{"paper_id":"1616d3ec-9131-48d6-af2b-86291d5e7f17","body_text":"Carbapenem or colistin resistant Klebsiella pneumoniae bacteremia in the intensive care unit: real life data | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Carbapenem or colistin resistant Klebsiella pneumoniae bacteremia in the intensive care unit: real life data Cihan Semet, Kadir Efe, Halis Akalın, Remzi İşçimen, Nermin Kelebek Girgin, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3956365/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 28 Oct, 2024 Read the published version in Scientific Reports → Version 1 posted 10 You are reading this latest preprint version Abstract Carbapenem-resistant Klebsiella pneumoniae (CRKp) infections continue to be an important cause of morbidity and mortality. In this study, the effect of carbapenem or colistin resistance on mortality in Klebsiella pneumoniae bacteremia and combined meropenem + colistin administration in CRKp bacteremia was retrospectively evaluated. A total of 139 adult patients diagnosed with K. pneumoniae bacteremia(73 carbapenem sensitive and 66 carbapenem resistant) were included in the study. The 30-day mortality in entire cohort were 19.4%. 30-day mortality was significantly higher in the carbapenem resistant-colistin sensitive group and in the carbapenem resistant-colistin resistant group compared to the carbapenem susceptible (ESBL positive) group. Meropenem + colistin combination was administered to 37 (95%) of carbapenem resistant–colistin sensitive (n=39) and 25 (93%) of carbapenem resistant–colistin resistant patients(n=27). Notably, mortality was not significantly affected regardless of whether CRKp was colistin sensitive and whether a high dose and prolonged infusion of meropenem was administered. Mortality is higher in carbapenem resistant Klebsiella pneumoniae bacteremia compared to carbapenem susceptible group. In cases of combined meropenem and colistin administration, high dose and prolonged infusion of meropenem is not superior to standard dose and infusion in both carbapenem resistant–colistin sensitive and carbapenem resistant–colistin resistant K. pneumoniae bacteremia. Biological sciences/Microbiology Health sciences/Medical research Klebsiella bacteremia carbapenem resistance colistin meropenem Introduction Carbapenem-resistant Klebsiella pneumoniae (CRKp) infections are an important cause of morbidity and mortality. In a meta-analysis evaluating mortality, clinical and microbiological response for CRKp infections, mortality rate was 37.2%, clinical response was 69%, and microbiological response was 63.7% ( 1 ). Paniagua-Garcia et al reported that the difference in 30-day mortality rates between patients with carbapenem–resistant Enterobacterales(88.5% Klebsiella spp.) infection compared with patients with carbapenem-susceptible(31.4% Klebsiella spp.) infection was 13.2%( 2 ). There are conflicting results in the carbapenem-resistant group on the effects of the bacteria also being resistant to colistin on mortality ( 3 – 7 ). Treatment with new antibiotics such as ceftazidime-avibactam was reported to significantly reduce mortality in CRKp infections compared with older antibiotics such as meropenem, polymyxin (polymyxin-B and colistin), tigecycline, fosfomycin, and aminoglycosides ( 8 – 11 ). However, access to new antibiotics is not always possible owing to economic factors, development of resistance, or intolerance. Therefore, older antibiotics may still be needed from time to time. One of the most commonly used combinations in CRKp infections is meropenem plus colistin ( 12 , 13 ). Tumbarello et al. showed that even if K. pneumoniae is carbapenem resistant, in combinations including meropenem (high dose, prolonged infusion) in the treatment, mortality was significantly lower in the MIC ≤ 8 mg/L group than infections caused by strains with MIC values > 8 mg/L ( 8 ). Similarly, Daikos et al. reported that mortality increased from 19.4–35.5% in drug combinations containing meropenem when the meropenem MIC value was > 8 mg/L ( 9 ). In a study by Gomez-Simmonds et al. (meropenem MIC ≥ 16 mg/L in 90% of the isolates), combination therapy (a single effective antibiotic + meropenem or broad-spectrum cephalosporin) was not superior to monotherapy (a single effective antibiotic) ( 10 ). Gianella et al. compared carbapenem-containing combinations with carbapenem-free combinations in bloodstream infections caused by CRKp and reported that meropenem-containing combinations were more effective than meropenem-free combinations in terms of 14-day mortality even if meropenem MIC was ≥ 16 mg/L ( 11 ). In the present study, the primary objective was the effect of carbapenem resistance or carbapenem and colistin resistance on mortality in Klebsiella pneumonia bacteremia. In addition to that combined meropenem + colistin administration in CRKp bacteremia was retrospectively evaluated using minimal inhibitory concentration (MIC) and synergy data as a secondary objective. Methods A total of 139 patients (age, > 18 years) with K. pneumoniae bacteremia who were hospitalized in the Anesthesia and Reanimation Intensive Care Unit of our hospital between 01/01/2000 and 31/07/2019 were included in the study. The study was performed in accordance with relevant guidelines and regulation and approved by the Clinical Research Ethics Committee of Uludağ University Faculty of Medicine (2021-9/3). After informed consent was obtained, all patient information was retrieved from the electronic file system of our hospital. A case follow-up form was filled by all patients. Bloodstream infection(BSI) was classified as primary, i.e., a laboratory confirmed BSI that is not secondary to another site infection, or secondary that is thought to be seeded from a site-specific infection at another body site ( 12 ). In the presence of a focus of infection, the source of bacteremia was defined according to whether K. pneumoniae was isolated in the culture obtained from the focus of infection the day before or the same day after the positive blood culture. Catheter-associated bacteremia was defined as K. pneumoniae growth in blood culture from a catheter or in quantitative culture of catheter tip and peripheral blood culture, provided that there was no other active focus of infection ( 13 – 16 ). All patients were classified as “sepsis,” “severe sepsis,” or “septic shock” based on consensus conference sepsis-1 criteria ( 17 ). For the diagnosis of nosocomial pneumonia, in addition to the development of pneumonia within at least 48 hours after the hospital admission and the presence of new or progressing infiltration on the chest radiography, at least two of the following criteria should be present ( 18 ): Presence of high fever (body temperature > 38°C). Presence of leukocytosis > 10,000/mm 3 or leukopenia < 4,000/mm 3 . Purulent bronchial secretion indicated by the presence of > 25 leukocytes and ≤ 10 epithelial cells in the gram staining examination of the Deep Endotracheal Aspiration (DTA) (10×). Decreased oxygenation. Diagnostic criteria of the international sepsis group were used for other infection diagnoses ( 19 ). Use of prednisone or an equivalent steroid by the patient at a dose of 20 mg/day for 2 weeks or 30 mg/day for 1 week within the last one month was considered as a risk factor for steroid use ( 20 ). Patients with a neutrophil count < 500/mm 3 at the time of diagnosis were considered neutropenic. Acute Physiology and Chronic Health Evaluation-II score was calculated within 24 hours of admission to the ICU ( 21 ). Pitt Bacteremia scores were calculated at the diagnosis of infection ( 22 ). The 14-day and 30-day mortality values were calculated according to the first 14 days and 30 days from the date of diagnosis. Antibiotics used by the patients before the diagnosis—i.e., used for at least 48 hours in the last 30 days—were evaluated( 23 ). Colistin was administered as a maintenance dose after the standard loading dose in all patients ( 24 ). Meropenem was administered either as standard dose(3 g/d) and infusion or as high dose(6 g/d) and prolonged infusion(4 hours) ( 25 ). Identification and antibiotic susceptibility testing of K. pneumoniae isolates were performed using a Phoenix 100 (Beckton Dickinson, USA) automated system. In order to confirm ESBL negativity and positivity of K. pneumoniae isolates, a combined disk confirmation test was performed as recommended by Clinical Laboratory Standarts Institute(CLSI). Carbapenem resistance was defined as a minimum inhibitory concentration (MIC) to meropenem of greater than 8 mg/L. The MIC of colistin was determined by broth microdilution method, and a strain with MIC ≤ 2 mg/L was considered to be susceptible to colistin( 26 ). For combinations containing colistin, meropenem, tigecycline, or fosfomycin, synergy testing was performed by gradient diffusion method and evaluated according to European Committee on Antimicrobial Susceptibility Testing(EUCAST) criteria. For Colistin, Meropenem, Tigecycline, and Fosfomycin, 0.5 McFarland turbidity bacterial suspensions were spread on 4 MHA plates. If the MIC values of antibiotics A and B, the combination of which was to be tested, were not known beforehand, gradient diffusion method strips containing the antibiotics were placed separately in a petri dish to determine their MICs individually. Strip B was placed in the third petri dish first and incubated for 1 hour. Strip B was removed with sterile forceps and strip A was placed on the same place. Strip A was placed in the fourth petri dish and stored for 1 hour. Strip A was removed and strip B was placed on the same place. After 24 hours of incubation at 35°C–37°C, the MIC of A in the presence of B in the third petri dish and the MIC of B in the presence of A in the fourth petri dish were measured and evaluated according to EUCAST recommendations. Interaction in combination tests was determined using fractional inhibition concentration (FIC) index and evaluated as synergistic for FIC ≤ 0.5, additive for 0.5 < FIC ≤ 1, indifferent for 1 < FIC < 4, and antagonistic for FIC ≥ 4 ( 26 – 28 ). Results A total of 139 adult patients diagnosed with K. pneumoniae bacteremia between 01/01/2000 and 31/07/2019 were included in the study. The median age was 61 (33–98) years. Antibiotics were used in 58 (41.7%) of the patients in the last 30 days and 36 (25.9%) of these patients used carbapenems, 11 (7.9%) used 3rd generation cephalosporins, 6 (4.3%) used 4th generation cephalosporins, and 3 (2.2%) used tigecyclines. The median length of stay in the intensive care unit until the diagnosis of K. pneumoniae bacteremia was 17 (1–42) days. Some demographic characteristics of the patients are shown in Table 1. Table-1 Demographic characteristics of patients Demographic Characteristics Number of Patients (n) Percentage (%) Sex Male Female 82 57 59 41 Age (years) ≥ 65 < 65 56 83 40.2 59.8 CVC + 87 62.6 APACHE II ≥ 20 57 41 APACHE II < 20 82 59 PBS ≥ 4 116 83.4 PBS < 4 23 16.6 Neutropenia 27 19.4 Mechanical Ventilation Support 100 71.9 Antibiotic use in the last 30 days 58 41.7 Carbapenem use in the last 30 days 36 25.9 APACHE-II: Acute Physiology and Chronic Health Evaluation-II; CVC: Central Venous Catheter; PBS: Pittsburg bacteremia score, A total of 97 (69.7%) patients had various underlying diseases. Among these, 29 (20.8%) had more than one underlying disease (Table 2). Table-2 Underlying diseases of the patients Underlying disease Number of patients (n) Percentage (%) COPD 10 7.1 CRF 29 20.8 DM 43 30.9 SOT 3 2.1 CHF 27 19.4 Other 8 5.7 Total illness 120 Total patients 97 69.7 CHF: Congestive Heart Failure, COPD: Chronic Obstructive Pulmonary Disease, CRF: Chronic Renal Failure, SOT: Solid Organ Transplantation, DM: Diabetes Mellitus The 14-day mortality was 8.6% (n = 12) and 30-day mortality was 19.4% (n = 27). No significant difference was noted between the 14- and 30-day mortality rates in terms of the source (Table-3). Table-3 Mortality rates by source of bacteremia 14-day mortality 30-day mortality Source Deceased n (%) Survivor n (%) P Deceased n (%) Survivor n (%) P Total n Primary bacteremia 6 (11.3) 47 (88.6) 12 (22.6) 41 (77.3) 53 Catheter-associated bacteremia 4 (6.4) 58 (93.5) 1.000 12 (19.3) 50 (80.6) 0.982 62 Ventilator-associated pneumonia 2 (8.3) 22 (91.6) 3 (12.5) 21 (87.5) 24 Total 12 (8.6) 127 (91.3) 27 (19.4) 112 (80.5) 139 14-day mortality was significantly higher in the carbapenem resistant-colistin resistant group compared to the carbapenem sensitive (extended spectrum beta-lactamase-ESBL positive) group and the carbapenem resistant-colistin sensitive group. 