Colonization with Extensively Drug-Resistant Acinetobacter Baumannii and Prognosis in Critically Ill Patients: An Observational Cohort Study

doi:10.21203/rs.3.rs-225795/v1

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Colonization with Extensively Drug-Resistant Acinetobacter Baumannii and Prognosis in Critically Ill Patients: An Observational Cohort Study

https://doi.org/10.21203/rs.3.rs-225795/v1

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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.

Critical Care & Emergency Medicine

Acinetobacter baumannii

extensively drug resistant

intensive care unit

colonization.

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.

Study design

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.

Participants

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.

Microbiology

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].

Definitions

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].

Statistical analyses

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.

Characteristics of participants

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.

Table 1

Descriptive Results of Potential Risk Factors and Outcomes
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).

Kaplan-Meier analysis of survival with colonization status

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).

Factors predicting 28-day mortality

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).

Table 2

Univariate Analysis of Factors Associated with 28-day mortality
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.

Table 3

Multivariate Logistic regression of Factors Associated with 28-day mortality
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.

Factors predicting six-month mortality

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.

Table 4

Univariate Analysis of Factors Associated with mortality in six months
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).

Table 5

Multivariate Cox regression model for Factors Associated with mortality in 6-month
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.

Falagas ME, Karveli EA, Siempos II, Vardakas KZ. Acinetobacter infections: a growing threat for critically ill patients. Epidemiol Infect. 2008;136(8):1009–19.
Perez F, Hujer AM, Hujer KM, Decker BK, Rather PN, Bonomo RA. Global challenge of multidrug-resistant Acinetobacter baumannii. Antimicrob Agents Chemother. 2007;51(10):3471–84.
Chinese XDRCWG, Guan X, He L, Hu B, Hu J, Huang X, Lai G, Li Y, Liu Y, Ni Y, et al. Laboratory diagnosis, clinical management and infection control of the infections caused by extensively drug-resistant Gram-negative bacilli: a Chinese consensus statement. Clin Microbiol Infect. 2016;22(Suppl 1):15–25.
Dijkshoorn L, Nemec A, Seifert H. An increasing threat in hospitals: multidrug-resistant Acinetobacter baumannii. Nat Rev Microbiol. 2007;5(12):939–51.
Garnacho-Montero J, Dimopoulos G, Poulakou G, Akova M, Cisneros JM, De Waele J, Petrosillo N, Seifert H, Timsit JF, Vila J, et al. Task force on management and prevention of Acinetobacter baumannii infections in the ICU. Intensive Care Med. 2015;41(12):2057–75.
Wong D, Nielsen TB, Bonomo RA, Pantapalangkoor P, Luna B, Spellberg B. Clinical and Pathophysiological Overview of Acinetobacter Infections: a Century of Challenges. Clin Microbiol Rev. 2017;30(1):409–47.
Magiorakos AP, Srinivasan A, Carey RB, Carmeli Y, Falagas ME, Giske CG, Harbarth S, Hindler JF, Kahlmeter G, Olsson-Liljequist B, et al. Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: an international expert proposal for interim standard definitions for acquired resistance. Clin Microbiol Infect. 2012;18(3):268–81.
Shlaes DM, Sahm D, Opiela C, Spellberg B. The FDA reboot of antibiotic development. Antimicrob Agents Chemother. 2013;57(10):4605–7.
Lob SH, Hoban DJ, Sahm DF, Badal RE. Regional differences and trends in antimicrobial susceptibility of Acinetobacter baumannii. Int J Antimicrob Agents. 2016;47(4):317–23.
Hu FP, Guo Y, Zhu DM, Wang F, Jiang XF, Xu YC, Zhang XJ, Zhang CX, Ji P, Xie Y, et al. Resistance trends among clinical isolates in China reported from CHINET surveillance of bacterial resistance, 2005–2014. Clin Microbiol Infect. 2016;22(Suppl 1):9–14.
