Risk factors for multidrug-resistant and carbapenem-resistant Klebsiella pneumoniae bloodstream infections in Shanghai: A five-year retrospective cohort study

Hongwen Cao; Siqi Zhou; Xuefeng Wang; Shuzhen Xiao; Shengyuan Zhao

doi:10.1371/journal.pone.0324925

. 2025 May 22;20(5):e0324925. doi: 10.1371/journal.pone.0324925

Risk factors for multidrug-resistant and carbapenem-resistant Klebsiella pneumoniae bloodstream infections in Shanghai: A five-year retrospective cohort study

Hongwen Cao ^1,^#, Siqi Zhou ^2,^#, Xuefeng Wang ², Shuzhen Xiao ^2,^‡,^*, Shengyuan Zhao ^3,^‡,^*

Editor: Ali Amanati⁴

PMCID: PMC12097643 PMID: 40403001

Abstract

Background

Multidrug-resistant Klebsiella pneumoniae (MDRKP) and carbapenem-resistant Klebsiella pneumoniae (CRKP) bloodstream infections (BSIs) account for significant mortality and healthcare costs.

Objectives

To investigate risk factors for MDRKP and CRKP BSIs

Methods

A retrospective analysis of inpatients with Klebsiella pneumoniae bloodstream infections (KP BSIs) was conducted in a tertiary care hospital in Shanghai from 01/01/2018–31/12/2022. Temporal distribution of mortality and department distribution of KP BSIs were assessed. A generalized linear model was used to determine risk factors for MDRKP and CRKP BSIs.

Results

A total of 379 inpatients with KP BSIs were included. The proportion of death for KP BSIs, MDRKP BSIs and CRKP BSIs gradually decreased since 2020. Majority of both MDRKP and CRKP BSIs patients were from Intensive Care Unit (ICU), burn unit, hematology and pancreatic surgery. Genitourinary disorders, invasive ventilator, history of antibiotic use, and carbapenem use were independently associated with MDRKP BSIs. Respiratory disease, gastric tubes, carbapenem use and its quantity were independently associated with CRKP BSIs.

Conclusions

ICU, burn unit, hematology and pancreatic surgery are common departments for MDRKP and CRKP BSIs. Genitourinary disorders, respiratory disorders, invasive ventilator, gastric tubes and antibiotic use (carbapenems in particular) within 90 days prior to onset of BSIs are independently associated with MDRKP and CRKP BSIs.

Introduction

Bloodstream infections (BSIs) are strongly associated with increased morbidity and mortality, prolonged hospital stays, and high healthcare costs [1]. Klebsiella pneumoniae (KP) is the second most common cause of Gram-negative BSIs [2]. Klebsiella pneumoniae bloodstream infections (KP BSIs) is a clinical healthcare concern receiving significant attention worldwide. Incidence of KP BSIs has been gradually increasing in recent years [3]. Moreover, KP BSIs resulted in high mortality rates ranged between 20% and 40% [4]. In previous study, we found the 30-day crude mortality rate of KP BSIs in East China has reached 26.39% [5].

It has been reported in the literature that the drug-resistant phenotype of the pathogen is strongly associated with bad prognosis [6,7]. Our previous study also showed that mortality and medical costs of patients with MDRKP (multidrug-resistant Klebsiella pneumoniae) or CRKP (carbapenem-resistant Klebsiella pneumoniae) BSIs were significantly higher than those of patients with non-MDR/CR BSIs [5]. Moreover, the proportion of MDRKP BSIs and CRKP BSIs among KP BSIs in Shanghai was as high as 66.49% and 51.98%, respectively [5]. Therefore, investigating the risk factors for MDRKP and CRKP BSIs is important for the prevention and control of KP BSIs.

Previous studies have explored risk factors for CRKP BSIs while very few studies have reported risk factors for MDRKP BSIs. Therefore, it is necessary to update risk factors investigation for MDRKP and CRKP BSIs. For this reason, we retrospectively analyzed risk factors for patients with MDRKP and CRKP BSIs in a large tertiary hospital in East China with a high bacterial resistance rate.

Materials and methods

Study design and setting

We used medical record data between 01/01/2018 and 31/12/2022 abstracted from Hospital Information System of Ruijin Hospital which is developed by the Computer Center of Ruijin Hospital. These data were retrospectively assessed for research purpose from 30/09/2023–31/10/2023. Ruijin Hospital is a tertiary-level hospital with 3,697 beds in East China. Ruijin Hospital has an annual outpatient and emergency care volume of approximately 5.36 million, with a total of nearly 150,000 discharges per year. All consecutively hospitalized patients with KP BSIs during the study period were included. Patients with at least one result of KP in blood culture were included in our study. Only the first episode of KP BSIs per patient was included. Patients with the following conditions were excluded: (i) positive culture results considered as contaminants; (ii) incomplete/inaccurate medical records; (iii) patients insisted on discharge from hospital against medical advice.

Ethics approval and consent to participate

The study was approved by the ethics committee of Ruijin Hospital (No. KY2023–083) on 13/07/2023. This is an observational retrospective study and all the data were obtained from medical record systems and analyzed anonymously, so the committee waived informed consent. The study was conducted in accordance with the Declaration of Helsinki. We investigated incidence, antimicrobial resistance, crude 30-day mortality rate, and risk factors for crude 30-day mortality of KP BSIs using the same dataset of this manuscript (S1 File) and published the findings in 2024 [5]. In this study, we investigated temporal distribution of proportion of KP BSIs attributed deaths, department distribution of KP BSIs and risk factors for MDRKP BSIs and CRKP BSIs which are entirely different research questions. There is no overlap in research content of the two studies.

Definitions

KP BSIs were defined as blood cultures positive for KP and accompanied by clinical signs and symptoms of infection [8]. The presence of KP BSIs was defined as the first positive blood culture of KP. Proportion of death for KP BSIs was defined as the number of KP BSIs attributed deaths per 100 patients with KP BSIs. Cases were defined as patients diagnosed with KP BSIs. MDR was defined as acquired insensitivity to at least one of three or more antimicrobial classes [9]. CR was defined as resistance to any carbapenems [10].

Data collection

The following clinical information about the patient was extracted from the hospital’s electronic medical record system: gender, age, department of admission, length of stay in ICU, length of hospitalization, underlying disease (malignancy, circulatory disease, endocrine disease, respiratory disease, genitourinary disease, gastrointestinal disease), history of invasive clinical procedures (surgery, paracentesis, arterial catheters, central venous catheters, invasive ventilators, urinary catheters, gastric catheters, drainage tubes), specific treatments (glucocorticosteroids, immunosuppressive agents, radiotherapy and chemotherapy), data on antibiotic therapy. Definitions of the variables collected are provided in S1 Table. All the datasets used and/or analyzed during the current study are listed in S1 File.

Microbiology

The KP isolates were all characterized using MALDITOF MS (bioMérieux, Marcy l’Etoile, France), and drug sensitivity was tested using VITEK®2 (bioMérieux, Marcy l’Etoile, France). Interpretation of drug sensitivity tests was in accordance with the 2022 Clinical and Laboratory Standard Institute (CLSI) standard [11].

Statistical analysis

Continuous variables that fit normal distribution were expressed as mean and standard deviation (SD), and continuous variables that did not fit normal distribution were expressed as median and interquartile range (IQR). Categorical variables were compared using the chi-square test and Fisher’s exact test. A generalized linear model was used to determine risk factors for infection. In conducting the risk factor analysis, univariate analysis was performed first. Correlations and relevant interactions between variables with P < 0.05 in univariate analysis were examined. After excluding highly correlated variables (correlation coefficients ≥0.70), the remaining variables were considered for inclusion in the multiple logistic regression model and screened using the Lease Absolute Shrinkage and Selection Operator (LASSO) penalization method (used to select the variables with λ = lambda.1se, which is the cross-validation error plus a standard error minimized by λ) [12]. Selected variables were included in the final multiple logistic regression model to determine their independent associations. The strength of these associations was determined by calculating odds ratio (OR) and 95% confidence interval (95% CI). All analyses were conducted using R version 4.2.1. To test the stability of the final multiple logistic regression model, variables were sequentially removed from the model and the significance of the remaining variables was checked [13]. Hosmer-Lemeshow test was performed to evaluate the goodness of fit of the regression models. P < 0.05 was considered statistically significant.

Results

Trends in the proportion of death for MDRKP BSIs and CRKP BSIs

A total of 379 eligible subjects were included in the study. Among 379 patients with KP BSIs, there were 252 (66.5%) MDRKP cases and 197 (52.0%) CRKP cases. There was a total of 119 deaths during admission, with the proportion of death was 40.9% (103/252) in the MDR group, 12.6% (16/127) in the non-MDR group, 47.2% (93/197) in the CR group, and 14.3% (26/182) in the non-CR group, with a statistically significant difference between resistant group and non-resistant group (both P < 0.001). The proportion of death for KP BSIs increased from 32.4% in 2018 to 36.0% in 2019, followed by a gradual decrease. The proportion of death for MDR group increased from 43.1% in 2018 to 52.2% in 2019, followed by a gradual decrease. The proportion of death for the non-MDR group gradually increased from 8.7% in 2018 to 16.2% in 2022. The proportion of death for the CR and non-CR groups increased from 48.7% and 14.3% in 2018 to 56.8% and 15.8% in 2019, respectively, and then gradually decreased. The details are shown in Fig 1.

Fig 1 — ALL, All KP BSIs; MDR, multidrug resistant; non-MDR, non-multidrug resistant; CR, carbapenem resistant; non-CR, non-carbapenem resistant.

Distribution of departments

KP BSIs were predominantly distributed in ICU, pancreatic surgery, burn unit, and hematology (23.0%, 14.2%, 12.1%, and 10.8%, respectively, as shown in Fig 2A). MDRKP BSIs were predominantly distributed in the ICU (31.0%), followed by burn unit (17.9%), hematology (11.5%), and pancreatic surgery (10.7%), details of which were shown in Fig 2B. Department distribution of CRKP BSIs was as well ICU (35.0%), followed by burn unit, hematology, and pancreatic surgery (22.3%, 11.2%, and 8.6%, respectively), as shown in detail in Fig 2C.