30-day mortality was significantly higher in the carbapenem resistant-colistin sensitive group compared to the carbapenem susceptible (ESBL positive) group and in the carbapenem resistant-colistin resistant group compared to the carbapenem susceptible (ESBL positive) group (Table-4). Table-4 Mortality rates according to resistance profile 14-day mortality 30-day mortality Number of patients (n) Percentage (%) P value Number of patients (n) Percentage (%) P value Carbapenem sensitive-ESBL positive (n = 73)* 1 1.3 1 1.3 Carbapenem resistant-colistin sensitive (n = 39) 0 0 1.000 15 38.4 < 0.001 Carbapenem sensitive-ESBL positive (n = 73)* 1 1.3 1 1.3 Carbapenem and colistin resistant (n = 27) 11 40.7 < 0.001 11 40.7 < 0.001 Carbapenem resistant-colistin sensitive (n = 39) 0 0 15 38.4 Carbapenem and colistin resistant (n = 27) 11 40.7 < 0.001 11 40.7 0.852 *All carbapenem-susceptible-ESBL postive patients were treated with carbapenem monotherapy. Meropenem + colistin combination was administered to 37 (95%) of carbapenem resistant–colistin sensitive (n = 39) patients. The 30-day mortality rate was 37.8% in 37 patients receiving meropenem + colistin. A high dose and prolonged infusion of meropenem was administered in 19 of 39 patients and as standard dose and infusion in 20 patients; furthermore, no intergroup differences in mortality were noted in terms of mortality (36% vs. 40%, p = 0.839). Synergy testing was performed in 14 of 37 patients receiving meropenem + colistin. No synergy or antagonism was detected between meropenem and colistin and was considered as indifferent. Meropenem MIC level was ≥ 32 mg/L in all strains. Of the 27 carbapenem resistant–colistin resistant patients, 25 (93%) received meropenem + colistin combination. In these 25 patients, the 30-day mortality rate was 40%. In 13 patients, a high dose and prolonged infusion of meropenem was administered, whereas 14 patients received a standard dose and infusion. No significant intergroup difference was noted in terms of mortality (38% vs. 42%, p = 0.816). In this group, synergy testing was performed in 16 of 25 patients receiving meropenem + colistin. No synergy or antagonism was detected between meropenem and colistin and was considered as indifferent. Meropenem MIC level was ≥ 32 mg/dl in all strains. Discussion Many studies have demonstrated that carbapenem resistance significantly increases mortality compared with carbapenem susceptible groups. In a multicenter study, 30-day mortality rate in bloodstream infections caused by CRKp was 44% ( 29 ). In a meta-analysis evaluating CRKp bacteremia, mortality was 42.14% in the carbapenem-resistant group and 21.16% in the carbapenem-sensitive group. Mortality was reported to be 54.30% in bloodstream infections and 13.52% in urinary tract infections ( 30 ). The very low mortality rates in the carbapenem susceptible group in the present study may be explained by the fact that carbapenem was used in all of these cases. Balkan et al reported that colistin resistance increased 28-day mortality in bloodstream infections due to carbapenem-resistant Klebsiella pneumoniae ( 5 ). Menekşe et al found that increasing MIC of colistin as a independent mortality factor in Klebsiella pneumoniae bloodstream infections( 6 ).On the other hand, Aslan et al reported that colistin resistance in CRKp had no impact on 30-day mortality( 3 ). In the present study, we found that the presence of colistin resistance in addition to carbapenem resistance did not affect 30-day mortality. However, we found that significantly increased 14-day mortality. Different colistin susceptibility methods, whether colistin loading dose was given or not, whether meropenem dose and prolonged infusion were used or not, meropenem MIC values, combination or monotherapy and design of studies may have played a role in these different results. In the present study, meropenem + colistin combination was indifferent (neither synergistic nor antagonistic) by gradient diffusion system. In vitro synergy studies for carbapenem-resistant Enterobacteriaceae, the combination of polymyxin + carbapenem was generally found to be synergistic ( 36 ). In their study with the time-kill method, Sharma et al. showed that the combination was bactericidal if the MIC of meropenem was ≤ 16 mg/L in colistin-susceptible and meropenem-resistant K. pneumoniae strains ( 37 ). Kulegowski et al. also showed that if the MIC of meropenem is ≤ 32 mg/L, the combination of meropenem + polymyxin B generally has a synergistic effect on polymyxin B-susceptible strains ( 38 ). However, in a study involving 19 patients with bloodstream infection caused by K. pneumoniae , Bono et al. did not reach the PK/PD targets in cases with MIC values ranging from 256 to 1024 mg/L, although the patients were given high dose and prolonged infusion. Furthermore, in vitro synergy with colistin was not detected. However, measured serum meropenem levels could reach the hypothetically determined T > 40% 1xMIC PK/PD targets of meropenem at a rate of 98% for the MIC value of 8 mg/L, 68% for 16 mg/L, and 32% for 32 mg/L ( 25 ). The lack of synergistic effect in our study may be attributable to meropenem MIC levels of ≥ 32 mg/L. There was no therapeutic drug monitoring(TDM) for meropenem to evaluate PK/PD parameters in our study. We consider that TDM could be useful for infections caused by CRKp with MIC ≤ 64 mg/L( 39 , 40 ). In the present study, no significant difference in mortality was noted between high dose - prolonged infusion of meropenem and normal dose - standard infusion of meropenem. In the carbapenem resistant-colistin sensitive and carbapenem resistant-colistin resistant groups, no significant difference in mortality was observed between high dose and prolonged infusion of meropenem and normal dose infusion. It was shown that meropenem MIC is very important in the success of meropenem plus colistin combination in CRKp infections. If meropenem MIC > 8 mg/L, we can expect higher mortality( 8 , 9 ). Gianella et al. compared carbapenem-containing combinations with carbapenem-free combinations in bloodstream infections caused by CRKp and reported that meropenem-containing combinations were more effective than meropenem-free combinations in terms of 14-day mortality even if meropenem MIC was ≥ 16 mg/L ( 11 ). The fact that the synergy test results were indifferent and that there was no mortality difference between high-dose and prolonged infusion of meropenem and standard dose infusion in both groups suggests that high-dose and prolonged infusion meropenem treatment does not provide any benefit compared to standard dose and infusion if the meropenem MIC is ≥ 32 mg/L. There are certain limitations of this study. The study was conducted retrospectively. The number of cases was relatively small and the study was single centered. Not all carbapenem-resistant strains were tested for synergy. The results were not compared with a group given colistin monotherapy. Lastly, the strains were not epidemiologically analyzed at the molecular level and carbapenemase enzymes were not analyzed. In conclusion, 30-day mortality was significantly higher in the carbapenem resistant-colistin sensitive group and in the carbapenem resistant-colistin resistant group compared to the carbapenem susceptible (ESBL positive) group. When combined with colistin, if meropenem MIC is ≥ 32 mg/L, meropenem administration with high dose and prolonged infusion is not superior to standard dose and infusion in both carbapenem resistant-colistin sensitive and carbapenem resistant-colistin resistant K. pneumoniae bacteremia. Acknowledments We would like to thank Prof. Dr. Güven Özkaya for evaluating the statistical analysis of our study. HA is responsible for the content of the manuscript, data analysis and interpretation, study design, writing of the manuscript, and critical review. CS contributed to data collection, data analysis, interpretation of results and the writing of the manuscript. Rİ, NKG and FK are responsible for clinical follow-up, data collection and data interpretation. CS, KE and CÖ contributed substantially to the in vitro study design, data analysis and interpretation, and the writing of the manuscript. Funding and Conflict of Interest This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. There is no conflict of interest. Declarations Acknowledments We would like to thank Prof. Dr. Güven Özkaya for evaluating the statistical analysis of our study. HA is responsible for the content of the manuscript, data analysis and interpretation, study design, writing of the manuscript, and critical review. CS contributed to data collection, data analysis, interpretation of results and the writing of the manuscript. Rİ, NKG and FK are responsible for clinical follow-up, data collection and data interpretation. CS, KE and CÖ contributed substantially to the in vitro study design, data analysis and interpretation, and the writing of the manuscript. Funding and Conflict of Interest This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. There is no conflict of interest. Author Contribution H.A. is responsible for the content of the manuscript, data analysis and interpretation, study design, writing of the manuscript, and critical review. C.S. contributed to data collection, data analysis, interpretation of results and the writing of the manuscript. R.İ., N.K.G. and F.K. are responsible for clinical follow-up, data collection and data interpretation. 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Özvatan T, Akalın H, Sınırtaş M, et al.: Nosocomial Acinetobacter pneumonia: treatment and prognostic factors in 356 cases. Respirology. 