Hu F, Guo Y, Yang Y, Zheng Y, Wu S, Jiang X, Zhu D, Wang F. China Antimicrobial Surveillance Network Study G: Resistance reported from China antimicrobial surveillance network (CHINET) in 2018. Eur J Clin Microbiol Infect Dis. 2019;38(12):2275–81.
Lee HY, Chen CL, Wu SR, Huang CW, Chiu CH. Risk factors and outcome analysis of acinetobacter baumannii complex bacteremia in critical patients. Crit Care Med. 2014;42(5):1081–8.
Fu Q, Ye H, Liu S. Risk factors for extensive drug-resistance and mortality in geriatric inpatients with bacteremia caused by Acinetobacter baumannii. Am J Infect Control. 2015;43(8):857–60.
Marchaim D, Navon-Venezia S, Schwartz D, Tarabeia J, Fefer I, Schwaber MJ, Carmeli Y. Surveillance cultures and duration of carriage of multidrug-resistant Acinetobacter baumannii. J Clin Microbiol. 2007;45(5):1551–5.
Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987;40(5):373–83.
Sundararajan V, Henderson T, Perry C, Muggivan A, Quan H, Ghali WA. New ICD-10 version of the Charlson comorbidity index predicted in-hospital mortality. J Clin Epidemiol. 2004;57(12):1288–94.
Knaus WA, Draper EA, Wagner DP, Zimmerman JE. APACHE II: a severity of disease classification system. Crit Care Med. 1985;13(10):818–29.
Clinical, Institute LS: Performance standards for antimicrobial susceptibility testing. In.: Clinical and Laboratory Standards Institute Wayne, PA; 2017.
Lin YC, Sheng WH, Chang SC, Wang JT, Chen YC, Wu RJ, Hsia KC, Li SY. Application of a microsphere-based array for rapid identification of Acinetobacter spp. with distinct antimicrobial susceptibilities. J Clin Microbiol. 2008;46(2):612–7.
Dautzenberg MJ, Wekesa AN, Gniadkowski M, Antoniadou A, Giamarellou H, Petrikkos GL, Skiada A, Brun-Buisson C, Bonten MJ, Derde LP. The association between colonization with carbapenemase-producing enterobacteriaceae and overall ICU mortality: an observational cohort study. Critical care medicine. 2015;43(6):1170–7.
Zhen X, Stalsby Lundborg C, Sun X, Zhu N, Gu S, Dong H. Economic burden of antibiotic resistance in China: a national level estimate for inpatients. Antimicrob Resist Infect Control. 2021;10(1):5.
Zhen X, Chen Y, Hu X, Dong P, Gu S, Sheng YY, Dong H. The difference in medical costs between carbapenem-resistant Acinetobacter baumannii and non-resistant groups: a case study from a hospital in Zhejiang province, China. Eur J Clin Microbiol Infect Dis. 2017;36(10):1989–94.
WHO Publishes. List of Bacteria for Which New Antibiotics Are Urgently Needed [https:// Accessed on 5 February 2021.
Kim YA, Park YS, Lee SS, Son YJ, Yeon JH, Seo YH, Lee K: Colonization Prevalence and Risk Factor Analysis of Carbapenem-Resistant Acinetobacter baumannii in an Intensive Care Unit without Outbreaks. kjhaicp 2019, 24(2):81–87.
Latibeaudiere R, Rosa R, Laowansiri P, Arheart K, Namias N, Munoz-Price LS. Surveillance cultures growing carbapenem-Resistant Acinetobacter baumannii predict the development of clinical infections: a retrospective cohort study. Clin Infect Dis. 2015;60(3):415–22.
Henig O, Weber G, Hoshen MB, Paul M, German L, Neuberger A, Gluzman I, Berlin A, Shapira C, Balicer RD. Risk factors for and impact of carbapenem-resistant Acinetobacter baumannii colonization and infection: matched case-control study. Eur J Clin Microbiol Infect Dis. 2015;34(10):2063–8.
Moghnieh R, Siblani L, Ghadban D, El Mchad H, Zeineddine R, Abdallah D, Ziade F, Sinno L, Kiwan O, Kerbaj F, et al. Extensively drug-resistant Acinetobacter baumannii in a Lebanese intensive care unit: risk factors for acquisition and determination of a colonization score. J Hosp Infect. 2016;92(1):47–53.
Falagas ME, Bliziotis IA, Siempos II. Attributable mortality of Acinetobacter baumannii infections in critically ill patients: a systematic review of matched cohort and case-control studies. Crit Care. 2006;10(2):R48.
Karakonstantis S, Gikas A, Astrinaki E, Kritsotakis EI. Excess mortality due to pandrug-resistant Acinetobacter baumannii infections in hospitalized patients. J Hosp Infect. 2020;106(3):447–53.
Shi J, Sun T, Cui Y, Wang C, Wang F, Zhou Y, Miao H, Shan Y, Zhang Y. Multidrug resistant and extensively drug resistant Acinetobacter baumannii hospital infection associated with high mortality: a retrospective study in the pediatric intensive care unit. BMC Infect Dis. 2020;20(1):597.