Risk factors for MDRKP BSIs and CRKP BSIs

Univariate analysis showed that age, male, some medical exposures within 90 days prior to the onset of BSIs, respiratory disease, genitourinary disease, gastrointestinal disease, some invasive procedures, use of some drugs within 90 days prior to diagnosis of BSIs were associated with MDRKP BSIs (Table 1). Multiple logistic regression analysis showed that genitourinary disease, invasive ventilator, history of antibiotic use in the 90 days prior to the diagnosis of BSIs, and carbapenem usage were independent risk factors for MDRKP BSIs (Table 1). The result of Hosmer-Lemeshow test (χ² = 8.78, P = 0.553) was indicative of good fit. Univariate analyses showed that the factors associated with CRKP BSIs included age, male, some medical exposures within 90 days prior to the onset of BSIs, respiratory disease, gastrointestinal disease, some invasive procedures, use of some drugs within 90 days prior to diagnosis of BSIs (Table 2). Independent risk factors for CRKP BSIs were respiratory disease, indwelling gastric tube, and carbapenem use and quantity (Table 2). The result of Hosmer-Lemeshow test (χ² = 1.66, P = 0.948) was indicative of good fit.

Table 1. Risk factors for multidrug-resistant Klebsiella pneumoniae bloodstream infections (MDRKP BSIs).

Characteristics	MDR (%) (N = 252)	non-MDR (%) (N = 127)	Univariate		Multiple
Characteristics	MDR (%) (N = 252)	non-MDR (%) (N = 127)	OR (95%CI)	P	aOR (95%CI)	P
Age (years), median (IQR)	61.50 (49.00-70.00)	64.00 (55.00-71.50)	0.99 (0.97-1.00)	0.042
Gender, male	189 (75.00)	81 (63.78)	1.70 (1.07-2.70)	0.023
Smoking	45 (17.86)	14 (11.02)	1.75 (0.94-3.44)	0.086
Alcohol drinking	37 (14.68)	11 (8.66)	1.81 (0.92-3.86)	0.100
Healthcare exposure
Time at risk (days), median (IQR)	16.00 (7.00-31.00)	6.00 (1.00-13.00)	1.03 (1.02-1.05)	0.000
Length of hospital stay (days), median (IQR)	19.00 (8.75-37.00)	10.00 (3.00-21.50)	1.02 (1.01-1.03)	0.000
ICU stay	75 (29.76)	17 (13.39)	2.74 (1.57-5.02)	0.000
Length of ICU stay (days), median (IQR)	0.00 (0.00-7.25)	0.00 (0.00-0.00)	1.02 (1.00-1.04)	0.027
Comorbidities
Chemotherapy or radiotherapy	26 (10.32)	17 (13.39)	0.74 (0.39-1.45)	0.375
Malignancy	49 (19.44)	25 (19.69)	0.98 (0.58-1.70)	0.956
Organic	23 (9.13)	12 (9.45)	0.96 (0.47-2.06)	0.919
Hematology	28 (11.11)	13 (10.24)	1.10 (0.56-2.26)	0.796
Disease of the circulatory system	94 (37.30)	44 (34.65)	1.12 (0.72-1.76)	0.612
Hypertension	77 (30.56)	40 (31.50)	0.96 (0.61-1.52)	0.852
Cerebrovascular disease	12 (4.76)	9 (7.09)	0.66 (0.27-1.65)	0.353
IHD	27 (10.71)	10 (7.87)	1.40 (0.68-3.14)	0.381
Endocrine, nutritional and metabolic diseases	63 (25.00)	35 (27.56)	0.88 (0.54-1.43)	0.591
Diabetes mellitus	47 (18.65)	32 (25.20)	0.68 (0.41-1.14)	0.140
Respiratory diseases	35 (13.89)	6 (4.72)	3.25 (1.43-8.79)	0.010
Diseases of the genitourinary system	36 (14.29)	5 (3.94)	4.07 (1.70-12.07)	0.004	3.43 (1.27-11.06)	0.023
Diseases of the gastrointestinal system	71 (28.17)	53 (41.73)	0.55 (0.35-0.86)	0.008
Invasive procedures
Surgery	167 (66.27)	70 (55.12)	1.60 (1.03-2.48)	0.035
Paracentesis	92 (36.51)	20 (15.75)	3.08 (1.82-5.41)	0.000	1.89 (0.99-3.70)	0.057
AC	52 (20.63)	13 (10.24)	2.28 (1.22-4.53)	0.013
Days of AC	0.00 (0.00-0.00)	0.00 (0.00-0.00)	1.04 (1.00-1.09)	0.090
CVC	181 (71.83)	60 (47.24)	2.85 (1.83-4.45)	0.000
Days of CVC	7.00 (0.00-21.25)	0.00 (0.00-5.50)	1.03 (1.02-1.05)	0.000
Invasive ventilator	110 (43.65)	17 (13.39)	5.01 (2.9-9.11)	0.000	2.02 (1.02-4.12)	0.047
Days of indwelling invasive ventilator	0.00 (0.00-7.00)	0.00 (0.00-0.00)	1.21 (1.11-1.34)	0.000
Urinary catheter	158 (62.70)	45 (35.43)	3.06 (1.97-4.80)	0.000
Days of indwelling urinary catheter	2.00 (0.00-15.00)	0.00 (0.00-2.00)	1.06 (1.03-1.09)	0.000
Gastric tube	108 (42.86)	19 (14.96)	4.26 (2.51-7.55)	0.000	1.38 (0.71-2.73)	0.348
Days of indwelling gastric tube	0.00 (0.00-13.00)	0.00 (0.00-0.00)	1.05 (1.02-1.08)	0.001
Drainage tube	130 (51.59)	38 (29.92)	2.50 (1.60-3.96)	0.000
Days of indwelling drainage tube	1.00 (0.00-15.00)	0.00 (0.00-1.50)	1.03 (1.01-1.06)	0.001
Drug usage
Corticosteroids	153 (60.71)	35 (27.56)	4.06 (2.57-6.52)	0.000	1.41 (0.78-2.54)	0.250
Immunosuppressor	24 (9.52)	9 (7.09)	1.38 (0.64-3.22)	0.429
Antibiotics	223 (88.49)	71 (55.91)	6.07 (3.63-10.33)	0.000	1.94 (1.00-3.80)	0.049
Combination therapy	204 (80.95)	44 (34.65)	8.02 (4.99-13.1)	0.000
Glycopeptides	117 (46.43)	21 (16.54)	4.37 (2.62-7.59)	0.000	1.27 (0.62-2.60)	0.514
Quantity (DDD), median (IQR)	0.00 (0.00-5.00)	0.00 (0.00-0.00)	1.17 (1.09-1.28)	0.000
Vancomycin	105 (41.67)	19 (14.96)	4.06 (2.39-7.20)	0.000
Quantity (DDD), median (IQR)	0.00 (0.00-4.10)	0.00 (0.00-0.00)	1.17 (1.08-1.29)	0.000
Oxyazolidinones
Linezolid	59 (23.41)	5 (3.94)	7.46 (3.2-21.81)	0.000	2.61 (0.99-8.18)	0.069
Quantity (DDD), median (IQR)	0.00 (0.00-0.00)	0.00 (0.00-0.00)	1.28 (1.14-1.53)	0.001
Carbapenems	168 (66.67)	32 (25.20)	5.94 (3.71-9.69)	0.000	1.23 (0.57-2.64)	0.602
Quantity (DDD), median (IQR)	3.92 (0.00-13.00)	0.00 (0.00-0.13)	1.16 (1.10-1.23)	0.000	1.05 (1.00-1.13)	0.050
Imipenem	106 (42.06)	27 (21.26)	2.69 (1.66-4.47)	0.000
Quantity (DDD), median (IQR)	0.00 (0.00-6.00)	0.00 (0.00-0.00)	1.10 (1.05-1.17)	0.000
Meropenem	96 (38.10)	8 (6.30)	9.15 (4.54-21.13)	0.000
Quantity (DDD), median (IQR)	0.00 (0.00-3.08)	0.00 (0.00-0.00)	1.30 (1.15-1.53)	0.000
Cephalosporins	114 (45.24)	36 (28.35)	2.09 (1.33-3.33)	0.002
Quantity (DDD), median (IQR)	0.00 (0.00-3.06)	0.00 (0.00-1.00)	1.05 (1.01-1.10)	0.040
β-lactam/β-lactamase inhibitor combinations	32 (12.70)	11 (8.66)	1.53 (0.77-3.29)	0.245
Quantity (DDD), median (IQR)	0.00 (0.00-0.00)	0.00 (0.00-0.00)	1.00 (0.97-1.04)	0.921
Piperacillin-tazobactam	15 (5.95)	6 (4.72)	1.28 (0.50-3.65)	0.623
Quantity (DDD), median (IQR)	0.00 (0.00-0.00)	0.00 (0.00-0.00)	0.99 (0.93-1.04)	0.628
Cefoperazone-sulbactam	16 (6.35)	5 (3.94)	1.65 (0.63-5.15)	0.337
Quantity (DDD), median (IQR)	0.00 (0.00-0.00)	0.00 (0.00-0.00)	1.02 (0.97-1.10)	0.496
Fluoroquinolones	57 (22.62)	10 (7.87)	3.42 (1.75-7.35)	0.007
Quantity (DDD), median (IQR)	0.00 (0.00-0.00)	0.00 (0.00-0.00)	1.09 (1.03-1.18)	0.020

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OR (95%CI), odds ratio (95% confidence interval); aOR (95%CI), adjusted odds ratio (95% confidence interval); IQR, interquartile range; BSIs, bloodstream infections; MDR, multidrug resistant; non-MDR, non-multidrug resistant; IHD, ischemic heart disease; ICU, intensive care unit; AC, arterial catheter; CVC, central venous catheter; DDD, defined daily dose.

Table 2. Risk factors for carbapenem-resistant Klebsiella pneumoniae bloodstream infections (CRKP BSIs).