2016; 21:363–369. Karaiskos I, Friberg L, Pontikis K, Ioannidis K, Tsagkari V, Galani L, Kostakou E, Baziaka F, Paskalis C, Koutsoukou A, et al. Colistin Population Pharmacokinetics after Application of a Loading Dose of 9 MU Colistin Methanesulfonate in Critically Ill Patients. Antimicrob. Agents Chemother. 2015; 59: 7240–7248. Del Bono V, Giacobbe DR, Marchese A, Parisini A, Fucile C, Coppo E et al. Meropenem for treating KPC-producing Klebsiella pneumoniae bloodstream infections: Should we get to the PK/PD root of the paradox? Virulence 2017;8:66–73. European Committee on Antimicrobial Susceptibility Testing. Breakpoint tables for interpretation of MICs and zone diameters. Version 8.0. EUCAST, 2018. Motos A, Avery LM, DeRonde KJ, Mullane EM, Kuti JL, Nicolau DP. Where should antibiotic gradient diffusion strips be crossed to assess synergy? 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Polymyxin B in combination with meropenem against carbapenemase-producing Klebsiella pneumoniae: pharmacodynamics and morphological changes. Int J Antimicrob Agents 2017;49:224–32. Kulengowski B, Campion JJ, Feola DJ, Burgess DS. Effect of the meropenem MIC on the killing activity of meropenem and polymyxin B in combination against KPC-producing Klebsiella pneumoniae. J Antibiotics 2017;70:974–8. Pea F, Siega PD, Cojutti P, Sartor A, Crapis M, Scarparo C et al. Might real-time pharmacokinetic/pharmacodynamic optimisation of high-dose continuous-infusion meropenem improve clinical cure in infections caused by KPC-producing Klebsiella pneumoniae ? Int J Antimicrob Agents 2017;49:255–8. Cojutti P, Sartor A, Righi E, Scarparo C, Bassetti M, Pea F. Population Pharmacokinetics of High-Dose Continuous-Infusion Meropenem and Considerations for Use in the Treatment of Infections Due to KPC Producing Klebsiella pneumoniae. Antimicrob Agents Chemother 2017;61: e00794-17. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 28 Oct, 2024 Read the published version in Scientific Reports → Version 1 posted Editorial decision: Revision requested 16 May, 2024 Reviews received at journal 14 May, 2024 Reviews received at journal 07 May, 2024 Reviewers agreed at journal 01 May, 2024 Reviewers agreed at journal 19 Apr, 2024 Reviewers invited by journal 17 Apr, 2024 Editor assigned by journal 15 Mar, 2024 Editor invited by journal 11 Mar, 2024 Submission checks completed at journal 11 Mar, 2024 First submitted to journal 14 Feb, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {\"props\":{\"pageProps\":{\"initialData\":{\"identity\":\"rs-3956365\",\"acceptedTermsAndConditions\":true,\"allowDirectSubmit\":false,\"archivedVersions\":[],\"articleType\":\"Article\",\"associatedPublications\":[],\"authors\":[{\"id\":278553159,\"identity\":\"da1d2256-384a-4dc4-b9c1-7d7bfce4b233\",\"order_by\":0,\"name\":\"Cihan Semet\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Uludağ University\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Cihan\",\"middleName\":\"\",\"lastName\":\"Semet\",\"suffix\":\"\"},{\"id\":278553160,\"identity\":\"a885033a-6b76-4308-ab0c-f86621ab4371\",\"order_by\":1,\"name\":\"Kadir Efe\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Uludağ University\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Kadir\",\"middleName\":\"\",\"lastName\":\"Efe\",\"suffix\":\"\"},{\"id\":278553161,\"identity\":\"b697f797-4e78-4c3a-a25c-27c0b929a2e0\",\"order_by\":2,\"name\":\"Halis Akalın\",\"email\":\"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA2ElEQVRIiWNgGAWjYBACAwbmhgMMFQwyDAwJID4zMVoYgVrOMPAgtLARoYWBsY0ULebsBxsP/px3mMfgePLjFwwV1okN8r0P8Gqx7ElsOMy7DajlzDMzC4Yz6YkNbOwG+B12AKiFEaTlRoKZAWPbYaAWAi4zOP+w4eDPOSAt6d8MGP8Ro+VGYsMB3gaQlhzjB4wNRGl5CFR/LJ1H8sybMoaEY+nGbWxphByWfPjjjxprOb7j6Zs/fKixlu1nPoZfCzJgk0hgIBwtKID5AymqR8EoGAWjYOQAAJQMS7a+WiE5AAAAAElFTkSuQmCC\",\"orcid\":\"\",\"institution\":\"Uludağ University\",\"correspondingAuthor\":true,\"prefix\":\"\",\"firstName\":\"Halis\",\"middleName\":\"\",\"lastName\":\"Akalın\",\"suffix\":\"\"},{\"id\":278553162,\"identity\":\"37569d77-31d7-470a-9431-5a4791ef509b\",\"order_by\":3,\"name\":\"Remzi İşçimen\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Uludağ University\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Remzi\",\"middleName\":\"\",\"lastName\":\"İşçimen\",\"suffix\":\"\"},{\"id\":278553163,\"identity\":\"688b68ac-f057-45d4-a939-8c7ad9a33310\",\"order_by\":4,\"name\":\"Nermin Kelebek Girgin\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Uludağ University\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Nermin\",\"middleName\":\"Kelebek\",\"lastName\":\"Girgin\",\"suffix\":\"\"},{\"id\":278553164,\"identity\":\"84bb388e-28dc-4589-8979-6589b39437ad\",\"order_by\":5,\"name\":\"Cüneyt Özakın\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Uludağ University\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Cüneyt\",\"middleName\":\"\",\"lastName\":\"Özakın\",\"suffix\":\"\"},{\"id\":278553165,\"identity\":\"8cafdec7-c571-4e3f-bfd3-bc22678e8506\",\"order_by\":6,\"name\":\"Ferda Kahveci\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Uludağ University\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Ferda\",\"middleName\":\"\",\"lastName\":\"Kahveci\",\"suffix\":\"\"}],\"badges\":[],\"createdAt\":\"2024-02-14 14:51:46\",\"currentVersionCode\":1,\"declarations\":\"\",\"doi\":\"10.21203/rs.3.rs-3956365/v1\",\"doiUrl\":\"https://doi.org/10.21203/rs.3.rs-3956365/v1\",\"draftVersion\":[],\"editorialEvents\":[{\"content\":\"https://doi.org/10.1038/s41598-024-73786-x\",\"type\":\"published\",\"date\":\"2024-10-28T16:20:23+00:00\"}],\"editorialNote\":\"\",\"failedWorkflow\":false,\"files\":[{\"id\":68207214,\"identity\":\"256c08c1-1e55-48c0-b1e7-f9759c8dd85e\",\"added_by\":\"auto\",\"created_at\":\"2024-11-04 16:35:52\",\"extension\":\"pdf\",\"order_by\":0,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"manuscript-pdf\",\"size\":458218,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"manuscript.pdf\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-3956365/v1/931ba3a9-8c57-483a-90ea-505c2ad875e1.pdf\"}],\"financialInterests\":\"No competing interests reported.\",\"formattedTitle\":\"Carbapenem or colistin resistant Klebsiella pneumoniae bacteremia in the intensive care unit: real life data \",\"fulltext\":[{\"header\":\"Introduction\",\"content\":\"\\u003cp\\u003eCarbapenem-resistant \\u003cem\\u003eKlebsiella pneumoniae\\u003c/em\\u003e (CRKp) infections are an important cause of morbidity and mortality. In a meta-analysis evaluating mortality, clinical and microbiological response for CRKp infections, mortality rate was 37.2%, clinical response was 69%, and microbiological response was 63.7% (\\u003cspan citationid=\\\"CR1\\\" class=\\\"CitationRef\\\"\\u003e1\\u003c/span\\u003e).\\u003c/p\\u003e \\u003cp\\u003ePaniagua-Garcia et al reported that the difference in 30-day mortality rates between patients with carbapenem\\u0026ndash;resistant Enterobacterales(88.5% \\u003cem\\u003eKlebsiella\\u003c/em\\u003e spp.) infection compared with patients with carbapenem-susceptible(31.4% \\u003cem\\u003eKlebsiella\\u003c/em\\u003e spp.) infection was 13.2%(\\u003cspan citationid=\\\"CR2\\\" class=\\\"CitationRef\\\"\\u003e2\\u003c/span\\u003e).\\u003c/p\\u003e \\u003cp\\u003eThere are conflicting results in the carbapenem-resistant group on the effects of the bacteria also being resistant to colistin on mortality (\\u003cspan additionalcitationids=\\\"CR4 CR5 CR6\\\" citationid=\\\"CR3\\\" class=\\\"CitationRef\\\"\\u003e3\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR7\\\" class=\\\"CitationRef\\\"\\u003e7\\u003c/span\\u003e).\\u003c/p\\u003e \\u003cp\\u003eTreatment with new antibiotics such as ceftazidime-avibactam was reported to significantly reduce mortality in CRKp infections compared with older antibiotics such as meropenem, polymyxin (polymyxin-B and colistin), tigecycline, fosfomycin, and aminoglycosides (\\u003cspan additionalcitationids=\\\"CR9 CR10\\\" citationid=\\\"CR8\\\" class=\\\"CitationRef\\\"\\u003e8\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR11\\\" class=\\\"CitationRef\\\"\\u003e11\\u003c/span\\u003e).\\u003c/p\\u003e \\u003cp\\u003eHowever, access to new antibiotics is not always possible owing to economic factors, development of resistance, or intolerance. Therefore, older antibiotics may still be needed from time to time. One of the most commonly used combinations in CRKp infections is meropenem plus colistin (\\u003cspan citationid=\\\"CR12\\\" class=\\\"CitationRef\\\"\\u003e12\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR13\\\" class=\\\"CitationRef\\\"\\u003e13\\u003c/span\\u003e).\\u003c/p\\u003e \\u003cp\\u003eTumbarello et al. showed that even if \\u003cem\\u003eK. pneumoniae\\u003c/em\\u003e is carbapenem resistant, in combinations including meropenem (high dose, prolonged infusion) in the treatment, mortality was significantly lower in the MIC\\u0026thinsp;\\u0026le;\\u0026thinsp;8 mg/L group than infections caused by strains with MIC values\\u0026thinsp;\\u0026gt;\\u0026thinsp;8 mg/L (\\u003cspan citationid=\\\"CR8\\\" class=\\\"CitationRef\\\"\\u003e8\\u003c/span\\u003e). Similarly, Daikos et al. reported that mortality increased from 19.4\\u0026ndash;35.5% in drug combinations containing meropenem when the meropenem MIC value was \\u0026gt;\\u0026thinsp;8 mg/L (\\u003cspan citationid=\\\"CR9\\\" class=\\\"CitationRef\\\"\\u003e9\\u003c/span\\u003e).\\u003c/p\\u003e \\u003cp\\u003eIn a study by Gomez-Simmonds et al. (meropenem MIC\\u0026thinsp;\\u0026ge;\\u0026thinsp;16 mg/L in 90% of the isolates), combination therapy (a single effective antibiotic\\u0026thinsp;+\\u0026thinsp;meropenem or broad-spectrum cephalosporin) was not superior to monotherapy (a single effective antibiotic) (\\u003cspan citationid=\\\"CR10\\\" class=\\\"CitationRef\\\"\\u003e10\\u003c/span\\u003e).\\u003c/p\\u003e \\u003cp\\u003eGianella et al. compared carbapenem-containing combinations with carbapenem-free combinations in bloodstream infections caused by CRKp and reported that meropenem-containing combinations were more effective than meropenem-free combinations in terms of 14-day mortality even if meropenem MIC was \\u0026ge;\\u0026thinsp;16 mg/L (\\u003cspan citationid=\\\"CR11\\\" class=\\\"CitationRef\\\"\\u003e11\\u003c/span\\u003e).\\u003c/p\\u003e \\u003cp\\u003eIn the present study, the primary objective was the effect of carbapenem resistance or carbapenem and colistin resistance on mortality in \\u003cem\\u003eKlebsiella pneumonia\\u003c/em\\u003e bacteremia. In addition to that combined meropenem\\u0026thinsp;+\\u0026thinsp;colistin administration in CRKp bacteremia was retrospectively evaluated using minimal inhibitory concentration (MIC) and synergy data as a secondary objective.\\u003c/p\\u003e\"},{\"header\":\"Methods\",\"content\":\"\\u003cp\\u003eA total of 139 patients (age, \\u0026gt;\\u0026thinsp;18 years) with \\u003cem\\u003eK. pneumoniae\\u003c/em\\u003e bacteremia who were hospitalized in the Anesthesia and Reanimation Intensive Care Unit of our hospital between 01/01/2000 and 31/07/2019 were included in the study. The study was performed in accordance with relevant guidelines and regulation and approved by the Clinical Research Ethics Committee of Uludağ University Faculty of Medicine (2021-9/3). After informed consent was obtained, all patient information was retrieved from the electronic file system of our hospital. A case follow-up form was filled by all patients.