Gkrania-Klotsas E, Hershow RC. Colonization or infection with multidrug-resistant Acinetobacter baumannii may be an independent risk factor for increased mortality. Clin Infect Dis. 2006;43(9):1224–5.
Molina J, Cisneros JM, Fernandez-Cuenca F, Rodriguez-Bano J, Ribera A, Beceiro A, Martinez-Martinez L, Pascual A, Bou G, Vila J, et al. Clinical features of infections and colonization by Acinetobacter genospecies 3. J Clin Microbiol. 2010;48(12):4623–6.
Ntusi NB, Badri M, Khalfey H, Whitelaw A, Oliver S, Piercy J, Raine R, Joubert I, Dheda K. ICU-associated Acinetobacter baumannii colonisation/infection in a high HIV-prevalence resource-poor setting. PLoS One. 2012;7(12):e52452.
Dautzenberg MJ, Wekesa AN, Gniadkowski M, Antoniadou A, Giamarellou H, Petrikkos GL, Skiada A, Brun-Buisson C, Bonten MJ, Derde LP, et al. The association between colonization with carbapenemase-producing enterobacteriaceae and overall ICU mortality: an observational cohort study. Crit Care Med. 2015;43(6):1170–7.
Agustí C, Pujol M, Argerich MJ, Ayats J, Badía M, Domínguez MA, Corbella X, Ariza J. Short-term effect of the application of selective decontamination of the digestive tract on different body site reservoir ICU patients colonized by multi-resistant Acinetobacter baumannii. J Antimicrob Chemother. 2002;49(1):205–8.
Teerawattanapong N, Kengkla K, Dilokthornsakul P, Saokaew S, Apisarnthanarak A, Chaiyakunapruk N. Prevention and Control of Multidrug-Resistant Gram-Negative Bacteria in Adult Intensive Care Units: A Systematic Review and Network Meta-analysis. Clin Infect Dis. 2017;64(suppl_2):51-s60.
Borer A, Gilad J, Porat N, Megrelesvilli R, Saidel-Odes L, Peled N, Eskira S, Schlaeffer F, Almog Y. Impact of 4% chlorhexidine whole-body washing on multidrug-resistant Acinetobacter baumannii skin colonisation among patients in a medical intensive care unit. J Hosp Infect. 2007;67(2):149–55.
Munoz-Price LS, Hota B, Stemer A, Weinstein RA. Prevention of bloodstream infections by use of daily chlorhexidine baths for patients at a long-term acute care hospital. Infect Control Hosp Epidemiol. 2009;30(11):1031–5.
Timsit JF, Garrait V, Misset B, Goldstein FW, Renaud B, Carlet J. The digestive tract is a major site for Acinetobacter baumannii colonization in intensive care unit patients. J Infect Dis. 1993;168(5):1336–7.
Parra Moreno ML, Arias Rivera S, de la Cal López MA, Frutos Vivar F, Cerdá Cerdá E, García Hierro P, Negro Vega E. [Effect of selective digestive decontamination on the nosocomial infection and multiresistant microorganisms incidence in critically ill patients]. Med Clin (Barc). 2002;118(10):361–4.
Corbella X, Pujol M, Ayats J, Sendra M, Ardanuy C, Domínguez MA, Liñares J, Ariza J, Gudiol F. Relevance of digestive tract colonization in the epidemiology of nosocomial infections due to multiresistant Acinetobacter baumannii. Clin Infect Dis. 1996;23(2):329–34.
Tacconelli E, Mazzaferri F, de Smet AM, Bragantini D, Eggimann P, Huttner BD, Kuijper EJ, Lucet JC, Mutters NT, Sanguinetti M, et al. ESCMID-EUCIC clinical guidelines on decolonization of multidrug-resistant Gram-negative bacteria carriers. Clin Microbiol Infect. 2019;25(7):807–17.
Kerver AJ, Rommes JH, Mevissen-Verhage EA, Hulstaert PF, Vos A, Verhoef J, Wittebol P. Prevention of colonization and infection in critically ill patients: a prospective randomized study. Crit Care Med. 1988;16(11):1087–93.

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Colonization with Extensively Drug-Resistant Acinetobacter Baumannii and Prognosis in Critically Ill Patients: An Observational Cohort Study

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Abstract

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Introduction

Methods

Study design

Participants

Microbiology

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Statistical analyses

Results

Characteristics of participants

Kaplan-Meier analysis of survival with colonization status

Factors predicting 28-day mortality

Factors predicting six-month mortality

Discussion

Conclusions

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