseline variables. The Cox proportional-hazards model with Efron’s method of handling ties was used to assess the magnitude of XDR-AB colonization differences between patients with different baseline characteristics.
Out of 431 patients, 77 (17.87%) were colonized with XDR-AB (Fig. 1). Table 1 presents the baseline characteristics and outcomes of the participants. The participants had a median age of 60 years and were mostly males (68%). The overall 28-day and six-month mortality rates were 15.5% and 48.0%, respectively.
Variables | Overall (n = 431) | XDR-AB Colonized (n = 77) | Not XDR-AB Colonized (n = 354) | P value | |
---|---|---|---|---|---|
Age (years) | 60.15 (18, 97) | 60.11 (18, 97) | 60.36 (22, 92) | 0.919 | |
Male | 292 (67.7) | 56 (72.7) | 236 (66.7) | 0.302 | |
Season | |||||
Spring | 147 (34.1) | 24 (31.2) | 123 (34.7) | 0.907 | |
Summer | 103 (23.9) | 18 (23.4) | 85 (24.0) | 0.811 | |
Autumn | 75 (17.4) | 15 (19.5) | 60 (16.9) | 0.497 | |
Winter | 106 (24.6) | 20 (26.0) | 86 (24.3) | 0.599 | |
Charlson Index | 4.22 ± 2.146 | 4.52 ± 2.180 | 4.16 ± 2.136 | 0.181 | |
Comorbidities | |||||
Cardiovascular diseases | 166 (38.5) | 41 (53.2) | 125 (35.3) | 0.003 | |
Chronic renal insufficiency | 61 (14.2) | 10 (13.0) | 51 (14.4) | 0.746 | |
COPD | 95 (22.0) | 24 (31.2) | 71 (20.1) | 0.033 | |
Type II diabetes mellitus | 101 (23.4) | 28 (36.4) | 73 (20.6) | 0.003 | |
Solid tumor | 106 (24.6) | 10 (13.0) | 96 (27.1) | 0.009 | |
Hematologic malignancy | 8 (1.9) | 2 (2.6) | 6 (1.7) | 0.595 | |
Current or former smoker | 160 (37.1) | 35 (45.5) | 125 (35.3) | 0.095 | |
Admission source | |||||
Emergency department | 110 (25.5) | 17 (22.1) | 93 (26.3) | 0.178 | |
Operation theatre | 106 (24.6) | 18 (23.4) | 88 (24.9) | 0.936 | |
Normal wards | 126 (29.2) | 19 (24.7) | 107 (30.2) | 0.761 | |
Other hospital | 89 (20.6) | 23 (29.9) | 66 (18.6) | 0.072 | |
Primary reason for ICU admission | |||||
Neurological | 53 (12.3) | 5 (6.5) | 48 (13.6) | 0.087 | |
Suspected sepsis | 101 (23.4) | 28 (36.4) | 73 (20.6) | 0.003 | |
Respiratory | 129 (29.9) | 25 (32.5) | 104 (29.4) | 0.592 | |
Cardiovascular (excluding stroke) | 65 (15.1) | 11 (14.3) | 54 (15.3) | 0.830 | |
Multiple trauma | 25 (5.8) | 3 (3.9) | 22 (6.2) | 0.430 | |
Burns | 7 (1.6) | 3 (3.9) | 4 (1.1) | 0.082 | |
Hepatobiliary and pancreatic | 21 (4.9) | 0 (0.0) | 21 (5.9) | 0.028 | |
Gastrointestinal | 19 (4.4) | 1 (1.3) | 18 (5.1) | 0.142 | |
Genitourinary | 11 (2.6) | 1 (1.3) | 10 (2.8) | 0.442 | |
APACHE II score | 15.278 ± 8.837 | 19.273 ± 8.871 | 15.409 ± 8.600 | < 0.001 | |
Intensity of care | |||||
Renal replacement therapy | 71 (16.5) | 20 (26.0) | 51 (14.4) | 0.013 | |
Invasive ventilation for more than five days | 209 (48.5) | 64 (83.1) | 145 (41.0) | < 0.001 | |
Vasopressor treatment for more than three days | 100 (23.2) | 28 (36.4) | 72 (20.3) | 0.003 | |
Clinical outcomes | |||||
Length of stay in ICU | 18.85 (3, 83) | 28.58 (3,76) | 16.74 (3,83) | < 0.001 | |
28-day mortality | 67 (15.5) | 12 (15.6) | 55 (15.5) | 0.992 | |
Six-month mortality | 207 (48.0) | 53 (68.8) | 154 (43.5) | < 0.001 | |
Data are number (%), median (IQR), or mean ± SD. XDR-AB, extensively drug-resistant Acinetobacter baumannii; COPD, chronic obstructive pulmonary disease; ICU, intensive care unit; APACHE, Acute Physiology and Chronic Health Evaluation; IQR, interquartile range; SD, standard deviation. |
Patients who tested positive for XDR-AB were more likely to have cardiovascular diseases, type II diabetes mellitus, solid tumors, suspected sepsis, and supportive treatment (e.g., renal replacement therapy, longer invasive ventilation, and vasopressor treatment). Compared to non-colonized patients, XDR-AB colonized patients had higher APACHE II scores and six-month mortality rates (68.8% vs 43.5%; P < 0.001) and longer ICU days. However, 28-day mortality did not differ between colonized and non-colonized patients (15.6% vs 15.5%, respectively; P = 0.992; Table 1).