\\u003c/p\\u003e \\u003cp\\u003eBloodstream infection(BSI) was classified as primary, i.e., a laboratory confirmed BSI that is not secondary to another site infection, or secondary that is thought to be seeded from a site-specific infection at another body site (\\u003cspan citationid=\\\"CR12\\\" class=\\\"CitationRef\\\"\\u003e12\\u003c/span\\u003e).\\u003c/p\\u003e \\u003cp\\u003eIn the presence of a focus of infection, the source of bacteremia was defined according to whether \\u003cem\\u003eK. pneumoniae\\u003c/em\\u003e was isolated in the culture obtained from the focus of infection the day before or the same day after the positive blood culture. Catheter-associated bacteremia was defined as \\u003cem\\u003eK. pneumoniae\\u003c/em\\u003e growth in blood culture from a catheter or in quantitative culture of catheter tip and peripheral blood culture, provided that there was no other active focus of infection (\\u003cspan additionalcitationids=\\\"CR14 CR15\\\" citationid=\\\"CR13\\\" class=\\\"CitationRef\\\"\\u003e13\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR16\\\" class=\\\"CitationRef\\\"\\u003e16\\u003c/span\\u003e).\\u003c/p\\u003e \\u003cp\\u003eAll patients were classified as \\u0026ldquo;sepsis,\\u0026rdquo; \\u0026ldquo;severe sepsis,\\u0026rdquo; or \\u0026ldquo;septic shock\\u0026rdquo; based on consensus conference sepsis-1 criteria (\\u003cspan citationid=\\\"CR17\\\" class=\\\"CitationRef\\\"\\u003e17\\u003c/span\\u003e).\\u003c/p\\u003e \\u003cp\\u003eFor the diagnosis of nosocomial pneumonia, in addition to the development of pneumonia within at least 48 hours after the hospital admission and the presence of new or progressing infiltration on the chest radiography, at least two of the following criteria should be present (\\u003cspan citationid=\\\"CR18\\\" class=\\\"CitationRef\\\"\\u003e18\\u003c/span\\u003e):\\u003c/p\\u003e \\u003cp\\u003e \\u003col\\u003e \\u003cspan\\u003e \\u003cli\\u003e \\u003cp\\u003ePresence of high fever (body temperature\\u0026thinsp;\\u0026gt;\\u0026thinsp;38\\u0026deg;C).\\u003c/p\\u003e \\u003c/li\\u003e \\u003c/span\\u003e \\u003cspan\\u003e \\u003cli\\u003e \\u003cp\\u003ePresence of leukocytosis\\u0026thinsp;\\u0026gt;\\u0026thinsp;10,000/mm\\u003csup\\u003e3\\u003c/sup\\u003e or leukopenia\\u0026thinsp;\\u0026lt;\\u0026thinsp;4,000/mm\\u003csup\\u003e3\\u003c/sup\\u003e.\\u003c/p\\u003e \\u003c/li\\u003e \\u003c/span\\u003e \\u003cspan\\u003e \\u003cli\\u003e \\u003cp\\u003ePurulent bronchial secretion indicated by the presence of \\u0026gt;\\u0026thinsp;25 leukocytes and \\u0026le;\\u0026thinsp;10 epithelial cells in the gram staining examination of the Deep Endotracheal Aspiration (DTA) (10\\u0026times;).\\u003c/p\\u003e \\u003c/li\\u003e \\u003c/span\\u003e \\u003cspan\\u003e \\u003cli\\u003e \\u003cp\\u003eDecreased oxygenation.\\u003c/p\\u003e \\u003c/li\\u003e \\u003c/span\\u003e \\u003c/ol\\u003e \\u003c/p\\u003e \\u003cp\\u003eDiagnostic criteria of the international sepsis group were used for other infection diagnoses (\\u003cspan citationid=\\\"CR19\\\" class=\\\"CitationRef\\\"\\u003e19\\u003c/span\\u003e).\\u003c/p\\u003e \\u003cp\\u003eUse of prednisone or an equivalent steroid by the patient at a dose of 20 mg/day for 2 weeks or 30 mg/day for 1 week within the last one month was considered as a risk factor for steroid use (\\u003cspan citationid=\\\"CR20\\\" class=\\\"CitationRef\\\"\\u003e20\\u003c/span\\u003e).\\u003c/p\\u003e \\u003cp\\u003ePatients with a neutrophil count\\u0026thinsp;\\u0026lt;\\u0026thinsp;500/mm\\u003csup\\u003e3\\u003c/sup\\u003e at the time of diagnosis were considered neutropenic.\\u003c/p\\u003e \\u003cp\\u003eAcute Physiology and Chronic Health Evaluation-II score was calculated within 24 hours of admission to the ICU (\\u003cspan citationid=\\\"CR21\\\" class=\\\"CitationRef\\\"\\u003e21\\u003c/span\\u003e). Pitt Bacteremia scores were calculated at the diagnosis of infection (\\u003cspan citationid=\\\"CR22\\\" class=\\\"CitationRef\\\"\\u003e22\\u003c/span\\u003e).\\u003c/p\\u003e \\u003cp\\u003eThe 14-day and 30-day mortality values were calculated according to the first 14 days and 30 days from the date of diagnosis. Antibiotics used by the patients before the diagnosis\\u0026mdash;i.e., used for at least 48 hours in the last 30 days\\u0026mdash;were evaluated(\\u003cspan citationid=\\\"CR23\\\" class=\\\"CitationRef\\\"\\u003e23\\u003c/span\\u003e).\\u003c/p\\u003e \\u003cp\\u003eColistin was administered as a maintenance dose after the standard loading dose in all patients (\\u003cspan citationid=\\\"CR24\\\" class=\\\"CitationRef\\\"\\u003e24\\u003c/span\\u003e). Meropenem was administered either as standard dose(3 g/d) and infusion or as high dose(6 g/d) and prolonged infusion(4 hours) (\\u003cspan citationid=\\\"CR25\\\" class=\\\"CitationRef\\\"\\u003e25\\u003c/span\\u003e).\\u003c/p\\u003e \\u003cp\\u003eIdentification and antibiotic susceptibility testing of \\u003cem\\u003eK. pneumoniae\\u003c/em\\u003e isolates were performed using a Phoenix 100 (Beckton Dickinson, USA) automated system. In order to confirm ESBL negativity and positivity of \\u003cem\\u003eK. pneumoniae\\u003c/em\\u003e isolates, a combined disk confirmation test was performed as recommended by Clinical Laboratory Standarts Institute(CLSI). Carbapenem resistance was defined as a minimum inhibitory concentration (MIC) to meropenem of greater than 8 mg/L. The MIC of colistin was determined by broth microdilution method, and a strain with MIC\\u0026thinsp;\\u0026le;\\u0026thinsp;2 mg/L was considered to be susceptible to colistin(\\u003cspan citationid=\\\"CR26\\\" class=\\\"CitationRef\\\"\\u003e26\\u003c/span\\u003e).\\u003c/p\\u003e \\u003cp\\u003e For combinations containing colistin, meropenem, tigecycline, or fosfomycin, synergy testing was performed by gradient diffusion method and evaluated according to European Committee on Antimicrobial Susceptibility Testing(EUCAST) criteria. For Colistin, Meropenem, Tigecycline, and Fosfomycin, 0.5 McFarland turbidity bacterial suspensions were spread on 4 MHA plates. If the MIC values of antibiotics A and B, the combination of which was to be tested, were not known beforehand, gradient diffusion method strips containing the antibiotics were placed separately in a petri dish to determine their MICs individually. Strip B was placed in the third petri dish first and incubated for 1 hour. Strip B was removed with sterile forceps and strip A was placed on the same place. Strip A was placed in the fourth petri dish and stored for 1 hour. Strip A was removed and strip B was placed on the same place. After 24 hours of incubation at 35\\u0026deg;C\\u0026ndash;37\\u0026deg;C, the MIC of A in the presence of B in the third petri dish and the MIC of B in the presence of A in the fourth petri dish were measured and evaluated according to EUCAST recommendations. Interaction in combination tests was determined using fractional inhibition concentration (FIC) index and evaluated as synergistic for FIC\\u0026thinsp;\\u0026le;\\u0026thinsp;0.5, additive for 0.5\\u0026thinsp;\\u0026lt;\\u0026thinsp;FIC\\u0026thinsp;\\u0026le;\\u0026thinsp;1, indifferent for 1\\u0026thinsp;\\u0026lt;\\u0026thinsp;FIC\\u0026thinsp;\\u0026lt;\\u0026thinsp;4, and antagonistic for FIC\\u0026thinsp;\\u0026ge;\\u0026thinsp;4 (\\u003cspan additionalcitationids=\\\"CR27\\\" citationid=\\\"CR26\\\" class=\\\"CitationRef\\\"\\u003e26\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR28\\\" class=\\\"CitationRef\\\"\\u003e28\\u003c/span\\u003e).\\u003c/p\\u003e\"},{\"header\":\"Results\",\"content\":\"\\u003cp\\u003eA total of 139 adult patients diagnosed with \\u003cem\\u003eK. pneumoniae\\u003c/em\\u003e bacteremia between 01/01/2000 and 31/07/2019 were included in the study. The median age was 61 (33\\u0026ndash;98) years. Antibiotics were used in 58 (41.7%) of the patients in the last 30 days and 36 (25.9%) of these patients used carbapenems, 11 (7.9%) used 3rd generation cephalosporins, 6 (4.3%) used 4th generation cephalosporins, and 3 (2.2%) used tigecyclines.\\u003c/p\\u003e \\u003cp\\u003eThe median length of stay in the intensive care unit until the diagnosis of \\u003cem\\u003eK. pneumoniae\\u003c/em\\u003e bacteremia was 17 (1\\u0026ndash;42) days. Some demographic characteristics of the patients are shown in Table\\u0026nbsp;1.\\u003c/p\\u003e \\u003cp\\u003e \\u003cstrong\\u003eTable-1\\u003c/strong\\u003e \\u003cp\\u003eDemographic characteristics of patients\\u003c/p\\u003e \\u003c/p\\u003e \\u003cp\\u003e \\u003cdiv class=\\\"gridtable\\\"\\u003e\\u003ctable float=\\\"No\\\" id=\\\"Taba\\\" border=\\\"1\\\"\\u003e \\u003ccolgroup cols=\\\"3\\\"\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c1\\\" colnum=\\\"1\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"char\\\" char=\\\".\\\" class=\\\"colspec\\\" colname=\\\"c2\\\" colnum=\\\"2\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c3\\\" colnum=\\\"3\\\"\\u003e\\u003c/div\\u003e \\u003cthead\\u003e \\u003ctr\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eDemographic Characteristics\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eNumber of Patients (n)\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003ePercentage (%)\\u003c/p\\u003e \\u003c/th\\u003e \\u003c/tr\\u003e \\u003c/thead\\u003e \\u003ctbody\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eSex\\u003c/p\\u003e \\u003cp\\u003eMale\\u003c/p\\u003e \\u003cp\\u003eFemale\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e82\\u003c/p\\u003e \\u003cp\\u003e57\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e59\\u003c/p\\u003e \\u003cp\\u003e41\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eAge (years)\\u003c/p\\u003e \\u003cp\\u003e\\u0026ge;\\u0026thinsp;65\\u003c/p\\u003e \\u003cp\\u003e\\u0026lt;\\u0026thinsp;65\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e56\\u003c/p\\u003e \\u003cp\\u003e83\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e40.2\\u003c/p\\u003e \\u003cp\\u003e59.8\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eCVC +\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e87\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e62.6\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eAPACHE II\\u0026thinsp;\\u0026ge;\\u0026thinsp;20\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e57\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e41\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eAPACHE II\\u0026thinsp;\\u0026lt;\\u0026thinsp;20\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e82\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e59\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003ePBS\\u0026thinsp;\\u0026ge;\\u0026thinsp;4\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e116\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e83.4\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003ePBS\\u0026thinsp;\\u0026lt;\\u0026thinsp;4\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e23\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e16.6\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eNeutropenia\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e27\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e19.4\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eMechanical Ventilation Support\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e100\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e71.9\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eAntibiotic use in the last 30 days\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e58\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e41.7\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eCarbapenem use in the last 30 days\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e36\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e25.9\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003c/tbody\\u003e \\u003c/colgroup\\u003e \\u003ctfoot\\u003e \\u003ctr\\u003e\\u003ctd colspan=\\\"3\\\"\\u003eAPACHE-II: Acute Physiology and Chronic Health Evaluation-II; CVC: Central Venous Catheter; PBS: Pittsburg bacteremia score,\\u003c/td\\u003e\\u003c/tr\\u003e \\u003c/tfoot\\u003e \\u003c/table\\u003e\\u003c/div\\u003e \\u003c/p\\u003e \\u003cp\\u003eA total of 97 (69.7%) patients had various underlying diseases. Among these, 29 (20.8%) had more than one underlying disease (Table\\u0026nbsp;2).