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ORIGINAL ARTICLE
Year : 2022  |  Volume : 12  |  Issue : 4  |  Page : 217-221

Risk factors and clinical outcomes of carbapenem-resistant Klebsiella pneumonia infection in intensive care unit: A retrospective observational study in a tertiary care hospital in Eastern India


1 Department of Critical Care Medicine, IMS and SUM Hospital, Bhubaneswar, Odisha, India
2 Department of Respiratory Medicine, IMS and SUM Hospital, Bhubaneswar, Odisha, India

Date of Submission29-Apr-2022
Date of Acceptance03-Aug-2022
Date of Web Publication26-Dec-2022

Correspondence Address:
Dr. Sagarika Panda
Department of Critical Care Medicine, IMS and SUM Hospital, Bhubaneswar, Odisha
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijciis.ijciis_34_22

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   Abstract 


Background: Carbapenem-resistant Enterobacteriaceae, especially Klebsiella pneumonia, have become a severe global problem with a significant threat to public health, but few studies have investigated the risk factors and epidemiology of carbapenem-resistant K. pneumonia (CRKP) infections in India.
Methods: We performed a retrospective observational study of 224 participants with K. pneumoniae who were admitted to the medical intensive care unit (ICU) of Institute of Medical Sciences and SUM Hospital, Bhubaneswar, India, between January 1 and December 30, 2020. Antibiotic susceptibility testing was done by automated broth microdilution VITEK® 2 (BioMerieux, Inc., Hazelwood, USA). The Clinical and Laboratory Standards Institute document M100-S22 (January 2020) was used to interpret antimicrobial susceptibility testing. Data were obtained from paper medical records.
Results: Two hundred and twenty-four subjects with culture-positive for K. pneumonia were retrieved during the study period, out of which 108 had CRKP. The risk factors for univariate analysis were Acute Physiology and Chronic Health Evaluation II, ICU length of stay (LOS), invasive mechanical ventilator days, central venous catheter days, and arterial line days. The multivariate analysis showed invasive mechanical ventilation and ICU LOS were independent risk factors for CRKP infection. Mortality in the CRKP group was 48 (44%) compared to 27 (23%) in the carbapenem-sensitive K. pneumonia (CSKP) group, which was statistically significant (P < 0.01).
Conclusion: Infection due to CRKP in the ICU was associated with 1.9 times higher mortality as compared to CSKP. Invasive mechanical ventilation and ICU LOS were found to be independent risk factors for CRKP infection.

Keywords: Carbapenem-resistant Enterobacteriaceae, epidemiology, Klebsiella infections, Klebsiella pneumoniae, mortality


How to cite this article:
Panda S, Dash A, Chhotray P, Nayak B, Mouli TC, Mishra SB. Risk factors and clinical outcomes of carbapenem-resistant Klebsiella pneumonia infection in intensive care unit: A retrospective observational study in a tertiary care hospital in Eastern India. Int J Crit Illn Inj Sci 2022;12:217-21

How to cite this URL:
Panda S, Dash A, Chhotray P, Nayak B, Mouli TC, Mishra SB. Risk factors and clinical outcomes of carbapenem-resistant Klebsiella pneumonia infection in intensive care unit: A retrospective observational study in a tertiary care hospital in Eastern India. Int J Crit Illn Inj Sci [serial online] 2022 [cited 2023 Feb 9];12:217-21. Available from: https://www.ijciis.org/text.asp?2022/12/4/217/364740




   Introduction Top


Carbapenems are a class of beta-lactam antibiotic which has the broadest spectrum of activity against both Gram-positive and Gram-negative bacteria. It is often used as an “antibiotic of last resort” and plays a crucial role in our antibiotic armamentarium. Carbapenem-resistant Enterobacteriaceae, particularly Klebsiella pneumonia, have increased globally as an emerging public health threat over the past decade.[1] A recent report published by the China Antimicrobial Surveillance Network showed a marked increase in carbapenem resistance among K. pneumoniae isolates. The resistance for meropenem and imipenem increased from 3.0% and 2.9% in 2005 to 20.9% and 24% in 2017, respectively.[2]