Figure 2 shows that the six-month survival rate was higher for non-colonized patients than for XDR-AB colonized patients (P < 0.001). In the analysis of events occurring before and after the 28-day follow-up, we observed that the survival rate before 28 days did not differ based on the colonization status (P = 0.845). However, the six-month survival rate was significantly lower in colonized patients after 28 days (P < 0.001).
The risk factors of 28-day mortality were identified through univariate analysis, including CCI, APACHE II score, ICU admission with cardiovascular diseases, support with renal replacement therapy, and extended invasive ventilation (all P < 0.10, Table 2). The risk factors and XDR-AB colonization were validated using a multivariate logistic regression model. The only independent risk factor for 28-day mortality was APACHE II score (OR 1.114, 95% CI 1.076–1.154; P < 0.001; Table 3).
Variables | Deaths at day 28 (n = 67) | Survivals at day 28 (n = 364) | P value | OR (95%CI) |
---|---|---|---|---|
Age | 61.42 (19,95) | 59.92 (18,97) | 0.509 | 1.005 (0.990–1.021) |
Male | 42 (62.7) | 250 (68.7) | 0.336 | 1.305 (0.759–2.245) |
Season | ||||
Spring | 25 (37.3) | 122 (33.5) | 0.547 | 1.181 (0.687–2.028) |
Summer | 11 (16.4) | 92 (25.3) | 0.122 | 0.581 (0.292–1.156) |
Autumn | 8 (11.9) | 67 (18.4) | 0.203 | 0.601 (0.274–1.317) |
Winter | 23 (34.3) | 83 (22.8) | 0.046 | 1.770 (1.010–3.100) |
Charlson Index | 4.640 ± 1.747 | 4.150 ± 2.205 | 0.084 | 1.104 (0.987–1.235) |
Comorbidities | ||||
Cardiovascular diseases | 28 (41.8) | 138 (37.9) | 0.549 | 1.176 (0.692–1.997) |
Chronic renal insufficiency | 13 (19.4) | 48 (13.2) | 0.183 | 1.585 (0.805–3.120) |
COPD | 19 (28.4) | 76 (20.9) | 0.177 | 1.500 (0.833–2.701) |
Type II diabetes mellitus | 17 (25.4) | 84 (23.1) | 0.684 | 1.133 (0.621–2.069) |
Solid tumor | 17 (25.4) | 89 (24.5) | 0.872 | 1.051 (0.577–1.914) |
Hematologic malignancy | 1 (1.5) | 7 (1.9) | 0.811 | 0.773 (0.094–6.384) |
Current or former smoker | 20 (29.9) | 140 (38.5) | 0.182 | 0.681 (0.387–1.197) |
Admission source | ||||
Emergency department | 21 (31.3) | 89 (24.5) | 0.236 | 1.411 (0.799–2.491) |
Operation theatre | 14 (20.9) | 92 (25.3) | 0.445 | 0.781 (0.414–1.473) |
Normal wards | 21 (31.3) | 105 (28.8) | 0.680 | 1.126 (0.641–1.979) |
Other hospital | 11 (16.4) | 78 (21.4) | 0.353 | 0.720 (0.360–1.441) |
Primary reason for ICU admission | ||||