\\u003c/p\\u003e \\u003cp\\u003e \\u003cstrong\\u003eTable-2\\u003c/strong\\u003e \\u003cp\\u003eUnderlying diseases of the patients\\u003c/p\\u003e \\u003c/p\\u003e \\u003cp\\u003e \\u003cdiv class=\\\"gridtable\\\"\\u003e\\u003ctable float=\\\"No\\\" id=\\\"Tabb\\\" border=\\\"1\\\"\\u003e \\u003ccolgroup cols=\\\"3\\\"\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c1\\\" colnum=\\\"1\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"char\\\" char=\\\".\\\" class=\\\"colspec\\\" colname=\\\"c2\\\" colnum=\\\"2\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"char\\\" char=\\\".\\\" class=\\\"colspec\\\" colname=\\\"c3\\\" colnum=\\\"3\\\"\\u003e\\u003c/div\\u003e \\u003cthead\\u003e \\u003ctr\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eUnderlying disease\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eNumber of patients (n)\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003ePercentage (%)\\u003c/p\\u003e \\u003c/th\\u003e \\u003c/tr\\u003e \\u003c/thead\\u003e \\u003ctbody\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eCOPD\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e10\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e7.1\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eCRF\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e29\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e20.8\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eDM\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e43\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e30.9\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eSOT\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e3\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e2.1\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eCHF\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e27\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e19.4\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eOther\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e8\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e5.7\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eTotal illness\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e120\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eTotal patients\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e97\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e69.7\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003c/tbody\\u003e \\u003c/colgroup\\u003e \\u003ctfoot\\u003e \\u003ctr\\u003e\\u003ctd colspan=\\\"3\\\"\\u003eCHF: Congestive Heart Failure, COPD: Chronic Obstructive Pulmonary Disease, CRF: Chronic Renal Failure, SOT: Solid Organ Transplantation, DM: Diabetes Mellitus\\u003c/td\\u003e\\u003c/tr\\u003e \\u003c/tfoot\\u003e \\u003c/table\\u003e\\u003c/div\\u003e \\u003c/p\\u003e \\u003cp\\u003eThe 14-day mortality was 8.6% (n\\u0026thinsp;=\\u0026thinsp;12) and 30-day mortality was 19.4% (n\\u0026thinsp;=\\u0026thinsp;27). No significant difference was noted between the 14- and 30-day mortality rates in terms of the source (Table-3).\\u003c/p\\u003e \\u003cp\\u003e \\u003cstrong\\u003eTable-3\\u003c/strong\\u003e \\u003cp\\u003eMortality rates by source of bacteremia\\u003c/p\\u003e \\u003c/p\\u003e \\u003cp\\u003e \\u003cdiv class=\\\"gridtable\\\"\\u003e\\u003ctable float=\\\"No\\\" id=\\\"Tabc\\\" border=\\\"1\\\"\\u003e \\u003ccolgroup cols=\\\"8\\\"\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c1\\\" colnum=\\\"1\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c2\\\" colnum=\\\"2\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c3\\\" colnum=\\\"3\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c4\\\" colnum=\\\"4\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c5\\\" colnum=\\\"5\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c6\\\" colnum=\\\"6\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c7\\\" colnum=\\\"7\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c8\\\" colnum=\\\"8\\\"\\u003e\\u003c/div\\u003e \\u003cthead\\u003e \\u003ctr\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u0026nbsp;\\u003c/th\\u003e \\u003cth align=\\\"left\\\" colspan=\\\"3\\\" nameend=\\\"c4\\\" namest=\\\"c2\\\"\\u003e \\u003cp\\u003e14-day mortality\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colspan=\\\"3\\\" nameend=\\\"c7\\\" namest=\\\"c5\\\"\\u003e \\u003cp\\u003e30-day mortality\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c8\\\"\\u003e\\u0026nbsp;\\u003c/th\\u003e \\u003c/tr\\u003e \\u003c/thead\\u003e \\u003ctbody\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eSource\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eDeceased n (%)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eSurvivor n (%)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eP\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003eDeceased n (%)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003eSurvivor n (%)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003eP\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003eTotal n\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003ePrimary bacteremia\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e6 (11.3)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e47 (88.6)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e12 (22.6)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e41 (77.3)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003e53\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eCatheter-associated bacteremia\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e4 (6.4)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e58 (93.5)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e1.000\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e12 (19.3)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e50 (80.6)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e0.982\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003e62\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eVentilator-associated pneumonia\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e2 (8.3)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e22 (91.6)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e3 (12.5)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e21 (87.5)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003e24\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eTotal\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e12 (8.6)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e127 (91.3)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e27 (19.4)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e112 (80.5)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003e139\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003c/tbody\\u003e \\u003c/colgroup\\u003e \\u003c/table\\u003e\\u003c/div\\u003e \\u003c/p\\u003e \\u003cp\\u003e14-day mortality was significantly higher in the carbapenem resistant-colistin resistant group compared to the carbapenem sensitive (extended spectrum beta-lactamase-ESBL positive) group and the carbapenem resistant-colistin sensitive group.\\u003c/p\\u003e \\u003cp\\u003e30-day mortality was significantly higher in the carbapenem resistant-colistin sensitive group compared to the carbapenem susceptible (ESBL positive) group and in the carbapenem resistant-colistin resistant group compared to the carbapenem susceptible (ESBL positive) group (Table-4).\\u003c/p\\u003e \\u003cp\\u003e \\u003cstrong\\u003eTable-4\\u003c/strong\\u003e \\u003cp\\u003eMortality rates according to resistance profile\\u003c/p\\u003e \\u003c/p\\u003e \\u003cp\\u003e \\u003cdiv class=\\\"gridtable\\\"\\u003e\\u003ctable float=\\\"No\\\" id=\\\"Tabd\\\" border=\\\"1\\\"\\u003e \\u003ccolgroup cols=\\\"7\\\"\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c1\\\" colnum=\\\"1\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c2\\\" colnum=\\\"2\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c3\\\" colnum=\\\"3\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c4\\\" colnum=\\\"4\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c5\\\" colnum=\\\"5\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c6\\\" colnum=\\\"6\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c7\\\" colnum=\\\"7\\\"\\u003e\\u003c/div\\u003e \\u003cthead\\u003e \\u003ctr\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u0026nbsp;\\u003c/th\\u003e \\u003cth align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c3\\\" namest=\\\"c2\\\"\\u003e \\u003cp\\u003e14-day mortality\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u0026nbsp;\\u003c/th\\u003e \\u003cth align=\\\"left\\\" colspan=\\\"3\\\" nameend=\\\"c7\\\" namest=\\\"c5\\\"\\u003e \\u003cp\\u003e30-day mortality\\u003c/p\\u003e \\u003c/th\\u003e \\u003c/tr\\u003e \\u003c/thead\\u003e \\u003ctbody\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eNumber of patients (n)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003ePercentage (%)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eP value\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003eNumber of patients (n)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003ePercentage (%)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003eP value\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eCarbapenem sensitive-ESBL positive (n\\u0026thinsp;=\\u0026thinsp;73)*\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e1\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e1.3\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e1\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e1.3\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eCarbapenem