Characteristics	CR (%) (N = 197)	non-CR (%) (N = 182)	Univariate		Multiple
Characteristics	CR (%) (N = 197)	non-CR (%) (N = 182)	OR (95%CI)	P	aOR (95%CI)	P
Age (years), median (IQR)	60.00 (48.00-70.00)	64.00 (55.00-72.00)	0.99 (0.97-1.00)	0.026
Gender, male	151 (76.65)	119 (65.38)	1.74 (1.11-2.73)	0.016
Smoking	36 (18.27)	23 (12.64)	1.55 (0.88-2.76)	0.132
Alcohol drinking	31 (15.74)	17 (9.34)	1.81 (0.98-3.47)	0.064
Healthcare exposure
Time at risk (days), median (IQR)	17.00 (8.00-31.00)	7.00 (2.00-18.00)	1.01 (1.00-1.02)	0.011
Length of hospital stay (days), median (IQR)	20.00 (9.00-37.00)	12.00 (3.00-26.75)	1.01 (1.00-1.02)	0.008
ICU stay	69 (35.03)	23 (12.64)	3.73 (2.23-6.42)	0.000	1.45 (0.73-2.89)	0.288
Length of ICU stay (days), median (IQR)	0.00 (0.00-10.00)	0.00 (0.00-0.00)	1.02 (1.01-1.04)	0.007
Comorbidities
Chemotherapy or radiotherapy	19 (9.64)	24 (13.19)	0.70 (0.37-1.33)	0.279
Malignancy	31 (15.74)	43 (23.63)	0.60 (0.36-1.01)	0.054
Organic	13 (6.60)	22 (12.09)	0.51 (0.24-1.04)	0.069
Hematology	18 (9.14)	23 (12.64)	0.70 (0.36-1.33)	0.275
Disease of the circulatory system	77 (39.09)	61 (33.52)	1.27 (0.84-1.94)	0.261
Hypertension	65 (32.99)	52 (28.57)	1.23 (0.80-1.91)	0.352
Cerebrovascular disease	9 (4.57)	12 (6.59)	0.68 (0.27-1.64)	0.392
Heart failure	7 (3.55)	7 (3.85)	0.92 (0.31-2.74)	0.880
IHD	18 (9.14)	19 (10.44)	0.86 (0.43-1.71)	0.670
Endocrine, nutritional and metabolic diseases	50 (25.38)	48 (26.37)	0.95 (0.60-1.51)	0.825
Diabetes mellitus	38 (19.29)	41 (22.53)	0.82 (0.50-1.35)	0.438
Respiratory diseases	32 (16.24)	9 (4.95)	3.73 (1.80-8.52)	0.001	3.39 (1.40-8.78)	0.009
Diseases of the genitourinary system	24 (12.18)	17 (9.34)	1.35 (0.70-2.63)	0.375
Diseases of the gastrointestinal system	52 (26.40)	72 (39.56)	0.55 (0.35-0.84)	0.007
Invasive procedures
Surgery	132 (67.01)	105 (57.69)	1.49 (0.98-2.27)	0.062
Paracentesis	71 (36.04)	41 (22.53)	1.94 (1.24-3.07)	0.004
AC	46 (23.35)	19 (10.44)	2.61 (1.49-4.75)	0.001
Days of AC	0.00 (0.00-0.00)	0.00 (0.00-0.00)	1.03 (1.00-1.07)	0.085
CVC	146 (74.11)	95 (52.20)	2.62 (1.71-4.06)	0.000
Days of CVC	8.00 (0.00-22.00)	1.00 (0.00-10.00)	1.01 (1.00-1.03)	0.007
Invasive ventilator	100 (50.76)	27 (14.84)	5.92 (3.65-9.85)	0.000	1.82 (0.95-3.47)	0.069
Days of indwelling invasive ventilator	1.00 (0.00-9.00)	0.00 (0.00-0.00)	1.13 (1.08-1.19)	0.000
Urinary catheter	135 (68.53)	68 (37.36)	3.65 (2.40-5.61)	0.000
Days of indwelling urinary catheter	5.00 (0.00-17.00)	0.00 (0.00-2.00)	1.05 (1.03-1.08)	0.000
Gastric tube	98 (49.75)	29 (15.93)	5.22 (3.25-8.60)	0.000	2.12 (1.15-3.90)	0.016
Days of indwelling gastric tube	0.00 (0.00-15.00)	0.00 (0.00-0.00)	1.06 (1.04-1.09)	0.000
Drainage tube	108 (54.82)	60 (32.97)	2.47 (1.63-3.76)	0.000
Days of indwelling drainage tube	1.00 (0.00-16.00)	0.00 (0.00-2.00)	1.03 (1.02-1.05)	0.000
Drug usage
Corticosteroids	128 (64.97)	60 (32.97)	3.77 (2.48-5.80)	0.000	1.36 (0.78-2.36)	0.276
Immunosuppressor	15 (7.61)	18 (9.89)	0.75 (0.36-1.54)	0.434
Antibiotics	184 (93.40)	110 (60.44)	9.26 (5.06-18.22)	0.000
Combination therapy	173 (87.82)	75 (41.21)	10.28(6.21-17.60)	0.000
Glycopeptides	102 (51.78)	36 (19.78)	4.35 (2.77-6.96)	0.000
Quantity (DDD), median (IQR)	0.25 (0.00-6.00)	0.00 (0.00-0.00)	1.09 (1.04-1.14)	0.000
Vancomycin	91 (46.19)	33 (18.13)	3.88 (2.44-6.27)	0.000
Quantity (DDD), median (IQR)	0.00 (0.00-5.00)	0.00 (0.00-0.00)	1.07 (1.03-1.13)	0.001
Oxyazolidinones
Linezolid	54 (27.41)	10 (5.49)	6.50 (3.33-13.96)	0.000	2.17 (0.98-5.08)	0.063
Quantity (DDD), median (IQR)	0.00 (0.00-1.50)	0.00 (0.00-0.00)	1.25 (1.14-1.41)	0.000
Aminoglycosides	26 (13.20)	5 (2.75)	5.38 (2.19-16.20)	0.001
Quantity (DDD), median (IQR)	0.00 (0.00-0.00)	0.00 (0.00-0.00)	1.19 (1.06-1.46)	0.033
Carbapenems	151 (76.65)	49 (26.92)	8.91 (5.64-14.32)	0.000	2.74 (1.43-5.23)	0.002
Quantity (DDD), median (IQR)	6.00 (0.25-15.00)	0.00 (0.00-0.75)	1.17 (1.13-1.23)	0.000	1.06 (1.01-1.12)	0.018
Imipenem	96 (48.73)	37 (20.33)	3.72 (2.38-5.93)	0.000
Quantity (DDD), median (IQR)	0.00 (0.00-9.00)	0.00 (0.00-0.00)	1.15 (1.09-1.22)	0.000
Meropenem	87 (44.16)	17 (9.34)	7.68 (4.43-14.01)	0.000
Quantity (DDD), median (IQR)	0.00 (0.00-4.50)	0.00 (0.00-0.00)	1.17 (1.10-1.26)	0.000
Cephalosporins	93 (47.21)	57 (31.32)	1.96 (1.29-3.00)	0.002
Quantity (DDD), median (IQR)	0.00 (0.00-4.00)	0.00 (0.00-1.00)	1.06 (1.02-1.10)	0.008
β-lactam/β-lactamase inhibitor combinations	25 (12.69)	18 (9.89)	1.32 (0.70-2.55)	0.392
Quantity (DDD), median (IQR)	0.00 (0.00-0.00)	0.00 (0.00-0.00)	1.00 (0.97-1.03)	0.930
Piperacillin-tazobactam	10 (5.08)	11 (6.04)	0.83 (0.34-2.02)	0.681
Quantity (DDD), median (IQR)	0.00 (0.00-0.00)	0.00 (0.00-0.00)	0.98 (0.91-1.03)	0.503
Cefoperazone-sulbactam	13 (6.60)	8 (4.40)	1.54 (0.63-3.97)	0.352
Quantity (DDD), median (IQR)	0.00 (0.00-0.00)	0.00 (0.00-0.00)	1.01 (0.97-1.07)	0.579
Fluoroquinolones	45 (22.84)	22 (12.09)	2.15 (1.25-3.81)	0.007
Quantity (DDD), median (IQR)	0.00 (0.00-0.00)	0.00 (0.00-0.00)	1.01 (0.98-1.04)	0.605

Open in a new tab

OR (95%CI), odds ratio (95% confidence interval); aOR (95%CI), adjusted odds ratio (95% confidence interval); IQR, interquartile range; BSIs, bloodstream infections; CR, carbapenem resistant; non-CR, non-carbapenem resistant; IHD, ischemic heart disease; ICU, intensive care unit; AC, arterial catheter; CVC, central venous catheter; DDD, defined daily dose.

Discussion

To the best of our knowledge, this is the first report of a risk factor analysis of both MDRKP and CRKP BSIs in eastern China, a region with a high prevalence of drug-resistant and virulent isolates [14]. The proportion of death for both MDRKP BSIs and CRKP BSIs rose to high point in 2019 and showed a gradual trend of decreasing afterwards, which we hypothesize is related to the fact that under China’s coronavirus disease 2019 (COVID-19) policy, all patients who tested positive for nucleic acid were transferred to sentinel hospital in a closed loop. As China’s COVID-19 control policy has been downgraded, more local studies should also be conducted in the future to analyze the impact of COVID-19 pandemics on mortality of BSIs.

Our study showed that the distribution of MDRKP and CRKP BSIs was highest in the ICU, which is consistent with other studies [15,16]. Interestingly, our risk factor analysis showed that ICU admission 90 days prior to diagnosis and the number of ICU days were risk factors for MDRKP and CRKP BSIs. The high prevalence of MDRKP and CRKP BSIs in the ICU maybe due to the presence of multiple infections in critically ill patients, a high number of invasive maneuvers, and frequent use of advanced antibiotic drugs. ICU has been described as factories that generate, spread and amplify antimicrobial resistance [1,17,18]. Selection of resistant strains and new mutations due to frequent and inappropriate application of antimicrobials influence emergence and rapid spread of multidrug-resistant pathogens in ICU [18]. Moreover, CRKP could be detected in various equipment of ICU including beds, tables, ﬂoors and ventilators, signiﬁcantly higher than that of ordinary wards [1]. Many previous studies have shown that ICU admission was a risk factor for CRKP BSIs [15,19–22]. However, ICU admission 90 days before diagnosis was not an independent risk factor in the multiple logistic regression analysis, which may be influenced by other confounding factors. In addition, MDRKP and CRKP BSIs were higher in burn units and hematology. Burn patients are more likely to undergo invasive procedures and are more susceptible to infection, owing to burn wounds are favorable sites for bacterial colonization prior to healing [23]. Hematology inpatients with underlying hematologic malignancies, radiation and chemotherapy, neutropenia, gastrointestinal mucositis, and prolonged hospitalization are favorable conditions for the spread of MDRKP and CRKP BSIs [24].

