Ceftazidime-Avibactam Use in Carbapenem-resistant Klebsiella pneumoniae Bloodstream Infections: A Retrospective Observational Multicenter Study in OXA-48 Endemic settings

Ceftazidime-Avibactam Use in Carbapenem-resistant Klebsiella pneumoniae Bloodstream Infections: A Retrospective Observational Multicenter Study in OXA-48 Endemic settings | 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 Ceftazidime-Avibactam Use in Carbapenem-resistant Klebsiella pneumoniae Bloodstream Infections: A Retrospective Observational Multicenter Study in OXA-48 Endemic settings Ali Mert, Okan Derin, Halis Akalın, Rıdvan Dumlu, Sibel Gündeş, and 12 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4259788/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 01 Nov, 2024 Read the published version in Scientific Reports → Version 1 posted 11 You are reading this latest preprint version Abstract Background. Experience of ceftazidime-avibactam (CAZ-AVI) use in OXA-48 producing K. pneumoniae bloodstream infections (OXA-48-Kp BSIs) is limited. We aimed to describe the clinical outcomes of OXA-48-Kp BSIs treated with CAZ-AVI in hospital settings, where OXA-48-producing K. pneumoniae is endemic. Methods. A multicenter retrospective observational study was conducted between January 2017 and September 2021. The aim of the study is to describe the clinical data that affects outcome, the 30-day mortality and relapse. The predictors of 30-day mortality are detected by using cox regression model. Results. We included 106 adults with CAZ-AVI-susceptible, carbapenem-resistant K. pneumoniae (CR-Kp) BSIs who received at least 72 hours of CAZ-AVI therapy. Mortality was found to be lower in those who started CAZ-AVI from the initial treatment compared to those who switched from colistin-based-regimen to CAZ-AVI[14.3% (n = 3/21) vs 37.7%(n = 32/85), p = 0.04].In multivariate analysis older age, having severe neutropenia were found to be significantly associated with the higher rate of mortality. Same-day CAZ-AVI start lowers mortality risk significantly.(HR:0.25, CI: 0.07–0.84, p = 0.025). Conclusions. Data of our cohort showed that CAZ-AVI monotherapy is an important treatment option in OXA-48-Kp BSIs. In addition, the study confirmed that early initiation of CAZ-AVI is more appropriate than switch to CAZ-AVI from a colistin-based-regimen. Health sciences/Diseases/Infectious diseases/Bacterial infection Biological sciences/Microbiology/Antimicrobials/Antimicrobial resistance Ceftazidime-avibactam carbapenemases OXA-48 producing Klebsiella pneumoniae Bloodstream infections Figures Figure 1 Introduction Emergence of carbapenem resistance Klebsiella pneumoniae (CR-Kp) is a significant global public health problem, but even more important in some areas including Turkey( 1 ). In K. pneumoniae infections, the most commonly reported carbapenemase type is OXA-48 in Turkey. The first isolate of K. pneumoniae with OXA-48 was identified in Turkey in 2004( 2 ). Since then, hospital outbreaks from Turkey and all over the world (especially Europe, the Middle East, and Northern Africa) have been extensively reported( 1 – 3 ). Avibactam which is a novel non-beta-lactam beta-lactamase inhibitor inhibits OXA-48 carbapenemases. Ceftazidime-avibactam (CAZ-AVI) is used in the treatment of OXA-48 producing K. pneumoniae bloodstream infections (OXA-48-Kp BSIs) of adult patients with limited treatment options( 4 ). Experience of use in this indication is limited. Therefore, we aimed to present the clinical outcomes of CR-Kp BSIs treated with CAZ-AVI in our country where OXA-48-producing K. pneumoniae is endemic, and responsible from the vast majority of CRE. Materials and Methods Study population We conducted a multicenter, retrospective, observational study including patients with CR-Kp bacteremia who were treated with CAZ-AVI in 23 hospitals (academic and nonacademic) in Turkey, between 1 January 2017 and 31 September 2021. The study was approved by the Ethics Committees of Medipol University Ethics Committee (E-10840098-772.02-2738). This retrospective observational study is in accordance with The World Medical Association, Decleration of Helsinki, Ethical Principles for Medical Research Involving Human Subjects.We included adult patients (≥ 18 years older) who had blood culture-documented monomicrobial CAZ-AVI susceptible CR-Kp infections and received the CAZ-AVI within the first 7 days of blood culture positivity. Charlson comorbidity index was determined at admission. Bacterial identification was performed with automated systems and MALDI-TOF. The routine antibiotic susceptibility testing was done by automated systems or broth microdilution method according to its own protocols in the microbiology laboratory of each center. All isolates were tested for susceptibility to CAZ-AVI with disc diffusion method, and susceptibility findings were interpreted in accordance with current EUCAST clinical breakpoints (EUCAST)( 5 ). CAZ-AVI was administered intravenously at the standard dose of 2/0.5 g every 8 hours as 2-hour-infusion. The dose was adjusted in cases of renal failure according to the manufacturer's instructions. CAZ-AVI was used as the initial treatment or as salvage therapy during the course of infection. Clinical cure was defined as resolution of all signs and symptoms of infection (assessed according to vital signs, and laboratory data) within 7 days of treatment initiation. Clinical success was defined as survival and absence of recurrence at 30 days following the onset of infection, resolution. Statistical analysis Categorical and continuous variables are compared by using chi-square and Mann–Whitney U tests, respectively. A “p” value of < 0.05 (2-sided test) was considered to