resistant-colistin sensitive (n\\u0026thinsp;=\\u0026thinsp;39)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e0\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e0\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e1.000\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e15\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e38.4\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003e\\u0026lt;\\u0026thinsp;0.001\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eCarbapenem sensitive-ESBL positive (n\\u0026thinsp;=\\u0026thinsp;73)*\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e1\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e1.3\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e1\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e1.3\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eCarbapenem and colistin resistant (n\\u0026thinsp;=\\u0026thinsp;27)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e11\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e40.7\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003e\\u0026lt;\\u0026thinsp;0.001\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e11\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e40.7\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003e\\u0026lt;\\u0026thinsp;0.001\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eCarbapenem resistant-colistin sensitive (n\\u0026thinsp;=\\u0026thinsp;39)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e0\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e0\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e15\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e38.4\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eCarbapenem and colistin resistant (n\\u0026thinsp;=\\u0026thinsp;27)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e11\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e40.7\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003e\\u0026lt;\\u0026thinsp;0.001\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e11\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e40.7\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003e0.852\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003c/tbody\\u003e \\u003c/colgroup\\u003e \\u003c/table\\u003e\\u003c/div\\u003e \\u003c/p\\u003e \\u003cp\\u003e*All carbapenem-susceptible-ESBL postive patients were treated with carbapenem monotherapy.\\u003c/p\\u003e \\u003cp\\u003eMeropenem\\u0026thinsp;+\\u0026thinsp;colistin combination was administered to 37 (95%) of carbapenem resistant\\u0026ndash;colistin sensitive (n\\u0026thinsp;=\\u0026thinsp;39) patients. The 30-day mortality rate was 37.8% in 37 patients receiving meropenem\\u0026thinsp;+\\u0026thinsp;colistin. A high dose and prolonged infusion of meropenem was administered in 19 of 39 patients and as standard dose and infusion in 20 patients; furthermore, no intergroup differences in mortality were noted in terms of mortality (36% vs. 40%, p\\u0026thinsp;=\\u0026thinsp;0.839). Synergy testing was performed in 14 of 37 patients receiving meropenem\\u0026thinsp;+\\u0026thinsp;colistin. No synergy or antagonism was detected between meropenem and colistin and was considered as indifferent. Meropenem MIC level was \\u0026ge;\\u0026thinsp;32 mg/L in all strains.\\u003c/p\\u003e \\u003cp\\u003eOf the 27 carbapenem resistant\\u0026ndash;colistin resistant patients, 25 (93%) received meropenem\\u0026thinsp;+\\u0026thinsp;colistin combination. In these 25 patients, the 30-day mortality rate was 40%. In 13 patients, a high dose and prolonged infusion of meropenem was administered, whereas 14 patients received a standard dose and infusion. No significant intergroup difference was noted in terms of mortality (38% vs. 42%, p\\u0026thinsp;=\\u0026thinsp;0.816). In this group, synergy testing was performed in 16 of 25 patients receiving meropenem\\u0026thinsp;+\\u0026thinsp;colistin. No synergy or antagonism was detected between meropenem and colistin and was considered as indifferent. Meropenem MIC level was \\u0026ge;\\u0026thinsp;32 mg/dl in all strains.\\u003c/p\\u003e\"},{\"header\":\"Discussion\",\"content\":\"\\u003cp\\u003eMany studies have demonstrated that carbapenem resistance significantly increases mortality compared with carbapenem susceptible groups. In a multicenter study, 30-day mortality rate in bloodstream infections caused by CRKp was 44% (\\u003cspan citationid=\\\"CR29\\\" class=\\\"CitationRef\\\"\\u003e29\\u003c/span\\u003e). In a meta-analysis evaluating CRKp bacteremia, mortality was 42.14% in the carbapenem-resistant group and 21.16% in the carbapenem-sensitive group. Mortality was reported to be 54.30% in bloodstream infections and 13.52% in urinary tract infections (\\u003cspan citationid=\\\"CR30\\\" class=\\\"CitationRef\\\"\\u003e30\\u003c/span\\u003e). The very low mortality rates in the carbapenem susceptible group in the present study may be explained by the fact that carbapenem was used in all of these cases.\\u003c/p\\u003e \\u003cp\\u003eBalkan et al reported that colistin resistance increased 28-day mortality in bloodstream infections due to carbapenem-resistant \\u003cem\\u003eKlebsiella pneumoniae\\u003c/em\\u003e(\\u003cspan citationid=\\\"CR5\\\" class=\\\"CitationRef\\\"\\u003e5\\u003c/span\\u003e). Menekşe et al found that increasing MIC of colistin as a independent mortality factor in \\u003cem\\u003eKlebsiella pneumoniae\\u003c/em\\u003e bloodstream infections(\\u003cspan citationid=\\\"CR6\\\" class=\\\"CitationRef\\\"\\u003e6\\u003c/span\\u003e).On the other hand, Aslan et al reported that colistin resistance in CRKp had no impact on 30-day mortality(\\u003cspan citationid=\\\"CR3\\\" class=\\\"CitationRef\\\"\\u003e3\\u003c/span\\u003e).\\u003c/p\\u003e \\u003cp\\u003eIn the present study, we found that the presence of colistin resistance in addition to carbapenem resistance did not affect 30-day mortality. However, we found that significantly increased 14-day mortality. Different colistin susceptibility methods, whether colistin loading dose was given or not, whether meropenem dose and prolonged infusion were used or not, meropenem MIC values, combination or monotherapy and design of studies may have played a role in these different results.\\u003c/p\\u003e \\u003cp\\u003eIn the present study, meropenem\\u0026thinsp;+\\u0026thinsp;colistin combination was indifferent (neither synergistic nor antagonistic) by gradient diffusion system.\\u003c/p\\u003e \\u003cp\\u003eIn vitro synergy studies for carbapenem-resistant Enterobacteriaceae, the combination of polymyxin\\u0026thinsp;+\\u0026thinsp;carbapenem was generally found to be synergistic (\\u003cspan citationid=\\\"CR36\\\" class=\\\"CitationRef\\\"\\u003e36\\u003c/span\\u003e).\\u003c/p\\u003e \\u003cp\\u003eIn their study with the time-kill method, Sharma et al. showed that the combination was bactericidal if the MIC of meropenem was \\u0026le;\\u0026thinsp;16 mg/L in colistin-susceptible and meropenem-resistant \\u003cem\\u003eK. pneumoniae\\u003c/em\\u003e strains (\\u003cspan citationid=\\\"CR37\\\" class=\\\"CitationRef\\\"\\u003e37\\u003c/span\\u003e).\\u003c/p\\u003e \\u003cp\\u003eKulegowski et al. also showed that if the MIC of meropenem is \\u0026le;\\u0026thinsp;32 mg/L, the combination of meropenem\\u0026thinsp;+\\u0026thinsp;polymyxin B generally has a synergistic effect on polymyxin B-susceptible strains (\\u003cspan citationid=\\\"CR38\\\" class=\\\"CitationRef\\\"\\u003e38\\u003c/span\\u003e).\\u003c/p\\u003e \\u003cp\\u003eHowever, in a study involving 19 patients with bloodstream infection caused by \\u003cem\\u003eK. pneumoniae\\u003c/em\\u003e, Bono et al. did not reach the PK/PD targets in cases with MIC values ranging from 256 to 1024 mg/L, although the patients were given high dose and prolonged infusion. Furthermore, in vitro synergy with colistin was not detected. However, measured serum meropenem levels could reach the hypothetically determined T\\u0026thinsp;\\u0026gt;\\u0026thinsp;40% 1xMIC PK/PD targets of meropenem at a rate of 98% for the MIC value of 8 mg/L, 68% for 16 mg/L, and 32% for 32 mg/L (\\u003cspan citationid=\\\"CR25\\\" class=\\\"CitationRef\\\"\\u003e25\\u003c/span\\u003e). The lack of synergistic effect in our study may be attributable to meropenem MIC levels of \\u0026ge;\\u0026thinsp;32 mg/L.\\u003c/p\\u003e \\u003cp\\u003eThere was no therapeutic drug monitoring(TDM) for meropenem to evaluate PK/PD parameters in our study. We consider that TDM could be useful for infections caused by CRKp with MIC\\u0026thinsp;\\u0026le;\\u0026thinsp;64 mg/L(\\u003cspan citationid=\\\"CR39\\\" class=\\\"CitationRef\\\"\\u003e39\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR40\\\" class=\\\"CitationRef\\\"\\u003e40\\u003c/span\\u003e).\\u003c/p\\u003e \\u003cp\\u003eIn the present study, no significant difference in mortality was noted between high dose - prolonged infusion of meropenem and normal dose - standard infusion of meropenem. In the carbapenem resistant-colistin sensitive and carbapenem resistant-colistin resistant groups, no significant difference in mortality was observed between high dose and prolonged infusion of meropenem and normal dose infusion.\\u003c/p\\u003e \\u003cp\\u003eIt was shown that meropenem MIC is very important in the success of meropenem plus colistin combination in CRKp infections. If meropenem MIC\\u0026thinsp;\\u0026gt;\\u0026thinsp;8 mg/L, we can expect higher mortality(\\u003cspan citationid=\\\"CR8\\\" class=\\\"CitationRef\\\"\\u003e8\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR9\\\" class=\\\"CitationRef\\\"\\u003e9\\u003c/span\\u003e).\\u003c/p\\u003e \\u003cp\\u003eGianella et al. compared carbapenem-containing combinations with carbapenem-free combinations in bloodstream infections caused by CRKp and reported that meropenem-containing combinations were more effective than meropenem-free combinations in terms of 14-day mortality even if meropenem MIC was \\u0026ge;\\u0026thinsp;16 mg/L (\\u003cspan citationid=\\\"CR11\\\" class=\\\"CitationRef\\\"\\u003e11\\u003c/span\\u003e).\\u003c/p\\u003e \\u003cp\\u003eThe fact that the synergy test results were indifferent and that there was no mortality difference between high-dose and prolonged infusion of meropenem and standard dose infusion in both groups suggests that high-dose and prolonged infusion meropenem treatment does not provide any benefit compared to standard dose and infusion if the meropenem MIC is \\u0026ge;\\u0026thinsp;32 mg/L.\\u003c/p\\u003e \\u003cp\\u003eThere are certain limitations of this study. The study was conducted retrospectively. The number of cases was relatively small and the study was single centered. Not all carbapenem-resistant strains were tested for synergy. The results were not compared with a group given colistin monotherapy. Lastly, the strains were not epidemiologically analyzed at the molecular level and carbapenemase enzymes were not analyzed.