As reported in other studies, age, male are risk factors for CRKP BSIs [1,16]. Our study found that age and male were risk factors for MDRKP BSIs. In addition, time at risk and length of hospitalization were risk factors for MDRKP and CRKP BSIs. The probability of bacterial infections developed from colonization rises as the length of hospitalization increases. Prolonged hospitalization has been reported to be a risk factor for colonization by antibiotic-resistant bacteria [25]. At the same time, infections with drug-resistant bacteria make the patient’s condition more complex and more difficult to treat, and ultimately lead to longer hospital stays.

Among the comorbidities, respiratory and genitourinary diseases were independent risk factors for CRKP BSIs and MDRKP BSIs, respectively. Most of the respiratory diseases are lung infections in this study (29/41, 70.7%), and previous studies have reported a relationship between lung infections and CRKP BSIs [16]. Common respiratory operations for patients with respiratory diseases, such as tracheal intubation, sputum suction, and tracheoscopy often lead to damage of airway mucosa, allowing the bacteria colonizing the respiratory tract or the equipment to enter the bloodstream, which can increase the probability of BSI [15,16]. Likewise, common invasive operations for patients with genitourinary diseases such as indwelling urinary catheter and urologic surgical procedures could damage the urinary tract and increase the risk of BSIs [15]. Additionally, our study found that surgical procedures and indwelling urinary catheter were strongly associated with MDRKP and CRKP BSIs (Tables 1 and 2). These operations tend to increase opportunities of infection by breaching the mucosal barrier, allowing bacteria to cross the barrier into the bloodstream [1,6,15].

Interestingly, both univariate and multiple logistic regression analyses indicated antibiotic exposure as a risk factor. Antibiotic exposure usually leads to the emergence of drug-resistant bacteria, and antibiotic use alters the microbiome, resulting in dominance of drug-resistant KP [24,26]. Carbapenems are usually considered as a last resort to combat infections caused by multidrug-resistant bacteria. Our results also confirmed that the use of carbapenems and its quantity prior to BSIs were independent risk factors for CRKP BSIs. Carbapenem use induces the production of acquired Klebsiella pneumoniae carbapenemase (KPC), which is one of the main mechanisms of CRKP resistance [27]. Moreover, CRKP can be transmitted by drug-resistant plasmids, which can cause more widespread CRKP infections [28]. Similar to some previous reports [29,30], we also found that prior exposure to quinolones was also an important risk factor. This may be due to the fact that the plasmid-encoded quinolone resistance determinant gene is located on the KP plasmid containing the KPC gene [31]. Additionally, quinolone use may have reduced Oprd pore protein expression and caused upregulation of the multidrug efflux pump MexEF-OprN, which is also a mechanism of carbapenem resistance [32]. We identified glucocorticoids as a risk factor for CRKP BSIs and MDRKP BSIs, however, multiple logistic regression analysis indicated that they were not an independent predictor. Glucocorticoids are recognized as a marker of an immunocompromised state and are more susceptible to serious infections [33]. Unlike other studies, we found that combination antimicrobial therapy may be a risk factor for MDRKP and CRKP BSIs, and we hypothesize that this is because combination therapy increases bacterial resistance to antibiotics [34]. In addition, we found that previous use of glycopeptides and cephalosporins were risk factors for MDRKP and CRKP BSIs, which is consistent with other studies [1,6]. We found that prior use of linezolid may increase the risk of MDRKP and CRKP BSIs, although multifactorial analyses showed that it was not an independent risk factor. This may be due to the fact that most of the patients with prior linezolid use in our study were concurrently using carbapenems and thus would have been skewed. And whether prior use of linezolid directly leads to increased infections with drug-resistant bacteria needs to be further investigated in the future.

This study has several limitations. First, this is a single-center retrospective investigation with a relatively limited sample size which may not fully represent the characteristics of inpatients from other regions in China. In the future, a large-scale prospective multicenter study is needed to validate the results and accordingly to enhance the generalizability and reliability of the findings. Second, data on environmental exposure such as contamination of KP on the surfaces of objects like hospital bed rail and stethoscope, and inpatient density of wards were not available. These factors might have had an impact on risk factors for MDRKP and CRKP BSIs. Future research should address these points. Additionally, the mechanisms of CRKP and MDRKP are complex and diverse, and the risk factors may vary with different resistant mechanisms. This study did not detect resistant mechanisms, and molecular and bioinformatics studies should be conducted in future studies to better understand the effect of resistance mechanisms on infections.

Our study sheds light on which inpatients are at high risk of acquiring MDRKP and CRKP BSIs. This may have important implications for clinical interventions and public health policies. First, the findings would guide clinicians to identify inpatients at high-risk of MDRKP and CRKP BSIs at an early stage and initiate prompt targeted infection control measures. Second, infection prevention strategies such as enhanced hand hygiene, environmental disinfection, and isolation protocols should be prioritized in the common departments of MDRKP and CRKP BSIs. Finally, the development of a screening or surveillance system for MDRKP and CRKP BSIs based on the findings might help to prevent and control MDRKP and CRKP BSIs.

Conclusions

Genitourinary disease, invasive ventilator, history of antibiotic use (carbapenems in particular) in the 90 days prior to the diagnosis of BSIs are independent risk factors for MDRKP BSIs, whereas independent risk factors for CRKP BSIs include respiratory disease, gastric tubes, and carbapenem use in the 90 days prior to the diagnosis of BSIs. ICU, burn unit, hematology and pancreatic surgery are common departments of MDRKP and CRKP BSIs. Pre-emptive identification and isolation measures among inpatients with these risk factors or from these departments would be a cost-effective way to identify, manage, and reduce the spread of MDRKP and CRKP BSIs.

Supporting information

S1 Table. Definitions of each variable included in risk factors analysis for multidrug-resistant Klebsiella pneumoniae and carbapenem-resistant Klebsiella pneumoniae bloodstream infections.

(DOCX)

pone.0324925.s001.docx^{(30.4KB, docx)}

S1 File. Dataset of clinical characteristics of 379 inpatients with Klebsiella pneumoniae bloodstream infections.

(XLSX)

pone.0324925.s002.xlsx^{(110.6KB, xlsx)}

Acknowledgments

We would like to thank Xuedong Wang for his assistance in the data organization process.

Data Availability

All relevant data are within the manuscript and its Supporting information files.

Funding Statement

The author(s) received no specific funding for this work.