Frequent use of the carbapenem group of antibiotics for multidrug-resistant bacteria has resulted in carbapenem-resistant isolates.[3] Infections due to these resistant isolates are challenging to treat as limited therapeutic options are available. Hence, it has resulted in higher treatment failure and mortality. Mortality rates for carbapenem-resistant K. pneumonia (CRKP) may reach up to 33%–50% compared to the sensitive isolates.[4] Knowledge about the risk factors for CRKP infections is essential for preventing these infections. Prior use of antibiotics, especially carbapenems or aminoglycosides, intensive care unit (ICU) admission, prolonged hospitalization, and invasive procedures are the reported risk factors for CRKP infections.[5],[6],[7]

Although numerous studies have investigated risk factors for developing CRKP, evidence from populations in India is lacking. The main objective of this study was to describe the risk factors, and clinical characteristics of CRKP infection in critically ill subjects admitted to an ICU in India.


   Methods Top


This observational retrospective study was conducted in a 20-bed Medical ICU (MICU) of IMS and SUM Hospital, Bhubaneswar, India. The institutional ethics committee approved the project, and the manuscript adheres to the STROBE guideline. All subjects of the age group >18 years who were admitted to MICU between January 1 and December 30, 2020, were included in the study protocol. The diagnoses of hospital-acquired infection (HAI) were made per the Center for Diseases Control and Prevention criteria.[8] Active surveillance was done daily by an infection control team to detect HAI. Only the first confirmed case was included in the final analysis in cases, where a single subject had multiple CRKP infections. Patients were excluded from the analysis for polymicrobial isolates, incomplete medical records, or terminal illness. The demographic data, comorbidities, and illness severity scores, including the Acute Physiology and Chronic Health Evaluation II (APACHE II) and the Sequential Organ Failure Assessment (SOFA) on admission to ICU, central venous catheter (CVC) days, arterial line days, organ failure score, invasive mechanical ventilator (IMV) days, ICU length of stay (LOS), and site of infection were obtained from the paper medical records. Antibiotic susceptibility testing was done by automated broth microdilution VITEK® 2 (BioMerieux, Inc., Hazelwood, USA). The Clinical and Laboratory Standards Institute document M100-S22 (January 2020) was used to interpret antimicrobial susceptibility testing. MIC level above 4 for carbapenem was defined as CRKP.

Statistical analysis

Categorical variables were expressed as frequencies and percentages, and continuous variables were expressed as medians and interquartile ranges if they were nonnormally distributed. Categorical variables were compared using Chi-square or Fisher's exact tests, and continuous variables were compared using the Mann–Whitney U-test, according to their distribution. For univariate analyses, results were reported as odds ratios with 95% confidence intervals and P values. Variables with P < 0.01 in the univariate analyses were selected for possible inclusion in multivariate logistic regression. We used backward stepwise logistic regression to select variables for inclusion in the final multivariate logistic regression model to evaluate risk factors for CRKP. The discrimination ability of the logistic regression model was assessed by estimating the area under the receiver operating characteristic curve. Model calibration was assessed using the Hosmer–Lemeshow test for goodness of fit. Other statistical analyses were performed with SPSS 20.0 software (IBM Corporation, Armonk, NY, USA). Two-tailed P < 0.05 were considered statistically significant.


   Results Top


Two hundred and twenty-nine subjects with culture-positive for K. pneumonia were retrieved during the study period. Among them, complete clinical data were not available for five subjects. Hence, a total of 224 subjects were included in the study, among which 116 had carbapenem-sensitive K. pneumonia (CSKP) isolates and 108 had CRKP.

The demographic profile of the two groups is described in [Table 1]. The baseline parameters were comparable between the two groups except for baseline APACHE II score, CVC days, and arterial line days. The median age was 65 years (range: 49–73) in the CRKP group and 62 years (range: 48–72) in the CSKP group. Female patients were 37% in the CRKP group compared to 46% in the CSKP group. The median APACHE II score was 25.50 (19.75–29) in the CRKP group compared to 21 (16.25–25.75) in the CSKP group with a P < 0.01. LOS and IMV days were also longer for the CRKP group (P < 0.001). The most common source of infection with K. pneumonia was bloodstream infection (BSI) (CRKP 66.7% CSKP 65.6%), followed by ventilator-associated pneumonia (VAP) (CRKP 33.3%, CSKP 34.4%).
Table 1: The baseline characteristic of patients