Neurological | 7 (10.4) | 46 (12.6) | 0.617 | 0.807 (0.348–1.871) |
Suspected sepsis | 14 (20.9) | 87 (23.9) | 0.594 | 0.841 (0.445–1.589) |
Respiratory | 20 (29.9) | 109 (29.9) | 0.988 | 0.996 (0.563–1.759) |
Cardiovascular (excluding stroke) | 16 (23.9) | 49 (13.5) | 0.031 | 2.017 (1.066–3.814) |
Multiple trauma | 2 (3.0) | 23 (6.3) | 0.295 | 0.456 (0.105–1.982) |
Burns | 1 (1.5) | 6 (1.6) | 0.926 | 0.904 (0.107–7.632) |
Hepatobiliary and pancreatic | 2 (3.0) | 19 (5.2) | 0.441 | 0.559 (0.127–2.457) |
Gastrointestinal | 2 (3.0) | 17 (4.7) | 0.540 | 0.628 (0.142–2.784) |
Genitourinary | 3 (4.5) | 8 (2.2) | 0.287 | 2.086 (0.539–8.073) |
XDR-AB colonization | 12 (17.9) | 65 (17.9) | 0.992 | 1.004 (0.509–1.980) |
Acuity score on admission | ||||
APACHE II score | 22.475 ± 6.647 | 13.953 ± 8.554 | < 0.001 | 1.114 (1.078–1.150) |
Intensity of care | ||||
Invasive ventilation for more than five days | 39 (58.2) | 170 (46.7) | 0.085 | 1.589 (0.938–2.693) |
Renal replacement therapy | 16 (23.9) | 55 (15.1) | 0.078 | 1.763 (0.938–3.311) |
Vasopressor treatment for more than three days | 67 (100) | 33 (9.1) | 0.992 | 3.279 (0.978–7.923) |
Data are number (%), median (IQR) or mean ± SD. OR, odds ratio; COPD, chronic obstructive pulmonary disease; ICU, intensive care unit; XDR-AB, extensively drug-resistant Acinetobacter baumannii; APACHE, Acute Physiology and Chronic Health Evaluation; IQR, interquartile range; SD, standard deviation. |
Variables | OR (95%CI) | P value |
---|---|---|
XDR-AB colonization | 0.517 (0.237–1.128) | 0.098 |
APACHE II score | 1.114 (1.076–1.154) | < 0.001 |
Charlson Index | 1.086 (0.951–1.239) | 0.222 |
Cardiovascular (excluding stroke) | 1.097 (0.519–2.318) | 0.809 |
Invasive ventilation for more than five days | 1.295 (0.718–2.337) | 0.390 |
Renal replacement therapy | 1.032 (0.500–2.132) | 0.932 |
OR, odds ratio; CI, confidence interval; XDR-AB, extensively drug-resistant Acinetobacter baumannii; APACHE, Acute Physiology and Chronic Health Evaluation. |
Using univariate analysis, we identified possible risk factors for six-month mortality (Table 4): age, Charlson Index, APACHE II score, presence of comorbidities (cardiovascular diseases, chronic renal insufficiency, COPD, type II diabetes mellitus, and solid tumors), admission to ICU with primary reasons (cardiovascular diseases and hepatobiliary/pancreatic diseases), renal replacement therapy, long invasive ventilation, vasopressor treatment, and XDR-AB colonization.