References

1.Chang H, Wei J, Zhou W, Yan X, Cao X, Zuo L, et al. Risk factors and mortality for patients with Bloodstream infections of Klebsiella pneumoniae during 2014-2018: clinical impact of carbapenem resistance in a large tertiary hospital of China. J Infect Public Health. 2020;13(5):784–90. doi: 10.1016/j.jiph.2019.11.014 [DOI] [PubMed] [Google Scholar]
2.Nielsen SL, Pedersen C, Jensen TG, Gradel KO, Kolmos HJ, Lassen AT. Decreasing incidence rates of bacteremia: a 9-year population-based study. J Infect. 2014;69(1):51–9. doi: 10.1016/j.jinf.2014.01.014 [DOI] [PubMed] [Google Scholar]
3.Diekema DJ, Hsueh P-R, Mendes RE, Pfaller MA, Rolston KV, Sader HS, et al. The microbiology of bloodstream infection: 20-year trends from the SENTRY antimicrobial surveillance program. Antimicrob Agents Chemother. 2019;63(7):e00355–19. doi: 10.1128/AAC.00355-19 [DOI] [PMC free article] [PubMed] [Google Scholar]
4.Chew KL, Lin RTP, Teo JWP. Klebsiella pneumoniae in Singapore: hypervirulent infections and the carbapenemase threat. Front Cell Infect Microbiol. 2017;7:515. doi: 10.3389/fcimb.2017.00515 [DOI] [PMC free article] [PubMed] [Google Scholar]
5.Xiao S, Zhou S, Cao H, Han L, Zhao S, Wang X. Incidence, antimicrobial resistance and mortality of Klebsiella pneumoniae bacteraemia in Shanghai, China, 2018–2022. Infectious Diseases. 2024;56(12):1021-1030. [DOI] [PubMed] [Google Scholar]
6.Xiao T, Zhu Y, Zhang S, Wang Y, Shen P, Zhou Y, et al. A retrospective analysis of risk factors and outcomes of carbapenem-resistant Klebsiella pneumoniae bacteremia in nontransplant patients. J Infect Dis. 2020;221(Suppl 2):S174–83. doi: 10.1093/infdis/jiz559 [DOI] [PubMed] [Google Scholar]
7.Ben-David D, Kordevani R, Keller N, Tal I, Marzel A, Gal-Mor O, et al. Outcome of carbapenem resistant Klebsiella pneumoniae bloodstream infections. Clin Microbiol Infect. 2012;18(1):54–60. doi: 10.1111/j.1469-0691.2011.03478.x [DOI] [PubMed] [Google Scholar]
8.Chen Y, Chen Y, Liu P, Guo P, Wu Z, Peng Y, et al. Risk factors and mortality for elderly patients with bloodstream infection of carbapenem resistance Klebsiella pneumoniae: a 10-year longitudinal study. BMC Geriatr. 2022;22(1):573. doi: 10.1186/s12877-022-03275-1 [DOI] [PMC free article] [PubMed] [Google Scholar]
9.Magiorakos A-P, Srinivasan A, Carey RB, Carmeli Y, Falagas ME, Giske CG, 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. doi: 10.1111/j.1469-0691.2011.03570.x [DOI] [PubMed] [Google Scholar]
10.Liu K-S, Tong Y-S, Lee M-T, Lin H-Y, Lu M-C. Risk factors of 30-day all-cause mortality in patients with carbapenem-resistant Klebsiella pneumoniae bloodstream infection. J Pers Med. 2021;11(7):616. doi: 10.3390/jpm11070616 [DOI] [PMC free article] [PubMed] [Google Scholar]
11.Fostervold A, Raffelsberger N, Hetland MAK, Bakksjø R, Bernhoff E, Samuelsen Ø, et al. Risk of death in Klebsiella pneumoniae bloodstream infections is associated with specific phylogenetic lineages. J Infect. 2024;88(5):106155. doi: 10.1016/j.jinf.2024.106155 [DOI] [PubMed] [Google Scholar]
12.Friedman J, Hastie T, Tibshirani R. Regularization paths for generalized linear models via coordinate descent. J Stat Softw. 2010;33(1):1–22. doi: 10.18637/jss.v033.i01 [DOI] [PMC free article] [PubMed] [Google Scholar]
13.Zhao S, Perry MR, Kennedy S, Wilson J, Chase-Topping ME, Anderson E, et al. Risk factors for carbapenemase-producing organisms among inpatients in Scotland: a national matched case-control study. Infect Control Hosp Epidemiol. 2021;42(8):968–77. doi: 10.1017/ice.2020.1351 [DOI] [PubMed] [Google Scholar]
14.Zhang Y, Zhao C, Wang Q, Wang X, Chen H, Li H, et al. High prevalence of hypervirulent Klebsiella pneumoniae infection in China: geographic distribution, clinical characteristics, and antimicrobial resistance. Antimicrob Agents Chemother. 2016;60(10):6115–20. doi: 10.1128/AAC.01127-16 [DOI] [PMC free article] [PubMed] [Google Scholar]
15.Li Y, Li J, Hu T, Hu J, Song N, Zhang Y, et al. Five-year change of prevalence and risk factors for infection and mortality of carbapenem-resistant Klebsiella pneumoniae bloodstream infection in a tertiary hospital in North China. Antimicrob Resist Infect Control. 2020;9(1):79. doi: 10.1186/s13756-020-00728-3 [DOI] [PMC free article] [PubMed] [Google Scholar]
16.Cao Z, Yue C, Kong Q, Liu Y, Li J. Risk factors for a hospital-acquired carbapenem-resistant Klebsiella pneumoniae bloodstream infection: a five-year retrospective study. Infect Drug Resist. 2022;15:641–54. doi: 10.2147/IDR.S342103 [DOI] [PMC free article] [PubMed] [Google Scholar]
17.Hu Y, Ping Y, Li L, Xu H, Yan X, Dai H. A retrospective study of risk factors for carbapenem-resistant Klebsiella pneumoniae acquisition among ICU patients. J Infect Dev Ctries. 2016;10(3):208–13. doi: 10.3855/jidc.6697 [DOI] [PubMed] [Google Scholar]
18.Brusselaers N, Vogelaers D, Blot S. The rising problem of antimicrobial resistance in the intensive care unit. Ann Intensive Care. 2011;1:47. doi: 10.1186/2110-5820-1-47 [DOI] [PMC free article] [PubMed] [Google Scholar]
19.Kofteridis DP, Valachis A, Dimopoulou D, Maraki S, Christidou A, Mantadakis E, et al. Risk factors for carbapenem-resistant Klebsiella pneumoniae infection/colonization: a case-case-control study. J Infect Chemother. 2014;20(5):293–7. doi: 10.1016/j.jiac.2013.11.007 [DOI] [PubMed] [Google Scholar]
20.Gómez Rueda V, Zuleta Tobón JJ. Risk factors for infection with carbapenem-resistant Klebsiella pneumoniae: a case-case-control study. Colomb Med (Cali). 2014;45(2):54–60. doi: 10.25100/cm.v45i2.1417 [DOI] [PMC free article] [PubMed] [Google Scholar]
21.Mills JP, Talati NJ, Alby K, Han JH. The epidemiology of carbapenem-resistant Klebsiella pneumoniae colonization and infection among long-term acute care hospital residents. Infect Control Hosp Epidemiol. 2016;37(1):55–60. doi: 10.1017/ice.2015.254 [DOI] [PMC free article] [PubMed] [Google Scholar]
22.Liao Q, Yuan Y, Zhang W, Deng J, Kang M. Carbapenemase genes, virulence genes, and molecular epidemiology of carbapenem-resistant Klebsiella pneumoniae derived from bloodstream infections. Sichuan Da Xue Xue Bao Yi Xue Ban. 2024;55(2):391–6. doi: 10.12182/20240360202 [DOI] [PMC free article] [PubMed] [Google Scholar]
23.Zhou S, Xiao S, Wang X, Wang X, Han L. Risk factors and pathogens of wound infection in burn inpatients from East China. Antibiotics (Basel). 2023;12(9):1432. doi: 10.3390/antibiotics12091432 [DOI] [PMC free article] [PubMed] [Google Scholar]
24.Micozzi A, Gentile G, Minotti C, Cartoni C, Capria S, Ballarò D, et al. Carbapenem-resistant Klebsiella pneumoniae in high-risk haematological patients: factors favouring spread, risk factors and outcome of carbapenem-resistant Klebsiella pneumoniae bacteremias. BMC Infect Dis. 2017;17(1):203. doi: 10.1186/s12879-017-2297-9 [DOI] [PMC free article] [PubMed] [Google Scholar]
25.Cohen MJ, Anshelevich O, Raveh D, Broide E, Rudensky B, Yinnon AM. Acquisition of multidrug-resistant organisms among hospital patients hospitalized in beds adjacent to critically ill patients. Infect Control Hosp Epidemiol. 2006;27(7):675–81. doi: 10.1086/505919 [DOI] [PubMed] [Google Scholar]
26.Bleumin D, Cohen MJ, Moranne O, Esnault VLM, Benenson S, Paltiel O, et al. Carbapenem-resistant Klebsiella pneumoniae is associated with poor outcome in hemodialysis patients. J Infect. 2012;65(4):318–25. doi: 10.1016/j.jinf.2012.06.005 [DOI] [PubMed] [Google Scholar]
27.Orsi GB, Bencardino A, Vena A, Carattoli A, Venditti C, Falcone M, et al. Patient risk factors for outer membrane permeability and KPC-producing carbapenem-resistant Klebsiella pneumoniae isolation: results of a double case-control study. Infection. 2013;41(1):61–7. doi: 10.1007/s15010-012-0354-2 [DOI] [PubMed] [Google Scholar]
28.Cross SN, Potter JA, Aldo P, Kwon JY, Pitruzzello M, Tong M, et al. Viral infection sensitizes human fetal membranes to bacterial lipopolysaccharide by MERTK inhibition and inflammasome activation. J Immunol. 2017;199(8):2885–95. doi: 10.4049/jimmunol.1700870 [DOI] [PMC free article] [PubMed] [Google Scholar]
29.Trecarichi EM, Pagano L, Martino B, Candoni A, Di Blasi R, Nadali G, et al. Bloodstream infections caused by Klebsiella pneumoniae in onco-hematological patients: clinical impact of carbapenem resistance in a multicentre prospective survey. Am J Hematol. 2016;91(11):1076–81. doi: 10.1002/ajh.24489 [DOI] [PubMed] [Google Scholar]
30.Tumbarello M, Trecarichi EM, Tumietto F, Del Bono V, De Rosa FG, Bassetti M, et al. Predictive models for identification of hospitalized patients harboring KPC-producing Klebsiella pneumoniae. Antimicrob Agents Chemother. 2014;58(6):3514–20. doi: 10.1128/AAC.02373-13 [DOI] [PMC free article] [PubMed] [Google Scholar]
31.Jiao Y, Qin Y, Liu J, Li Q, Dong Y, Shang Y, et al. Risk factors for carbapenem-resistant Klebsiella pneumoniae infection/colonization and predictors of mortality: a retrospective study. Pathog Glob Health. 2015;109(2):68–74. doi: 10.1179/2047773215Y.0000000004 [DOI] [PMC free article] [PubMed] [Google Scholar]
32.Tanimoto K, Tomita H, Fujimoto S, Okuzumi K, Ike Y. Fluoroquinolone enhances the mutation frequency for meropenem-selected carbapenem resistance in Pseudomonas aeruginosa, but use of the high-potency drug doripenem inhibits mutant formation. Antimicrob Agents Chemother. 2008;52(10):3795–800. doi: 10.1128/AAC.00464-08 [DOI] [PMC free article] [PubMed] [Google Scholar]
33.Ababneh MA, Rababa’h AM, Almomani BA, Ayoub AM, Al-Azzam SI. A ten-year surveillance of P aeruginosa bloodstream infections in a tertiary care hospital: trends and risk factors for mortality. Int J Clin Pract. 2021;75(9):e14409. doi: 10.1111/ijcp.14409 [DOI] [PubMed] [Google Scholar]
34.Paul M, Carmeli Y, Durante-Mangoni E, Mouton JW, Tacconelli E, Theuretzbacher U, et al. Combination therapy for carbapenem-resistant gram-negative bacteria. J Antimicrob Chemother. 2014;69(9):2305–9. doi: 10.1093/jac/dku168 [DOI] [PubMed] [Google Scholar]

PLoS One. 2025 May 22;20(5):e0324925. doi: 10.1371/journal.pone.0324925.r001

Author response to Decision Letter 0

31 Dec 2024

PLoS One. doi: 10.1371/journal.pone.0324925.r002

Decision Letter 0

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11 Feb 2025

PONE-D-24-58014Risk factors for multidrug-resistant and carbapenem-resistant Klebsiella pneumoniae bloodstream infections in Shanghai: a five-year retrospective cohort studyPLOS ONE

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Your manuscript [PONE-D-24-58014] has passed the review stage and is ready for ‎revision. ‎To ensure the Editor and Reviewers can recommend that your revised manuscript be ‎accepted, ‎‎‎please pay careful attention to each comment posted underneath ‎this email. This way we ‎can ‎‎avoid future clarifications and revisions, moving swiftly to ‎a decision.‎

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Why wasn't there an investigation into the risk factors for mortality in Klebsiella pneumoniae bloodstream infections?

The study effectively explores CRKP and MDR KP. However, incorporating a discussion of risk scoring systems like the Increment CPE Score could strengthen the paper by providing a framework for predicting and understanding mortality risk in these infections. I recommend the authors consider adding this to the discussion.

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Reviewer #1: I appreciate the opportunity to evaluate this manuscript. It provides valuable insights into the risk factors for multidrug-resistant and carbapenem-resistant Klebsiella pneumoniae bloodstream infections, and I have a few comments and suggestions that may help enhance its clarity and impact.

The introduction contains several long sentences that could be broken down for better readability. For example, the sentence "Moreover, KP BSIs resulted in high mortality rates ranged between 20% and 40%, which has attracted attention" could be split into two sentences for clarity.

The terms "MDRKP" and "CRKP" are introduced without prior definitions in the background section.