\\u003c/p\\u003e \\u003cp\\u003eIn conclusion, 30-day mortality was significantly higher in the carbapenem resistant-colistin sensitive group and in the carbapenem resistant-colistin resistant group compared to the carbapenem susceptible (ESBL positive) group. When combined with colistin, if meropenem MIC is \\u0026ge;\\u0026thinsp;32 mg/L, meropenem administration with high dose and prolonged infusion is not superior to standard dose and infusion in both carbapenem resistant-colistin sensitive and carbapenem resistant-colistin resistant \\u003cem\\u003eK. pneumoniae\\u003c/em\\u003e bacteremia.\\u003c/p\\u003e\"},{\"header\":\"Acknowledments\",\"content\":\"\\u003cp\\u003eWe would like to thank Prof. Dr. G\\u0026uuml;ven \\u0026Ouml;zkaya for evaluating the statistical analysis of our study.\\u003c/p\\u003e \\u003cp\\u003eHA is responsible for the content of the manuscript, data analysis and interpretation, study design, writing of the manuscript, and critical review. CS contributed to data collection, data analysis, interpretation of results and the writing of the manuscript. Rİ, NKG and FK are responsible for clinical follow-up, data collection and data interpretation. CS, KE and C\\u0026Ouml; contributed substantially to the in vitro study design, data analysis and interpretation, and the writing of the manuscript.\\u003cdiv class=\\\"BlockQuote\\\"\\u003e\\u003cp\\u003e \\u003cb\\u003eFunding and Conflict of Interest\\u003c/b\\u003e \\u003c/p\\u003e\\u003c/div\\u003e\\u003c/p\\u003e \\u003cp\\u003eThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. There is no conflict of interest.\\u003c/p\\u003e\"},{\"header\":\"Declarations\",\"content\":\"\\n\\u003cp\\u003e\\u003cstrong\\u003eAcknowledments\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eWe would like to thank Prof. Dr. G\\u0026uuml;ven \\u0026Ouml;zkaya for evaluating the statistical analysis of our study.\\u003c/p\\u003e\\n\\u003cp\\u003eHA is responsible for the content of the manuscript, data analysis and interpretation, study design, writing of the manuscript, and critical review. CS contributed to data collection, data analysis, interpretation of results and the writing of the manuscript. Rİ, NKG and FK are responsible for clinical follow-up, \\u0026nbsp;data collection and data interpretation. CS, KE and C\\u0026Ouml; contributed substantially to the in vitro study design, data analysis and interpretation, and the writing of the manuscript.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eFunding and Conflict of Interest\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. There is no conflict of interest.\\u003c/p\\u003e\\u003ch2\\u003eAuthor Contribution\\u003c/h2\\u003e\\u003cp\\u003eH.A. is responsible for the content of the manuscript, data analysis and interpretation, study design, writing of the manuscript, and critical review. C.S. contributed to data collection, data analysis, interpretation of results and the writing of the manuscript. R.İ., N.K.G. and F.K. are responsible for clinical follow-up, data collection and data interpretation. C.S., K.E. and C.\\u0026Ouml;. contributed substantially to the in vitro study design, data analysis and interpretation, and the writing of the manuscript.\\u003c/p\\u003e\"},{\"header\":\"References\",\"content\":\"\\u003col\\u003e\\u003cli\\u003e\\u003cspan\\u003eAgyeman AA, Bergen PJ, Rao GG, Nation RL, Landersdorfer CB. A systematic review and meta-analysis of treatment outcomes following antibiotic therapy among patients with carbapenem-resistant Klebsiella-pneumoniae infections. Int J Antimicrob Agents 2020;55(1):105833.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003ePaniagua-Garcia M, Bravo-Ferrer JM, Perez-Galera S, Kostyanev T, de Kraker MEA, Feifel J, et al. Attributable mortality of infections caused by carbapenem-resistant Enterobacterales: results from a prospective, multinational case-control-control matched cohorts study(EURECA). Clin Microbiol Infect 2024;30:223\\u0026ndash;30.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eAslan AT, Kırbaş E, Sancak B, Tanrıverdi ES, Otlu B, G\\u0026uuml;rsoy NC, et al. A retrospective observational cohort study of the clinical epidemiology of bloodstream infections due to carbapenem-resistant Klebsiella pneumoniae in an OXA-48 endemic setting. Int J Antimicrob Agents 2022;59(4):106554.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eRojas LJ, Salim M, Cober E, Richter SS, Perez F, Salata RA, et al. Colistin Resistance in Carbapenem-Resistant Klebsiella pneumoniae: Laboratory Detection and Impact on Mortality. Clin Infect Dis 2017;64(6):711\\u0026ndash;8.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eBalkan II, Alkan M, Ayg\\u0026uuml;n G, Kuşkucu M, Ankaralı H, Karag\\u0026ouml;z A, et al. Colistin resistance increases 28-day mortality in bloodstream infections due to carbapenem-resistant Klebsiella pneumoniae. Eur J Clin Microbiol Infect Dis 2021;40(10):2161\\u0026ndash;70.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eMenekşe Ş, \\u0026Ccedil;ağ Y, Işık ME, Şahin S, Hacıseyitoğlu D, Can F, et al. The effect of colistin resistance and other predictors on fatality among patients with bloodstream infections due to Klebsiella pneumoniae in an OXA-48 dominant region. Int J Infect Dis 2019;86:208\\u0026ndash;11.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eAydın M, Erg\\u0026ouml;n\\u0026uuml;l \\u0026Ouml;, Azap A, Bilgin H, Aydın G, \\u0026Ccedil;avuş SA et al. Rapid emergence of colistin resistance and its impact on fatality among healthcare-associated infections. J Hosp Infect 2018;98:260\\u0026ndash;263.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eChen Y, Huang HB, Peng JM, Weng L, Du B. Efficacy and safety of ceftazidime-avibactam for the treatment of carbapenem-resistant Enterobacterales blood-stream infection: a systematic review and meta-analysis. Microbiol Spectr 2022;10(2)::e0260321.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003evan Duin D, Lok JJ, Early M, Cober E, Richter SS, Perez F, et al. Colistin versus ceftazidime-avibactam in the treatment of infections due to carbapenem-resistant Enterobacteriaceae. Clin Infect Dis 2018;66(2):163\\u0026ndash;71.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eTumbarello M, Trecarichi EM, Corona A, De Rosa FG, Bassetti M, Mussini C, et al. Efficacy of Ceftazidime-Avibactam Salvage Therapy in Patients With Infections Caused by Klebsiella pneumoniae Carbapenemase-producing K. pneumoniae. Clin Infect Dis 2019;68(3):355\\u0026ndash;64.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eKaraiskos I, Daikos GL, Gkoufa A, Adamis G, Stefos A, Symbardi S, et al. Ceftazidime-avibactam in the era of carbapenemase-producing Klebsiella pneumoniae: experience from a national registry study. J Antimicrob Chemother 2021;76(3):775\\u0026ndash;83.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eQureshi ZA, Paterson DL, Potoski BA, Kilayko MC, Sandovsky G, Sordillo E, et al. Treatment outcome of bacteremia due to KPC-producing Klebsiella pneumoniae: superiority of combination antimicrobial regimens. Antimicrob Agents Chemother 2012;56(4):2108\\u0026ndash;13.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eTumbarello M, Viale P, Viscoli C, Trecarichi EM, Tumietto F, Marchese A, et al. Predictors of mortality in bloodstream infections caused by Klebsiella pneumoniae carbapenemase-producing K. pneumoniae: importance of combination therapy. Clin Infect Dis 2012;55(7):943\\u0026ndash;50.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eTumbarello M, Trecarichi EM, De Rosa FG, Giannella M, Giacobbe DR, Bassetti M, et al. Infections caused by KPC-producing Klebsiella pneumoniae: differences in therapy and mortality in a multicentre study. J Antimicrob Chemother 2015;70(7):2133\\u0026ndash;43.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eDaikos GL, Tsaousi S, Tzouvelekis LS, Anyfantis I, Psichogiou M, Argyropoulou A, et al. Carbapenemase-producing Klebsiella pneumoniae bloodstream infections: lowering mortality by antibiotic combination schemes and the role of carbapenems. Antimicrob Agents Chemother 2014;58(4):2322\\u0026ndash;8.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eGomez-Simmonds A, Nelson B, Eiras DP, Loo A, Jenkins SG, Whittier S, et al. Combination Regimens for Treatment of Carbapenem-Resistant Klebsiella pneumoniae Bloodstream Infections. Antimicrob Agents Chemother 2016;60(6):3601\\u0026ndash;7.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eGiannella M, Trecarichi EM, Giacobbe DR, De Rosa FG, Bassetti M, Bartoloni A, et al. Effect of combination therapy containing a high-dose carbapenem on mortality in patients with carbapenem-resistant Klebsiella pneumoniae bloodstream infection. Int J Antimicrob Agents 2018;51(2):244\\u0026ndash;8.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eCDC, National Healthcare Safety Network (NHSN) Patient Safety Component Manual. (2023) Available at: \\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003ehttps://www.cdc.gov/nhsn/pdfs/pscmanual/pcsmanual_current.pdf\\u003c/span\\u003e\\u003cspan address=\\\"https://www.cdc.gov/nhsn/pdfs/pscmanual/pcsmanual_current.pdf\\\" targettype=\\\"URL\\\" class=\\\"RefTarget\\\"\\u003e\\u003c/span\\u003e\\u003c/span\\u003e (Accessed on 09.02.2023).\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eMatthaios Papadimitriou-Olivgeris, Markos Marangos, Myrto Christofidou, et al. Risk factors for infection and predictors of mortality among patients with KPC-producing Klebsiella pneumoniae bloodstream infections in the intensive care unit, Scand J Infect Dis 2014;46:642\\u0026ndash;648.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eWintenberger C, Epaulard O, Hincky-Vitrat V, et al. Outcome of central venous catheter-related bacteraemia according to compliance with guidelines: experience with 91 episodes. J Hosp Infect. 2012;80:245\\u0026ndash;51.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eMaki DG, Weise CE, Sarafin HW: A semiquantitative culture method for identifying intravenous-catheterrelated infection. N Engl J Med. 1977; 296:1305\\u0026ndash;1309.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eLai CH, Wong WW, Chin C, et al.: Central venous catheter-related Stenotrophomonas maltophilia bacteraemia and associated relapsing bacteraemia in haematology and oncology patients. Clin Microbiol Infect. 2006; 12:986\\u0026ndash;991.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eBone R, Balk RA, Cerra FB et al. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Chest 1992;101:1656\\u0026ndash;1662.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eKwa AL, Low JG, Lee E et al. The impact of multidrug resistance on the outcomes of critically ill patients with gram-negative bacterial pneumonia. Diagn Microbiol Infect Dis 2007;58:99\\u0026ndash;104.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eCalandra T, Cohen J, International Sepsis Forum Definition of Infection in the ICU Consensus Conference. International sepsis forum definition of infection in the intensive care unit. Crit Care Med. 2005;33:1538\\u0026ndash;48.