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The clinical outcomes of the patient group are shown in [Table 2]. Mortality in the CRKP group was 48 (44%) compared to 27 (23%) in the CSKP group, which was statistically significant (P < 0.01). There was no significant difference between survivors and nonsurvivors in the CRKP groups in terms of baseline APACHE II, SOFA score, ICU LOS, IMV days, CVC days, and arterial line days [Table 3].
Table 2: Outcomes

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Table 3: Baseline characteristics and outcomes in the carbapenem-resistant Klebsiella pneumoniae Scientific Name Search  group

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The results of the univariate analysis to identify risk factors associated with CRKP BSIs are baseline APACHE II, ICU LOS, IMV days, CVC days, and arterial line days. However, the multivariate logistic analysis found that LOS and IMV days were independent risk factors for CRKP. Hosmer–Lemeshow test for goodness of fit found χ2 (8) =4.8 with P = 0.77. Cox–Snell's R square = 0.27.


   Discussion Top


Carbapenem antibiotics are increasingly used to treat extended-spectrum beta-lactamase-producing K. pneumoniae isolates. The use of broad-spectrum antibiotics contributes to the development of CRKP. Prolonged immunosuppression, prior use of broad-spectrum antibiotics, prolonged duration of CVC and nasogastric catheter, and high baseline APACHE II score may be the risk factors for the emergence of carbapenem resistance. Candevir Ulu et al. found that treatment with third-generation cephalosporins, neurosurgical ICU admission, and nasogastric catheter use are the risk factors for the development of CRKP isolates.[9] Antibiotics including third-generation cephalosporins, fourth-generation cephalosporins, macrolides, carbapenem, fluoroquinolones, beta-lactam/beta-lactamase inhibitor combinations, and combinations of carbapenems with fluoroquinolones are contributing factors for the emergence of CRKP.[10],[11],[12],[13],[14]

To the best of our knowledge, this is one of the most extensive studies on ICU patients, with 48% of infections being due to carbapenem-resistant organisms. Although several variables were examined to identify the risk factors, only APACHE II, ICU LOS, duration of IMV, CVC days, and arterial catheter days were associated with CRKP infection in univariate analysis. Invasive mechanical ventilation and ICU LOS were the independent risk factors in the multivariate logistic regression analysis.

Our study also highlights the importance of minimizing inappropriate use and early removal of CVC and arterial catheters. Our study result agrees with the findings of Correa et al., who observed a similar risk factor of the length of CVC as an independent risk factor for carbapenem resistance in multivariable analysis.[6] Routes, in his study, also observed that VAP and the presence of additional intravascular devices contribute to the emergence of CRKP.[15] Addressing the risk factors for colonization with CRKP isolates would help prevent the acquisition of CRKP infection and hence would help reduce the mortality associated with it. Kontopoulou et al. in their prospective study observed that the median time for the detection of CRKP colonization was 8 days from hospital admission, while the median time for bloodstream infection from colonization was 4 days. The risk factors for CRKP colonization were prior use of antianaerobic antimicrobials, duration of ICU LOS, and patient-to-nurse ratio.[16]

Borer et al. conducted a prospective study to demonstrate the predictors for CRKP colonization and progression to infection. Antibiotic therapy, especially aminopenicillin therapy, nursing home residents, and bedridden status were independent predictors of CRKP rectal colonization. Risk factors for developing CRKP infection in colonized patients are comorbidities such as diabetes mellitus, solid tumor, previous invasive procedure, tracheostomy, urinary catheter, and use of antipseudomonal penicillin. They suggested that limiting antipseudomonal penicillin and carbapenem may prevent CRKP infection. They further suggest close compliance with infection control bundles to prevent infection.[17] Qin et al. conducted a 3-month prospective cohort study and found that 28% of patients (68 of 243) had K. pneumonia colonization, and 15% had a baseline CRKP colonization on admission to ICU.[18] Compared to patients without K. pneumoniae colonization, patients with CSKP colonization were more likely to acquire CRKP colonization during the ICU stay.

We found significant mortality in the CRKP group (44%). The baseline SOFA and APACHE scores were not different between the 28 days survivor and nonsurvivor among the CRKP group. The ICU LOS and duration of IMV also did not differ significantly between the two groups. Other variables such as the number of organ failure and the number of CVC and arterial catheter days were also similar among survivors and nonsurvivors. The results signify that the disease's severity is the principal cause of mortality, which is explained by the very high baseline median APACHE II (26 in our study). We analyzed the baseline variables between the two groups of CRKP, which were obtained at the time of admission to ICU and did not get any difference. However, the result may be different if we had analyzed the parameters between the two groups at the onset of infection instead of baseline.