The phrase "the resistance situation has become more serious in recent years" is somewhat redundant, as it implies a known trend without providing specific evidence.

The sentence "Only the first episode of each patient was included and only one episode per patient was included" is redundant. It can be simplify to: "Only the first episode of KP BSI per patient was included."

The phrasing "Definition of each variable corresponding to these data was listed in Appendix Table 1" is vague and should be made clearer. It can be stated as "Definitions of the variables collected are provided in Appendix Table 1."

The phrase "Because of the retrospective nature of the study, the committee waived informed consent" may lead to misinterpretation and could benefit from further clarification.

The discussion around ICU admissions is well-articulated, linking it to the increased prevalence of MDRKP and CRKP BSIs. However, it would strengthen the argument to include references or data that support the assertion that ICUs "generate, spread, and amplify antimicrobial resistance." Citing specific studies or statistics could bolster this claim.

The identification of respiratory and genitourinary diseases as independent risk factors is significant. Consider discussing the biological plausibility behind these associations in more detail, perhaps by referencing studies that have explored the mechanisms linking these conditions to increased susceptibility to infections.

To enhance the clarity and readability of your paper, I recommend avoiding nested parentheses (lines 96-97 and line 103).

In line 120, you mentioned the ratio of ratios (OR). It should be referred to as the Odds Ratio.

Have you used a generalized linear mixed model or a generalized linear model? (Line 110).

How did you assess the goodness of fit of the logistic regression model?

Multiple logistic regression is the more appropriate term than multivariate logistic regression.

Reviewer #2: Dear Authors

Thank for you the write-up. Kindly address the following concerns

General concerns

If patients with less than 48 hours of admission were excluded, then the title and focus of the study should reflect Hospital-acquired Klebsiella blood stream infections in order to properly align with the exclusion criteria otherwise, a clear and scientifically justifiable explanation should be given for the referenced exclusion criterion

The conclusion sounds too sentimental and would be better rephrased

specific concerns

Abstract should contain at least a statement of reflecting background before jumping to objectives

An abbreviation “CR” was introduced in the abstract which had not been previously explained

Line 51, readers will appreciate better if ‘good’ or ‘bad’ is used to properly qualify the ‘prognosis’ in the text.

Line 54% - please clarify is it proportion among all blood culture isolates or among Klebsiella isolates?

Line 57 – the import of the statement is not well articulated and difficult to understand

Line 120, kindly correct, ‘ratio of ratios’

Reviewer #3: Compared with some prior submissions, the writing in this article is exceptionally good. I read through it enough to get the sense that a fairly good writer composed this work, compared with the struggles one sometimes sees in articles that have to undergo repeated rewrites. This is a very useful topic in need of review across each health care system, and region with its own unique epidemiological, demographic and climatic-meteorologic-ecological settings. Long term studies focused on bacteriological phenotypic changes regarding MDRKP and CRKP treatment are most important, and very long term studies of changes in frequencies over time for a patter of ten to twenty years certain provides us with very important insights into the evolutionary process of pathogens and the development of drug resistance. This article is certain succinct enough for me with regard to how it reports the overall findings. Some individuals might be a little too detail oriented with figure 2, but that alone is not enough to really demand much of a change in the three (2 + 1) color patterns theoretically expressed due to the minor differences in figure A (ALL) versus the remaining two (a Cardiothoracic Surgery vs Pancreatic Surgery vs Burn Unit color mismatch.). This may very well be due to the printing of these figures and software issues, but I do not necessarily require that somehow this be fully and completely dealt with. In theory, such a correction or change should be quite easy to render in the submission of a final draft for publication. This change is requested, even suggested, but is not required.

Reviewer #4: Review Comments to the Author

The study is well-designed and addresses an important topic with significant clinical relevance, especially in regions with high levels of antimicrobial resistance. The statistical analysis is thorough, and the conclusions are well-supported by the data. The manuscript is written in clear English, and the figures and tables effectively illustrate the findings. However, the following recommendations are suggested to enhance the paper:

1. A more detailed discussion of the limitations is crucial for improving transparency and providing a clearer framework for future research.

2. Expanding on the implications for clinical interventions and public health policies would significantly increase the practical impact of the findings.

3. Additionally, the descriptive captions for figures and tables should be improved to ensure they are clear and easily understandable on their own.

4. The author should specify the name of the electronic medical record system used.

**********

6. PLOS authors have the option to publish the peer review history of their article (what does this mean? ). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy .

Reviewer #1: Yes: Farzane Ahmadi

Reviewer #2: No

Reviewer #3: Yes: Brian L Altonen

Reviewer #4: No

**********

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PLoS One. 2025 May 22;20(5):e0324925. doi: 10.1371/journal.pone.0324925.r003

Author response to Decision Letter 1

12 Mar 2025

Dear Editor,

We have submitted the manuscript entitled “Risk factors for multidrug-resistant and carbapenem-resistant Klebsiella pneumoniae bloodstream infections in Shanghai: a five-year retrospective cohort study” to PLOS ONE (manuscript ID: PONE-D-24-58014). Now we submitted a revised version of this manuscript, in which each point raised by editor and the reviewers has been addressed and all the changes have been highlighted in yellow throughout the manuscript. We deeply appreciate the valuable comments and suggestions.

Why wasn't there an investigation into the risk factors for mortality in Klebsiella pneumoniae bloodstream infections?

Response: Thank you for your advice. Actually we have investigated risk factors for crude 30-day mortality of Klebsiella pneumoniae bloodstream infections (KP BSIs) using the same dataset of this manuscript and published the findings in 2024, please see reference 5 (https://doi.org/10.1080/23744235.2024.2374980). We found that MDR/CR phenotypes were associated with increased mortality of KP BSIs and healthcare costs (reference 5 and lines 50-55) and CR phenotype was one of independent risk factors for crude 30-day mortality of KP BSIs (reference 5). Therefore, we focused on exploring risk factors for MDRKP and CRKP BSIs in this manuscript. Although we reported in-hospital mortality rate in the current study, given that we have published the work on risk factors for crude 30-day mortality of KPBSIs using the same dataset, we did not look any further into risk factors for in-hospital mortality of KPBSIs in this study.

Thank you very much for your kind support and consideration of our manuscript.

Kind regards,

Shengyuan

Dear reviewers,

Thank you very much for your valuable comments and suggestions. We have responded to each of your comments and questions and revised the manuscript accordingly. We highlighted all the revisions throughout the manuscript in yellow. Please see our responses in the below.

Response: Thank you for your advice. We have double checked the background section and broken down several long sentences as suggested. Please see lines 41-42, 44-47, 50-55.

The terms "MDRKP" and "CRKP" are introduced without prior definitions in the background section.

Response: Apologies. We have added the definitions of “MDRKP” and “CRKP” as suggested. Please see lines 51-52.

The phrase "the resistance situation has become more serious in recent years" is somewhat redundant, as it implies a known trend without providing specific evidence.

Response: Apologies. You are right. We have deleted the phrase to make the sentence clear and meaningful. Please see lines 57-58.

Response: Thank you for your advice. We have simplified the sentence as suggested to “Only the first episode of KP BSIs per patient was included.”, please see line 73.

Response: Apologies. To make it clearer, we have rewritten the sentence as “Definitions of the variables collected are provided in S1 Table.” as suggested, please see lines 99-100.

The phrase "Because of the retrospective nature of the study, the committee waived informed consent" may lead to misinterpretation and could benefit from further clarification.

Response: Apologies. We have rewritten the sentence as “This is an observational retrospective study and all the data were obtained from medical record systems and analyzed anonymously, so the committee waived informed consent.” to make it clearer. Please see lines 79-81.

Response: Thank you for your advice. We have added more supporting information and references as suggested, please see lines 202-206.

Response: Thank you for your advice. We have added more discussion and references as suggested, please see lines 227-236.

To enhance the clarity and readability of your paper, I recommend avoiding nested parentheses (lines 96-97 and line 103).

Response: Apologies. We have deleted unnecessary expressions to avoid nested parentheses as suggested, please see lines 96-98 and 104-105.

In line 120, you mentioned the ratio of ratios (OR). It should be referred to as the Odds Ratio.

Response: Apologies. We have corrected this mistake as suggested. Please see line 121.

Have you used a generalized linear mixed model or a generalized linear model? (Line 110).

Response: Apologies. We used a generalized linear model, and we have corrected this, please see line 111.

How did you assess the goodness of fit of the logistic regression model?

Response: Hosmer-Lemeshow test was performed to assess the goodness of fit of the logistic regression models. We have added this in the methods section (lines 125-126) and reported the results in results section (lines 170-171 and 176-177).

Multiple logistic regression is the more appropriate term than multivariate logistic regression.

Response: Thank you for your advice. We have changed to multiple logistic regression throughout the manuscript as suggested.

Reviewer #2: Dear Authors

Thank for you the write-up. Kindly address the following concerns

General concerns

Response: In this study, the inclusion criteria for patients was primarily based on the results of blood cultures. Inpatients with at least one result of Klebsiella pneumoniae in blood culture were included in our study. According to the Centres for Disease Control and Prevention’s criteria, hospital-associated bloodstream infection (BSI) was defined as a BSI that occurred more than 48 hours after admission to hospital or within 48 hours of the last hospital discharge (doi:10.1016/j.ajic. 2008.03.002). For inpatients with more than 48 hours hospitalization but whose bloodstream infection occurred within 48 hours of hospital admission, we did not exclude them. In this study, there was one patient with schizophrenia who did not take the right amount of medicines on time as the physician suggested and was transferred to a psychiatric hospital for treatment 32 hours after hospital admission. This patient took the first positive blood culture of Klebsiella pneumoniae 20 hours after hospital admission. We could not know the exact amount of medicines the patient took by checking medical records. Therefore, we excluded this patient due to inaccurate medical records. There was one elder patient with advanced malignancy who was suggested to be admitted to ICU at admission given that the illness was very severe and the clinical prognosis would be quite poor without life support equipment. Both the patient and families refused to be transferred to ICU and insisted on discharge because they could not afford the healthcare costs for treatment. This patient took the first positive blood culture of Klebsiella pneumoniae at hospital admission. Therefore, we excluded this patient. The two patients mentioned above excluded from this study happened to be with less than 48 hours of hospitalization. As you suggested, the expression of “patients with less than 48 hours of hospitalization were excluded” is misleading, so we have rewritten the exclusion criteria to make it clearly justified as suggested, please see lines 75-76.