Variables | Deaths at six months (n = 207) | Survival at six months (n = 224) | P value | HR (95%CI) |
---|---|---|---|---|
Age | 65.3 (19,97) | 55.4 (18,94) | < 0.001 | 1.026 (1.017–1.035) |
Male | 138 (66.7) | 154 (68.8) | 0.464 | 1.114 (0.834–1.487) |
Season | ||||
Spring | 70 (33.8) | 77 (34.4) | 0.879 | 0.978 (0.733–1.304) |
Summer | 45 (21.7) | 58 (25.9) | 0.226 | 0.815 (0.586–1.134) |
Autumn | 36 (17.4) | 39 (17.4) | 0.900 | 1.023 (0.714–1.466) |
Winter | 56 (27.1) | 50 (222.3) | 0.190 | 1.227 (0.903–1.668) |
Charlson Index | 4.630 ± 2.063 | 3.850 ± 2.158 | < 0.001 | 1.114 (1.056–1.175) |
Comorbidities | ||||
Cardiovascular diseases | 103 (49.8) | 63 (28.1) | < 0.001 | 1.859 (1.414–2.443) |
Chronic renal insufficiency | 46 (22.2) | 15 (6.7) | < 0.001 | 2.231 (1.605–3.101) |
COPD | 63 (30.4) | 32 (14.3) | < 0.001 | 1.897 (1.409–2.554) |
Type II diabetes mellitus | 56 (27.1) | 45 (20.1) | 0.093 | 1.301 (0.957–1.769) |
Solid tumor | 41 (19.8) | 65 (29.0) | 0.064 | 0.724 (0.514–1.019) |
Hematologic malignancy | 5 (2.4) | 3 (1.3) | 0.500 | 1.357 (0.559–3.296) |
Current or former smoker | 73 (35.3) | 87 (38.8) | 0.322 | 0.866 (0.651–1.152) |
Admission source | ||||
Emergency department | 56 (27.1) | 54 (24.1) | 0.503 | 1.111 (0.817–1.509) |
Operation theatre | 51 (24.6) | 55 (24.6) | 0.981 | 1.004 (0.732–1.377) |
Normal wards | 58 (28.0) | 68 (30.4) | 0.719 | 0.946 (0.698–1.281) |
Other hospital | 42 (20.3) | 47 (21.0) | 0.737 | 0.944 (0.672–1.324) |
Primary reason for ICU admission | ||||
Neurological | 22 (10.6) | 31 (13.8) | 0.298 | 0.791 (0.508–1.230) |
Suspected sepsis | 53 (25.6) | 48 (21.4) | 0.363 | 1.156 (0.846–1.579) |
Respiratory | 63 (30.4) | 66 (29.5) | 0.871 | 1.025 (0.762–1.378) |
Cardiovascular (excluding stroke) | 40 (19.3) | 25 (11.2) | 0.005 | 1.640 (1.161–2.318) |
Multiple trauma | 9 (4.3) | 16 (7.1) | 0.217 | 0.656 (0.337–1.281) |
Burns | 2 (1.0) | 5 (2.2) | 0.341 | 0.508 (0.126–2.047) |
Hepatobiliary and pancreatic | 4 (1.9) | 17 (7.6) | 0.024 | 0.321 (0.119–0.864) |
Gastrointestinal | 7 (3.4) | 12 (5.4) | 0.362 | 0.704 (0.332–1.497) |
Genitourinary | 6 (2.9) | 5 (2.2) | 0.770 | 1.129 (0.501–2.542) |
XDR-AB colonization | 53 (25.6) | 24 (10.7) | < 0.001 | 1.898 (1.387–2.598) |
Acuity score on admission | ||||
APACHE II score | 21.936 ± 7.406 | 9.125 ± 4.556 | < 0.001 | 1.107 (1.094–1.121) |
Intensity of care | ||||
Invasive ventilation for more than five days | 118 (57.0) | 91 (40.6) | < 0.001 | 1.641 (1.246–2.161) |
Renal replacement therapy | 44 (21.3) | 27 (12.1) | 0.005 | 1.616 (1.158–2.255) |
Vasopressor treatment for more than three days | 91 (44.0) | 9 (4.0) | < 0.001 | 7.849 (5.913–10.419) |
Data are number (%), median (IQR) or mean ± SD. HR, hazard ratio; COPD, chronic obstructive pulmonary disease; ICU, intensive care unit; XDR-AB, extensively drug-resistant Acinetobacter baumannii; APACHE, Acute Physiology and Chronic Health Evaluation; IQR, interquartile range; SD, standard deviation. |
Using multivariate Cox regression, we found XDR-AB as an independent risk factor of death at six months (HR 1.968, 95% CI 1.245–2.938). Other risk factors are age, high APACHE II scores, COPD, cardiovascular diseases as primary reasons for ICU admission, and extended vasopressor treatments. (Table 5).