Another retrospective cohort study found that the all-cause mortality in patients with CRKP BSI was 52%. The risk factors of mortality were delayed microbiologic eradication (>7 days), lower platelet count, and higher Pitt Bacteremia Score.[19] Dai et al. also found that carbapenem resistance, deep-vein cannulation, urinary catheter, IMV, tracheotomy, and high APACHE II scores were related to high in-hospital mortality.[14]

Our study has few limitations, first, the retrospective nature, small sample size, and single-center study does not permit desired modifications in the design of the study. Second, the observational nature of the study might have the risk of adding selection bias. Third, data on time-to-eradication and dosage of vasopressor requirement were not collected. Fourth, we did not have data on antibiotic appropriateness, and finally, the organ failure data were collected at the time of admission only, rather than at the time of development of infection. However, the acquired data help to fill a significant knowledge gap in South Asia countries and further sets the stage for subsequent research.


   Conclusion Top


Infection due to CRKP in the ICU was associated with 1.9 times higher mortality as compared to CSKP. ICU LOS and invasive mechanical ventilation days were found to be independent risk factors for CRKP infection.

Research quality and ethics statement

This study was approved by the Institutional Review Board/Ethics Committee at Institute of Medical Sciences and SUM Hospital (Approval # DRI/IMS.SH/SOA/2021/118; Approval date March 28, 2021). The authors followed the applicable EQUATOR Network (http://www.equator-network.org/) guideline, specifically the STROBE guideline, during the conduct of this research project.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
   References Top

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World Health Organization. Antimicrobial Resistance Global Report on Surveillance. Available from: https://apps.who.int/iris/bitstream/handle/10665/112642/9789241564748_eng.pdf. [Last accessed on 2022 Mar 19].  Back to cited text no. 1
    
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Falagas ME, Rafailidis PI, Kofteridis D, Virtzili S, Chelvatzoglou FC, Papaioannou V, et al. Risk factors of carbapenem-resistant Klebsiella pneumoniae infections: A matched case control study. J Antimicrob Chemother 2007;60:1124-30.  Back to cited text no. 5
    
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Correa L, Martino MD, Siqueira I, Pasternak J, Gales AC, Silva CV, et al. A hospital-based matched case-control study to identify clinical outcome and risk factors associated with carbapenem-resistant Klebsiella pneumoniae infection. BMC Infect Dis 2013;13:80.  Back to cited text no. 6
    
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Zhu WM, Yuan Z, Zhou HY. Risk factors for carbapenem-resistant Klebsiella pneumoniae infection relative to two types of control patients: A systematic review and meta-analysis. Antimicrob Resist Infect Control 2020;9:23.  Back to cited text no. 7
    
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Candevir Ulu A, Kurtaran B, Inal AS, Kömür S, Kibar F, Yapıcı Çiçekdemir H, et al. Risk factors of carbapenem-resistant Klebsiella pneumoniae infection: A serious threat in ICUs. Med Sci Monit 2015;21:219-24.  Back to cited text no. 9
    
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Ahn JY, Song JE, Kim MH, Choi H, Kim JK, Ann HW, et al. Risk factors for the acquisition of carbapenem-resistant Escherichia coli at a tertiary care center in South Korea: A matched case-control study. Am J Infect Control 2014;42:621-5.  Back to cited text no. 11
    
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Kritsotakis EI, Tsioutis C, Roumbelaki M, Christidou A, Gikas A. Antibiotic use and the risk of carbapenem-resistant extended-spectrum-{beta}-lactamase-producing Klebsiella pneumoniae infection in hospitalized patients: Results of a double case-control study. J Antimicrob Chemother 2011;66:1383-91.  Back to cited text no. 13
    
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Qin X, Wu S, Hao M, Zhu J, Ding B, Yang Y, et al. The colonization of carbapenem-resistant Klebsiella pneumoniae: Epidemiology, resistance mechanisms, and risk factors in patients admitted to Intensive Care UNITS in China. J Infect Dis 2020;221:S206-14.  Back to cited text no. 18
    
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