The conclusion sounds too sentimental and would be better rephrased

Response: Thank you for your advice. We have rephrased the conclusion section as suggested, please see lines 35-39 and 286-293.

specific concerns

Abstract should contain at least a statement of reflecting background before jumping to objectives

Response: Thank you for your advice. We have added the background statement as suggested, please see lines 19-21.

An abbreviation “CR” was introduced in the abstract which had not been previously explained

Response: Apologies. CR means CRKP BSIs, we have rewritten the sentence to make it clearer. Please see line 29.

Line 51, readers will appreciate better if ‘good’ or ‘bad’ is used to properly qualify the ‘prognosis’ in the text.

Response: Apologies. It should be bad prognosis. We have added the word to make it clear as suggested. Please see line 50.

Line 54 - please clarify is it proportion among all blood culture isolates or among Klebsiella isolates?

Response: Apologies. The proportion is among Klebsiella pneumoniae isolates. We have clarified this as suggested, please see line 54.

Line 57 – the import of the statement is not well articulated and difficult to understand

Response: Apologies. The phrase is somewhat redundant as it implies a known trend and not clear. We have rephrased the sentence to make it clear and meaningful. Please see lines 57-58.

Line 120, kindly correct, ‘ratio of ratios’

Response: Apologies. We have corrected this mistake as suggested. Please see line 121.

Response: Apologies. We have corrected the colors of Figure 2 to make sure that the colors match departments among the three groups as suggested.

Reviewer #4: Review Comments to the Author

1. A more detailed discussion of the limitations is crucial for improving transparency and providing a clearer framework for future research.

Response: Thank you for your advice. We have added more detailed information about limitations in the discussion section as suggested, please see lines 264-275.

2. Expanding on the implications for clinical interventions and public health policies would significantly increase the practical impact of the findings.

Response: Thank you for your advice. We have added more discussion on the implications for clinical interventions and public health policies as suggested, please see lines 276-283.

3. Additionally, the descriptive captions for figures and tables should be improved to ensure they are clear and easily understandable on their own.

Response: Apologies. We have rephrased the descriptive captions for figures and tables to make them clear and easily understandable on their own as suggested.

4. The author should specify the name of the electronic medical record system used.

Response: Apologies. We have specified this as suggested, please see lines 65-67.

Attachment

Submitted filename: Response to Reviewers.docx

pone.0324925.s004.docx^{(36.1KB, docx)}

PLoS One. doi: 10.1371/journal.pone.0324925.r004

Decision Letter 1

Ali Amanati

24 Apr 2025

PONE-D-24-58014R1Risk factors for multidrug-resistant and carbapenem-resistant Klebsiella pneumoniae bloodstream infections in Shanghai: a five-year retrospective cohort studyPLOS ONE

Dear Dr. Zhao,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. Please submit your revised manuscript by Jun 08 2025 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org . When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

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We look forward to receiving your revised manuscript.

Kind regards,

Ali Amanati

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

Additional Editor Comments :

Dear authors,‎

We are pleased to inform you that your manuscript has successfully passed the ‎review stage and is ready for revision. Although the overall presentation of the ‎manuscript has improved following amendments, it still requires further ‎revision.‎

Yours sincerely,‎

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #1: Yes

Reviewer #2: No

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #1: Yes

Reviewer #2: (No Response)

**********

6. Review Comments to the Author

Reviewer #1: Dear authors,

Thank you for addressing all the comments in your manuscript. I have no further comments to add.

Reviewer #2: Dear authors

If the data set for this write-up has been used in previous publication (s), in order to conform to ethical standards, this must be clearly stated in the methodology section and the new or entirely different research question this write-up seeks to address unambiguously stated as well.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean? ). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy .

Reviewer #1: Yes: Farzane Ahmadi

Reviewer #2: No

**********

PLoS One. 2025 May 22;20(5):e0324925. doi: 10.1371/journal.pone.0324925.r005

Author response to Decision Letter 2

1 May 2025

Dear reviewer,

Thank you very much for your valuable comments and suggestions. We have responded to your comment and revised the manuscript accordingly. We highlighted all the revisions throughout the manuscript in yellow. Please see our responses in the below.

Response: Thank you. We have added the statement “We investigated incidence, antimicrobial resistance, crude 30-day mortality rate, and risk factors for crude 30-day mortality of KP BSIs using the same dataset of this manuscript (S1 File) and published the findings in 2024 [5]. In this study, we investigated temporal distribution of proportion of KP BSIs attributed deaths, department distribution of KP BSIs and risk factors for MDRKP BSIs and CRKP BSIs which are entirely different research questions. There is no overlap in research content of the two studies.” in the methodology section as suggested, please see lines 82-88.

Attachment

Submitted filename: Response_to_Reviewers_auresp_2.docx

pone.0324925.s005.docx^{(18.8KB, docx)}

PLoS One. doi: 10.1371/journal.pone.0324925.r006

Decision Letter 2

Ali Amanati

4 May 2025

Risk factors for multidrug-resistant and carbapenem-resistant Klebsiella pneumoniae bloodstream infections in Shanghai: a five-year retrospective cohort study

PONE-D-24-58014R2

Dear Dr. Shengyuan Zhao,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Kind regards,

Ali Amanati

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

The authors have managed to use all the available resources and data to re-shape ‎the manuscript in a manner that is more scientifically sound than previously.‎

PLoS One. doi: 10.1371/journal.pone.0324925.r007

Acceptance letter

Ali Amanati

PONE-D-24-58014R2

PLOS ONE

Dear Dr. Zhao,

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now being handed over to our production team.

At this stage, our production department will prepare your paper for publication. This includes ensuring the following:

* All references, tables, and figures are properly cited

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You will receive further instructions from the production team, including instructions on how to review your proof when it is ready. Please keep in mind that we are working through a large volume of accepted articles, so please give us a few days to review your paper and let you know the next and final steps.

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Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Professor Ali Amanati

Academic Editor

PLOS ONE

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

S1 Table. Definitions of each variable included in risk factors analysis for multidrug-resistant Klebsiella pneumoniae and carbapenem-resistant Klebsiella pneumoniae bloodstream infections.

(DOCX)

pone.0324925.s001.docx^{(30.4KB, docx)}

S1 File. Dataset of clinical characteristics of 379 inpatients with Klebsiella pneumoniae bloodstream infections.

(XLSX)

pone.0324925.s002.xlsx^{(110.6KB, xlsx)}

Attachment

Submitted filename: Response to Reviewers.docx

pone.0324925.s004.docx^{(36.1KB, docx)}

Attachment

Submitted filename: Response_to_Reviewers_auresp_2.docx

pone.0324925.s005.docx^{(18.8KB, docx)}

Data Availability Statement

All relevant data are within the manuscript and its Supporting information files.

[pone.0324925.ref001] 1.Chang H, Wei J, Zhou W, Yan X, Cao X, Zuo L, et al. Risk factors and mortality for patients with Bloodstream infections of Klebsiella pneumoniae during 2014-2018: clinical impact of carbapenem resistance in a large tertiary hospital of China. J Infect Public Health. 2020;13(5):784–90. doi: 10.1016/j.jiph.2019.11.014 [DOI] [PubMed] [Google Scholar]

[pone.0324925.ref002] 2.Nielsen SL, Pedersen C, Jensen TG, Gradel KO, Kolmos HJ, Lassen AT. Decreasing incidence rates of bacteremia: a 9-year population-based study. J Infect. 2014;69(1):51–9. doi: 10.1016/j.jinf.2014.01.014 [DOI] [PubMed] [Google Scholar]

[pone.0324925.ref003] 3.Diekema DJ, Hsueh P-R, Mendes RE, Pfaller MA, Rolston KV, Sader HS, et al. The microbiology of bloodstream infection: 20-year trends from the SENTRY antimicrobial surveillance program. Antimicrob Agents Chemother. 2019;63(7):e00355–19. doi: 10.1128/AAC.00355-19 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0324925.ref004] 4.Chew KL, Lin RTP, Teo JWP. Klebsiella pneumoniae in Singapore: hypervirulent infections and the carbapenemase threat. Front Cell Infect Microbiol. 2017;7:515. doi: 10.3389/fcimb.2017.00515 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0324925.ref005] 5.Xiao S, Zhou S, Cao H, Han L, Zhao S, Wang X. Incidence, antimicrobial resistance and mortality of Klebsiella pneumoniae bacteraemia in Shanghai, China, 2018–2022. Infectious Diseases. 2024;56(12):1021-1030. [DOI] [PubMed] [Google Scholar]

[pone.0324925.ref006] 6.Xiao T, Zhu Y, Zhang S, Wang Y, Shen P, Zhou Y, et al. A retrospective analysis of risk factors and outcomes of carbapenem-resistant Klebsiella pneumoniae bacteremia in nontransplant patients. J Infect Dis. 2020;221(Suppl 2):S174–83. doi: 10.1093/infdis/jiz559 [DOI] [PubMed] [Google Scholar]

[pone.0324925.ref007] 7.Ben-David D, Kordevani R, Keller N, Tal I, Marzel A, Gal-Mor O, et al. Outcome of carbapenem resistant Klebsiella pneumoniae bloodstream infections. Clin Microbiol Infect. 2012;18(1):54–60. doi: 10.1111/j.1469-0691.2011.03478.x [DOI] [PubMed] [Google Scholar]

[pone.0324925.ref008] 8.Chen Y, Chen Y, Liu P, Guo P, Wu Z, Peng Y, et al. Risk factors and mortality for elderly patients with bloodstream infection of carbapenem resistance Klebsiella pneumoniae: a 10-year longitudinal study. BMC Geriatr. 2022;22(1):573. doi: 10.1186/s12877-022-03275-1 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0324925.ref009] 9.Magiorakos A-P, Srinivasan A, Carey RB, Carmeli Y, Falagas ME, Giske CG, 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. doi: 10.1111/j.1469-0691.2011.03570.x [DOI] [PubMed] [Google Scholar]