Variables | HR (95%CI) | P value |
---|---|---|
Age | 1.019(1.007–1.031) | 0.002 |
APACHE II Score | 1.121(1.101–1.142) | ༜0.001 |
Charlson Index | 1.067(0.978–1.163) | 0.143 |
Presence of cardiovascular diseases | 1.051(0.744–1.486) | 0.777 |
Presence of chronic renal insufficiency | 1.109(0.751–1.636) | 0.603 |
Presence of COPD | 1.461(1.191–2.161) | 0.045 |
Presence of type II diabetes mellitus | 0.774(0.547–1.095) | 0.147 |
Presence of solid tumor | 1.580(0.373–1.099) | 0.105 |
Cardiovascular diseases (excluding stroke) as primary reason for ICU admission | 2.056(1.340–3.157) | 0.001 |
Hepatobiliary and pancreatic diseases as primary reason for ICU admission | 1.254(0.090–1.718) | 0.256 |
XDR-AB colonization | 1.968(1.245–2.938) | 0.001 |
Invasive ventilation for more than five days | 0.833(0.613–1.133) | 0.244 |
Renal replacement therapy | 0.822(0.562–1.202) | 0.312 |
Vasopressor treatment for more than three days | 9.037(6.466–12.630) | ༜0.001 |
HR, hazard ratio; APACHE, Acute Physiology and Chronic Health Evaluation; COPD, chronic obstructive pulmonary disease; ICU, intensive care unit; XDR-AB, extensively drug-resistant Acinetobacter baumannii. |
The impact of colonization with XDR-AB in subgroups with different baseline characteristics are presented in Fig. 3. In most subgroups, the number of survival days was lower for colonized patients than for non-colonized patients.
A. baumannii is one of the most threatening nosocomial microorganisms, characterized by its capacity to survive in various environments and to develop antibiotic resistance. Drug-resistant A. baumannii is prevalent in several healthcare facilities in China. The rapid growth of antibiotic resistance poses considerable economic and medical burdens. In 2017, carbapenem resistant-A. baumannii (CRAB) had a prevalence of 56.1% in China and was related to higher costs, longer hospital stays, and increased mortality in hospital [21]. A study conducted in China estimated that there is a 1.5-fold increase in total medical costs as a result of CRAB [22]. Due to increasing occurrence of XDR and pan drug-resistant A. baumannii strains, WHO reported that there is an urgent need of novel antibiotics [23], emphasizing the importance of preventing and treating drug-resistant A. baumannii.
This study assessed the effect of XDR-AB colonization on prognoses of severely ill patients. We conducted the study in two mixed adult ICUs in China, where XDR-AB is the most common pathogen in nosocomial infections. The findings revealed that XDR-AB colonization had no effect on the short-term (28-day) mortality of ICU patients but contributed to a 1.97-fold increase in mortality risk at six months.
In our study, the overall peripheral colonization rate of XDR-AB was 18%, which is higher than in previous reports. In Korean ICUs without outbreaks, 5.2% of patients were colonized with CRAB at admission [24]. A prevalence of 13.5% CRAB was observed in trauma ICU patients (n = 364) at an American tertiary hospital from 2010 to 2011 [25]. The relatively high prevalence obtained in our study indicated a possible regional epidemic of XDR-AB in our ICUs.
Studies have elucidated several risk factors of XDR-AB colonization, such as previous admission to long-term healthcare facilities, invasive operations, presence of comorbidities, low socioeconomic status, and previous use of carbapenems [24, 26, 27]. In this study, critical patients with more comorbidities and higher intensity of care were more likely to be colonized with XDR-AB. There are possible reasons for this finding. First, in critically ill patients, immune system disorders lead to poor defensive responses, making them more susceptible to opportunistic pathogens. Second, invasive operations, such as vascular and urinary catheters, tracheostomy, and drainage, provide chances for pathogen colonization through wounds and invasive devices due to impairments in skin and mucosal barriers. Finally, decolonization has not been adopted in ICUs in China; therefore, long hospitalizations coupled with poor baseline conditions and more intensive care might increase opportunities for colonization.
There is not much information on the impact of XDR-AB colonization on patient prognosis. It has been wildly accepted that A. baumannii infections can lead to higher death rates. Among critically ill patients, the estimated increase of in-hospital mortality rate due to A. baumannii infection ranges between 7.8% and 23%, and attributable ICU mortality ranges from 10–43% [28]. High mortality rates have been reported in patients infected with drug-resistant A. baumannii [29, 30]. Colonization with multiple drug-resistant A. baumannii (MDR-AB) upon ICU admission is related with a 1.4-fold increase in in-hospital death rate [15]. Several studies have concluded that colonization and infection with A. baumannii is an independent risk factor of mortality [26, 31–33], without distinguishing between colonization and infection. In this study, we identified colonization using nasopharyngeal and perirectal samplings, which are generally used to identify colonization [25] [34] [35]. As far as we know, this is the first research to assess the effect of XDR-AB colonization on long-term mortality in critical patients. The results revealed that XDR-AB colonization has no impact on the 28-day prognosis based on the multivariate analysis findings but was associated with higher mortality rates at six months. XDR-AB colonization is an independent risk factor of poor long-term prognoses, indicating the necessity of essential surveillance during the early stage and efficient measures of decolonization.