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eVall\\u0026eacute;s J, Rello J, Ochagav\\u0026iacute;a A, Garnacho J, Alcal\\u0026aacute; MA. Community-acquired bloodstream infection in critically ill adult patients: impact of shock and inappropriate antibiotic therapy on survival. Chest 2003;123:1615\\u0026ndash;1624.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eKnaus WA, Draper EA, Wagner DP, Zimmerman JE. APACHE II: a severity of disease classification system. Crit Care Med. 1985;3:818\\u0026ndash;29.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003ePaterson DL, Ko WC, Von Gottberg A, et al.: International prospective study of Klebsiella pneumoniae bacteremia: implications of extended-spectrum beta-lactamase production in nosocomial Infections. Ann Intern Med. 2004, 140:26\\u0026ndash;32.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003e\\u0026Ouml;zvatan T, Akalın H, Sınırtaş M, et al.: Nosocomial Acinetobacter pneumonia: treatment and prognostic factors in 356 cases. Respirology. 2016; 21:363\\u0026ndash;369.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eKaraiskos I, Friberg L, Pontikis K, Ioannidis K, Tsagkari V, Galani L, Kostakou E, Baziaka F, Paskalis C, Koutsoukou A, et al. Colistin Population Pharmacokinetics after Application of a Loading Dose of 9 MU Colistin Methanesulfonate in Critically Ill Patients. Antimicrob. Agents Chemother. 2015; 59: 7240\\u0026ndash;7248.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eDel Bono V, Giacobbe DR, Marchese A, Parisini A, Fucile C, Coppo E et al. Meropenem for treating KPC-producing Klebsiella pneumoniae bloodstream infections: Should we get to the PK/PD root of the paradox? Virulence 2017;8:66\\u0026ndash;73.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eEuropean Committee on Antimicrobial Susceptibility Testing. Breakpoint tables for interpretation of MICs and zone diameters. Version 8.0. EUCAST, 2018.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eMotos A, Avery LM, DeRonde KJ, Mullane EM, Kuti JL, Nicolau DP. Where should antibiotic gradient diffusion strips be crossed to assess synergy? A comparison of the standard method with a novel method using steady-state antimicrobial concentrations. Int J Antimicrob Agents 2019; 53:698\\u0026ndash;702.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eKorenian M. E test practical guide: Synergy testing \\u0026amp; antibiotic combinations. AB Biodisk, Solna-Sweden, 1999.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eİşler B, \\u0026Ouml;zer B, \\u0026Ccedil;ınar G, Aslan AT, Vatansever C, Falconer C et al. Characteristics and outcomes of carbapenemases harbouring carbapenem-resistant Klebsiella spp. bloodstream infections: a multicentre prospective cohort study in an OXA-48 endemic setting. Eur J Clin Microbiol Infect Dis 2022;41:841\\u0026ndash;7.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eXu L, Sun X, Ma X. Systematic review and meta-analysis of mortality of patients infected with carbapenem-resistant Klebsiella pneumoniae. Ann Clin Microbiol Antimicrob 2017;16(1):18.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eCarrara E, Bragantini D, Tacconelli E. Combination versus monotherapy for the treatment of infections due to carbapenem-resistant Enterobacteriaceae. Curr Opin Infect Dis 2018;31(6):594\\u0026ndash;99.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eSharma R, Patel S, Abboud C, Diep J, Ly NS, Pogue JM et al. Polymyxin B in combination with meropenem against carbapenemase-producing Klebsiella pneumoniae: pharmacodynamics and morphological changes. Int J Antimicrob Agents 2017;49:224\\u0026ndash;32.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eKulengowski B, Campion JJ, Feola DJ, Burgess DS. Effect of the meropenem MIC on the killing activity of meropenem and polymyxin B in combination against KPC-producing Klebsiella pneumoniae. J Antibiotics 2017;70:974\\u0026ndash;8.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003ePea F, Siega PD, Cojutti P, Sartor A, Crapis M, Scarparo C et al. Might real-time pharmacokinetic/pharmacodynamic optimisation of high-dose continuous-infusion meropenem improve clinical cure in infections caused by KPC-producing \\u003cem\\u003eKlebsiella pneumoniae\\u003c/em\\u003e? Int J Antimicrob Agents 2017;49:255\\u0026ndash;8.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eCojutti P, Sartor A, Righi E, Scarparo C, Bassetti M, Pea F. Population Pharmacokinetics of High-Dose Continuous-Infusion Meropenem and Considerations for Use in the Treatment of Infections Due to KPC Producing \\u003cem\\u003eKlebsiella pneumoniae.\\u003c/em\\u003e Antimicrob Agents Chemother 2017;61: e00794-17.\\u003c/span\\u003e\\u003c/li\\u003e\\u003c/ol\\u003e\"}],\"fulltextSource\":\"\",\"fullText\":\"\",\"funders\":[],\"hasAdminPriorityOnWorkflow\":false,\"hasManuscriptDocX\":true,\"hasOptedInToPreprint\":true,\"hasPassedJournalQc\":\"\",\"hasAnyPriority\":false,\"hideJournal\":false,\"highlight\":\"\",\"institution\":\"\",\"isAcceptedByJournal\":true,\"isAuthorSuppliedPdf\":false,\"isDeskRejected\":\"\",\"isHiddenFromSearch\":false,\"isInQc\":false,\"isInWorkflow\":false,\"isPdf\":false,\"isPdfUpToDate\":true,\"isWithdrawnOrRetracted\":false,\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"scientific-reports\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":false,\"externalIdentity\":\"scirep\",\"sideBox\":\"Learn more about [Scientific Reports](http://www.nature.com/srep/)\",\"snPcode\":\"\",\"submissionUrl\":\"\",\"title\":\"Scientific Reports\",\"twitterHandle\":\"\",\"acdcEnabled\":true,\"dfaEnabled\":true,\"editorialSystem\":\"stoa\",\"reportingPortfolio\":\"Scientific Reports\",\"inReviewEnabled\":true,\"inReviewRevisionsEnabled\":true},\"keywords\":\"Klebsiella, bacteremia, carbapenem resistance, colistin, meropenem\",\"lastPublishedDoi\":\"10.21203/rs.3.rs-3956365/v1\",\"lastPublishedDoiUrl\":\"https://doi.org/10.21203/rs.3.rs-3956365/v1\",\"license\":{\"name\":\"CC BY 4.0\",\"url\":\"https://creativecommons.org/licenses/by/4.0/\"},\"manuscriptAbstract\":\"Carbapenem-resistant Klebsiella pneumoniae (CRKp) infections continue to be an important cause of morbidity and mortality.\\nIn this study, the effect of carbapenem or colistin resistance on mortality in Klebsiella pneumoniae bacteremia and combined meropenem + colistin administration in CRKp bacteremia was retrospectively evaluated.\\nA total of 139 adult patients diagnosed with K. pneumoniae bacteremia(73 carbapenem sensitive and 66 carbapenem resistant) were included in the study. The 30-day mortality in entire cohort were 19.4%.\\n30-day mortality was significantly higher in the carbapenem resistant-colistin sensitive group and in the carbapenem resistant-colistin resistant group compared to the carbapenem susceptible (ESBL positive) group.\\nMeropenem + colistin combination was administered to 37 (95%) of carbapenem resistant–colistin sensitive (n=39) and 25 (93%) of carbapenem resistant–colistin resistant patients(n=27). Notably, mortality was not significantly affected regardless of whether CRKp was colistin sensitive and whether a high dose and prolonged infusion of meropenem was administered.\\nMortality is higher in carbapenem resistant Klebsiella pneumoniae bacteremia compared to carbapenem susceptible group. In cases of combined meropenem and colistin administration, high dose and prolonged infusion of meropenem is not superior to standard dose and infusion in both carbapenem resistant–colistin sensitive and carbapenem resistant–colistin resistant K. pneumoniae bacteremia.\",\"manuscriptTitle\":\"Carbapenem or colistin resistant Klebsiella pneumoniae bacteremia in the intensive care unit: real life data \",\"msid\":\"\",\"msnumber\":\"\",\"nonDraftVersions\":[{\"code\":1,\"date\":\"2024-03-13 11:51:25\",\"doi\":\"10.21203/rs.3.rs-3956365/v1\",\"editorialEvents\":[{\"type\":\"communityComments\",\"content\":0},{\"type\":\"decision\",\"content\":\"Revision requested\",\"date\":\"2024-05-16T16:39:41+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"editorInvitedReview\",\"content\":\"\",\"date\":\"2024-05-14T16:56:50+00:00\",\"index\":\"hide\",\"fulltext\":\"\"},{\"type\":\"editorInvitedReview\",\"content\":\"\",\"date\":\"2024-05-07T07:12:19+00:00\",\"index\":\"hide\",\"fulltext\":\"\"},{\"type\":\"reviewerAgreed\",\"content\":\"3962c74e-3943-436b-9e56-db351834c5a2\",\"date\":\"2024-05-01T07:06:54+00:00\",\"index\":\"hide\",\"fulltext\":\"\"},{\"type\":\"reviewerAgreed\",\"content\":\"2956265c-9487-4e78-9ae4-4f550173374a\",\"date\":\"2024-04-19T07:21:34+00:00\",\"index\":\"hide\",\"fulltext\":\"\"},{\"type\":\"reviewersInvited\",\"content\":\"\",\"date\":\"2024-04-17T12:24:33+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"editorAssigned\",\"content\":\"\",\"date\":\"2024-03-15T12:14:30+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"editorInvited\",\"content\":\"\",\"date\":\"2024-03-11T13:59:10+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"checksComplete\",\"content\":\"\",\"date\":\"2024-03-11T13:45:45+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"submitted\",\"content\":\"Scientific Reports\",\"date\":\"2024-02-14T14:46:34+00:00\",\"index\":\"\",\"fulltext\":\"\"}],\"status\":\"published\",\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"scientific-reports\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":false,\"externalIdentity\":\"scirep\",\"sideBox\":\"Learn more about [Scientific Reports](http://www.nature.com/srep/)\",\"snPcode\":\"\",\"submissionUrl\":\"\",\"title\":\"Scientific Reports\",\"twitterHandle\":\"\",\"acdcEnabled\":true,\"dfaEnabled\":true,\"editorialSystem\":\"stoa\",\"reportingPortfolio\":\"Scientific Reports\",\"inReviewEnabled\":true,\"inReviewRevisionsEnabled\":true}}],\"origin\":\"\",\"ownerIdentity\":\"4d0b2659-0337-4816-ae62-205f7cfd10d6\",\"owner\":[],\"postedDate\":\"March 13th, 2024\",\"published\":true,\"recentEditorialEvents\":[],\"rejectedJournal\":[],\"revision\":\"\",\"amendment\":\"\",\"status\":\"published-in-journal\",\"subjectAreas\":[{\"id\":29337581,\"name\":\"Biological sciences/Microbiology\"},{\"id\":29337582,\"name\":\"Health sciences/Medical research\"}],\"tags\":[],\"updatedAt\":\"2024-11-04T16:27:47+00:00\",\"versionOfRecord\":{\"articleIdentity\":\"rs-3956365\",\"link\":\"https://doi.org/10.1038/s41598-024-73786-x\",\"journal\":{\"identity\":\"scientific-reports\",\"isVorOnly\":false,\"title\":\"Scientific Reports\"},\"publishedOn\":\"2024-10-28 16:20:23\",\"publishedOnDateReadable\":\"October 28th, 2024\"},\"versionCreatedAt\":\"2024-03-13 11:51:25\",\"video\":\"\",\"vorDoi\":\"10.1038/s41598-024-73786-x\",\"vorDoiUrl\":\"https://doi.org/10.1038/s41598-024-73786-x\",\"workflowStages\":[]},\"version\":\"v1\",\"identity\":\"rs-3956365\",\"journalConfig\":\"researchsquare\"},\"__N_SSP\":true},\"page\":\"/article/[identity]/[[...version]]\",\"query\":{\"redirect\":\"/article/rs-3956365\",\"identity\":\"rs-3956365\",\"version\":[\"v1\"]},\"buildId\":\"8U1c8b4HqxoKbykW_rLl7\",\"isFallback\":false,\"isExperimentalCompile\":false,\"dynamicIds\":[84888],\"gssp\":true,\"scriptLoader\":[]}","source_license":"CC-BY-4.0","license_restricted":false}