[pone.0324925.ref010] 10.Liu K-S, Tong Y-S, Lee M-T, Lin H-Y, Lu M-C. Risk factors of 30-day all-cause mortality in patients with carbapenem-resistant Klebsiella pneumoniae bloodstream infection. J Pers Med. 2021;11(7):616. doi: 10.3390/jpm11070616 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0324925.ref011] 11.Fostervold A, Raffelsberger N, Hetland MAK, Bakksjø R, Bernhoff E, Samuelsen Ø, et al. Risk of death in Klebsiella pneumoniae bloodstream infections is associated with specific phylogenetic lineages. J Infect. 2024;88(5):106155. doi: 10.1016/j.jinf.2024.106155 [DOI] [PubMed] [Google Scholar]

[pone.0324925.ref012] 12.Friedman J, Hastie T, Tibshirani R. Regularization paths for generalized linear models via coordinate descent. J Stat Softw. 2010;33(1):1–22. doi: 10.18637/jss.v033.i01 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0324925.ref013] 13.Zhao S, Perry MR, Kennedy S, Wilson J, Chase-Topping ME, Anderson E, et al. Risk factors for carbapenemase-producing organisms among inpatients in Scotland: a national matched case-control study. Infect Control Hosp Epidemiol. 2021;42(8):968–77. doi: 10.1017/ice.2020.1351 [DOI] [PubMed] [Google Scholar]

[pone.0324925.ref014] 14.Zhang Y, Zhao C, Wang Q, Wang X, Chen H, Li H, et al. High prevalence of hypervirulent Klebsiella pneumoniae infection in China: geographic distribution, clinical characteristics, and antimicrobial resistance. Antimicrob Agents Chemother. 2016;60(10):6115–20. doi: 10.1128/AAC.01127-16 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0324925.ref015] 15.Li Y, Li J, Hu T, Hu J, Song N, Zhang Y, et al. Five-year change of prevalence and risk factors for infection and mortality of carbapenem-resistant Klebsiella pneumoniae bloodstream infection in a tertiary hospital in North China. Antimicrob Resist Infect Control. 2020;9(1):79. doi: 10.1186/s13756-020-00728-3 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0324925.ref016] 16.Cao Z, Yue C, Kong Q, Liu Y, Li J. Risk factors for a hospital-acquired carbapenem-resistant Klebsiella pneumoniae bloodstream infection: a five-year retrospective study. Infect Drug Resist. 2022;15:641–54. doi: 10.2147/IDR.S342103 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0324925.ref017] 17.Hu Y, Ping Y, Li L, Xu H, Yan X, Dai H. A retrospective study of risk factors for carbapenem-resistant Klebsiella pneumoniae acquisition among ICU patients. J Infect Dev Ctries. 2016;10(3):208–13. doi: 10.3855/jidc.6697 [DOI] [PubMed] [Google Scholar]

[pone.0324925.ref018] 18.Brusselaers N, Vogelaers D, Blot S. The rising problem of antimicrobial resistance in the intensive care unit. Ann Intensive Care. 2011;1:47. doi: 10.1186/2110-5820-1-47 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0324925.ref019] 19.Kofteridis DP, Valachis A, Dimopoulou D, Maraki S, Christidou A, Mantadakis E, et al. Risk factors for carbapenem-resistant Klebsiella pneumoniae infection/colonization: a case-case-control study. J Infect Chemother. 2014;20(5):293–7. doi: 10.1016/j.jiac.2013.11.007 [DOI] [PubMed] [Google Scholar]

[pone.0324925.ref020] 20.Gómez Rueda V, Zuleta Tobón JJ. Risk factors for infection with carbapenem-resistant Klebsiella pneumoniae: a case-case-control study. Colomb Med (Cali). 2014;45(2):54–60. doi: 10.25100/cm.v45i2.1417 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0324925.ref021] 21.Mills JP, Talati NJ, Alby K, Han JH. The epidemiology of carbapenem-resistant Klebsiella pneumoniae colonization and infection among long-term acute care hospital residents. Infect Control Hosp Epidemiol. 2016;37(1):55–60. doi: 10.1017/ice.2015.254 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0324925.ref022] 22.Liao Q, Yuan Y, Zhang W, Deng J, Kang M. Carbapenemase genes, virulence genes, and molecular epidemiology of carbapenem-resistant Klebsiella pneumoniae derived from bloodstream infections. Sichuan Da Xue Xue Bao Yi Xue Ban. 2024;55(2):391–6. doi: 10.12182/20240360202 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0324925.ref023] 23.Zhou S, Xiao S, Wang X, Wang X, Han L. Risk factors and pathogens of wound infection in burn inpatients from East China. Antibiotics (Basel). 2023;12(9):1432. doi: 10.3390/antibiotics12091432 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0324925.ref024] 24.Micozzi A, Gentile G, Minotti C, Cartoni C, Capria S, Ballarò D, et al. Carbapenem-resistant Klebsiella pneumoniae in high-risk haematological patients: factors favouring spread, risk factors and outcome of carbapenem-resistant Klebsiella pneumoniae bacteremias. BMC Infect Dis. 2017;17(1):203. doi: 10.1186/s12879-017-2297-9 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0324925.ref025] 25.Cohen MJ, Anshelevich O, Raveh D, Broide E, Rudensky B, Yinnon AM. Acquisition of multidrug-resistant organisms among hospital patients hospitalized in beds adjacent to critically ill patients. Infect Control Hosp Epidemiol. 2006;27(7):675–81. doi: 10.1086/505919 [DOI] [PubMed] [Google Scholar]

[pone.0324925.ref026] 26.Bleumin D, Cohen MJ, Moranne O, Esnault VLM, Benenson S, Paltiel O, et al. Carbapenem-resistant Klebsiella pneumoniae is associated with poor outcome in hemodialysis patients. J Infect. 2012;65(4):318–25. doi: 10.1016/j.jinf.2012.06.005 [DOI] [PubMed] [Google Scholar]

[pone.0324925.ref027] 27.Orsi GB, Bencardino A, Vena A, Carattoli A, Venditti C, Falcone M, et al. Patient risk factors for outer membrane permeability and KPC-producing carbapenem-resistant Klebsiella pneumoniae isolation: results of a double case-control study. Infection. 2013;41(1):61–7. doi: 10.1007/s15010-012-0354-2 [DOI] [PubMed] [Google Scholar]

[pone.0324925.ref028] 28.Cross SN, Potter JA, Aldo P, Kwon JY, Pitruzzello M, Tong M, et al. Viral infection sensitizes human fetal membranes to bacterial lipopolysaccharide by MERTK inhibition and inflammasome activation. J Immunol. 2017;199(8):2885–95. doi: 10.4049/jimmunol.1700870 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0324925.ref029] 29.Trecarichi EM, Pagano L, Martino B, Candoni A, Di Blasi R, Nadali G, et al. Bloodstream infections caused by Klebsiella pneumoniae in onco-hematological patients: clinical impact of carbapenem resistance in a multicentre prospective survey. Am J Hematol. 2016;91(11):1076–81. doi: 10.1002/ajh.24489 [DOI] [PubMed] [Google Scholar]

[pone.0324925.ref030] 30.Tumbarello M, Trecarichi EM, Tumietto F, Del Bono V, De Rosa FG, Bassetti M, et al. Predictive models for identification of hospitalized patients harboring KPC-producing Klebsiella pneumoniae. Antimicrob Agents Chemother. 2014;58(6):3514–20. doi: 10.1128/AAC.02373-13 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0324925.ref031] 31.Jiao Y, Qin Y, Liu J, Li Q, Dong Y, Shang Y, et al. Risk factors for carbapenem-resistant Klebsiella pneumoniae infection/colonization and predictors of mortality: a retrospective study. Pathog Glob Health. 2015;109(2):68–74. doi: 10.1179/2047773215Y.0000000004 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0324925.ref032] 32.Tanimoto K, Tomita H, Fujimoto S, Okuzumi K, Ike Y. Fluoroquinolone enhances the mutation frequency for meropenem-selected carbapenem resistance in Pseudomonas aeruginosa, but use of the high-potency drug doripenem inhibits mutant formation. Antimicrob Agents Chemother. 2008;52(10):3795–800. doi: 10.1128/AAC.00464-08 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0324925.ref033] 33.Ababneh MA, Rababa’h AM, Almomani BA, Ayoub AM, Al-Azzam SI. A ten-year surveillance of P aeruginosa bloodstream infections in a tertiary care hospital: trends and risk factors for mortality. Int J Clin Pract. 2021;75(9):e14409. doi: 10.1111/ijcp.14409 [DOI] [PubMed] [Google Scholar]

[pone.0324925.ref034] 34.Paul M, Carmeli Y, Durante-Mangoni E, Mouton JW, Tacconelli E, Theuretzbacher U, et al. Combination therapy for carbapenem-resistant gram-negative bacteria. J Antimicrob Chemother. 2014;69(9):2305–9. doi: 10.1093/jac/dku168 [DOI] [PubMed] [Google Scholar]

PERMALINK

Risk factors for multidrug-resistant and carbapenem-resistant Klebsiella pneumoniae bloodstream infections in Shanghai: A five-year retrospective cohort study

Hongwen Cao

Siqi Zhou

Xuefeng Wang

Shuzhen Xiao

Shengyuan Zhao

Roles

Abstract

Background

Objectives

Methods

Results

Conclusions

Introduction

Materials and methods

Study design and setting

Ethics approval and consent to participate

Definitions

Data collection

Microbiology

Statistical analysis

Results

Trends in the proportion of death for MDRKP BSIs and CRKP BSIs

Fig 1. Proportion of death among 379 inpatients with Klebsiella pneumoniae bloodstream infections (KP BSIs) from 2018 to 2022 by antimicrobial resistance phenotypes.

Distribution of departments

Fig 2. Distribution of departments of 379 inpatients with Klebsiella pneumoniae bloodstream infections (KP BSIs) by antimicrobial resistance phenotypes.

Risk factors for MDRKP BSIs and CRKP BSIs

Table 1. Risk factors for multidrug-resistant Klebsiella pneumoniae bloodstream infections (MDRKP BSIs).

Table 2. Risk factors for carbapenem-resistant Klebsiella pneumoniae bloodstream infections (CRKP BSIs).

Discussion

Conclusions

Supporting information

Acknowledgments

Data Availability

Funding Statement

References

Author response to Decision Letter 0

Decision Letter 0

Ali Amanati

Roles

Author response to Decision Letter 1

Decision Letter 1

Ali Amanati

Roles

Author response to Decision Letter 2

Decision Letter 2

Ali Amanati

Roles

Acceptance letter

Ali Amanati

Roles

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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