A meta-analysis reported that decolonization reduces infection caused by multidrug-resistant Gram-negative bacteria when combined with standard care, especially in Europe, where decolonization has been widely applied as an infection prevention and control strategy [36]. However, considering there is a lack of effective antibiotics, it is challenging to eliminate XDR-AB. Daily whole-body bathing with chlorhexidine was efficient in removing MDR-AB from the skin [37] and was helpful in reducing bloodstream infections in patients colonized with XDR Gram-negative bacilli [38], making it a practicable approach to decolonize XDR-AB. Decontamination of alimentary tract with polymyxin E and tobramycin was effective in patients colonized with MDR-AB [35, 39–41]. However, there is no clinical evidence on systematic antibiotics for the decolonization of XDR-AB. Additionally, standard nosocomial care is of vital importance, e.g., hand hygiene, exposure precautions, conventional screening, and environmental sterilization especially in wards with highly prevalent strains [3]. According to guidelines established by the European Committee on Infection Control (EUCIC), there is not enough information supporting decolonization of CRAB [42]. Our data provided some evidence supporting the need for decolonization, but further interventional studies are required for strategy development and efficacy validation.
Even though our study did not focus on subsequent infections of XDR-AB, it has been acknowledged that in critical patients, colonization with Gram-negative bacteria contributes to more nosocomial infections [43]. The risk of developing subsequent A. baumannii infections is 8.4 times higher in patients colonized with CRAB [25]. In this study, we observed a greater use of colistin or tigecycline after detecting XDR-AB colonization, which indicated a higher incidence of infections. It is possible that subsequent infections might contribute to the increased risk of mortality.
Subgroup analyses of six-month mortality rates were performed in patients with different characteristics, showing consistent results. Patients colonized with XDR-AB had the worse prognosis (with HR > 1) in all groups; however, some of the subgroups did not show statistical significance. Colonization of XDR-AB was recognized as a risk factor of six-month mortality regardless of age, admission season, comorbidity, and APACHE II scores upon admission. In addition, XDR-AB colonization was worse in ICU patients who were hospitalized for more than 14 days (HR 2.022, 95% CI: 1.393–2.936), indicating the harmful effect of XDR-AB colonization on critical patients with prolonged ICU length of stay.
Our study had some limitations. First, there is no information on the effect of colonization with sensitive or MDR-AB on patient prognosis. Approximately 95% of A. baumannii strains isolated were XDR strains, and sensitive and multidrug-resistant strains were rare. Second, we assumed that colonized patients remained colonized with XDR-AB at discharge, because decolonization measures were not performed.
Our study provided some evidence on the impact of XDR-AB colonization on the prognosis of critically ill patients. XDR-AB colonization had no effect on short-term mortality of ICU patients; however, it increased six-month mortality rates by 1.97-fold. Studies should evaluate proper prevention and control methods of nosocomial drug-resistant A. baumannii.
APACHE, Acute Physiology and Chronic Health Evaluation; CCI, Charlson Comorbidity Index; CI, confidence interval; CLSI, American Clinical and Laboratory Standards Institute; COPD, chronic obstructive pulmonary disease; CRAB, carbapenem resistant Acinetobacter baumannii; EUCIC, European Committee on Infection Control; HR, hazard ratio; ICU, intensive care unit; IQR, interquartile range; MDR-AB, multiple drug-resistant Acinetobacter baumannii; OR, odds ratio; SD, standard deviation; WHO, World Health Organization; XDR-AB, extensively drug-resistant Acinetobacter baumannii.
Ethics approval and consent to participate
The study was approved by by Qilu Hospital’s Ethics Committee and a waiver for informed consent was granted.
Consent for publication
Not applicable.
Availability of data and materials
Data will be available from the corresponding authors on reasonable requests after publication.
Competing interests
The authors declare that they have no competing interests.
Funding
This work was supported by grants from National Natural Science Foundation of China (82072231, 81873927), China Postdoctoral Science Foundation (2018M632685).
Authors’ contributions
Yue Zheng contributed to data interpretation and manuscript preparing. Nana Xu contributed to information collection and data analysis. Jiaojiao Pang, Hui Han and Hongna Yang helped data interpretation. Weidong Qin, Hui Zhang and Wei Li helped data collection. Hao Wang and Yuguo Chen contributed to study design and manuscript writing. All authors approved the final manuscript and are responsible for the content.