indicate significance. To evaluate the prognostic value of significant variables, hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated by using logistic regression model. The Kaplan-Meier method was used for survival analysis. Results We included 106 adults with CAZ-AVI susceptible, CR-Kp BSIs who received at least 72 hours of CAZ-AVI therapy. Demographic characteristics and univariate analysis of 106 patients with CR-Kp bacteremia who received the CAZ-AVI within 7 days of positive blood culture were presented in Table 1. Mean age was higher in fatal cases than the survived ones (59 vs 51, p=0.033). Mean Pittsburg bacteremia score was significantly higher among the fatal cases than the survived ones (7 vs 4.1, p<0.001), however no significant difference between fatal and survived cases was detected in Charlson comorbidity index, having malignancy, and having neutropenia (Table 1). Mean days of starting CAZ-AVI after taking the blood culture was 2.1 days among the survived cases, whereas it was 2.9 days among the fatal cases (p=0.035). Starting CAZ-AVI on the same day of obtaining culture was significantly more common among the survived cases than the fatal cases (32.3% vs 8.5%, p=0.007) (Table 1). Mortality was found to be lower in those who started CAZ-AVI as first line treatment compared to those who switched treatment to CAZ-AVI [14.3% (n=3/21) vs 37.7% (n=32/85) (chi-square test p=0.04, and fisher exact test p=0.06)]. No development of resistance or relapse was detected in any of the cases. In multivariate analysis for the prediction of the fatality, gender, age, Charlson comorbidity index, severe neutropenia (neutrophil count<500), starting CAZ-AVI on the same day of obtaining culture were included in the model (Table 2). Older age, and having severe neutropenia were found to be significantly associated with higher rate of fatality. Starting CAZ-AVI on the same day of obtaining culture compared to switching treatment from colistin-based-regimen to CAZ-AVI significantly reduced fatality (HR:0.25, CI: 0.07-0.84, p=0.025) (Table 2 and Figure 1). Discussion The OXA-48-producing Klebsiella pneumoniae is an endemic in Turkey. CR-Kp BSIs are associated with high mortality, and treatment options are limited. Clinical trial data on the management of CR-Kp BSIs is scarce. There are only 4 studies analyzing the clinical outcomes of CR-Kp BSIs treated with CAZ-AVI( 6 – 9 ). The data from observational studies recommend the use of ‘last-resort’ agents (eg,colistin, polymyxin-B, aminoglycosides, fosfomycin, tigecycline and/or carbapenems) only as a combined therapy when there is no access to CAZ-AVI and the bacteria is susceptible to the aforementioned agents ( 10 – 12 ). The studies show 30-day mortality rate in polymyxin-based regimens for KPC or OXA-48-Kp BSIs is around 50%( 10 – 12 ). CAZ-AVI treatment in CR-Kp BSIs has been associated with lower mortality rates than the ‘last-resort’ antibiotic regimens (~ 25% vs ~ 50%)( 6 – 12 ). In our study, 30-day mortality rate of the patients was calculated at around 35%. In a recent multicentered study from Turkey, OXA-48-like carbapenemases comprised the largest carbapenemase group with 75% of CR-Kp bloodstream isolates and 16% of them were accompanied with NDM type beta lactamases ( 13 ). Likewise, the OXA-48 and NDM-1 positivity rates were found to be as 81% and 19% among carbapenem and colistin resistant Kp in Turkey, respectively( 14 ). Falcone et al. showed that shorter median time to appropriate antibiotic treatment improved survival in Cr-Kp-BSIs ( 15 ). Our finding were consistent with Falcone et al. Resistance may develop during treatment with CAZ-AVI. It is reported that 1.4–3.6% resistance has developed in studies of CR-Kp BSIs since the introduction of CAZ-AVI ( 7 – 9 ). In our cohort, no resistance was observed during CAZ-AVI treatment. It is also reported that the prevalence of resistance to the ‘last-resort’ antibiotics in CRE has been increasing. As a result of the increasing prevalence of resistance, CAZ-AVI emerges as a first line therapy for CRE infections. Main risk factors predicting the mortality in patients of CR-Kp BSIs treated with CAZ-AVI are Charlson comorbidity index ≥ 2, presence at infection onset of septic shock, neutropenia, an INCREMENT score ≥ 8, lower respiratory tract infection (LRTI), CAZ-AVI dose adjustment for renal function( 7 – 9 ). Prolonging CAZ-AVI infusions to ≥ 3 hours have been shown to reduce mortality in one study ( 9 ). In our chort, according to Cox Regression analyses, age, severe neutropenia and CAZ-AVI started on the same day of obtaining culture were independent clinical determinants of mortality. There were several limitations of our study. The observational retrospective character of the study and non-determination of carbapenemase types were intrinsic study limitations. Whether BSIs are primary or secondary or as catheter related has not been identified. In conclusion, this multicenter retrospective cohort showed that the mortality was ~ 30% and CAZ-AVI monotherapy is an important treatment option in OXA-48- Kp BSIs. In addition, our study confirmed that early initiation of CAZ-AVI is more appropriate than conversion to CAZ-AVI from a colistin-based regimen. Declarations Funding: The study was not funded. Conflicts of interest/Competing interests: All the authors declare no conflict of interest. Data availability statement: The datasets used and analysed during the current study available from the corresponding author on reasonable request. Code availability: Yes, the analysis was performed by STATA. Informed Consent Statement: The study was approved by the Non-invasive Clinical Research Ethics Committee of Medipol University(E-10840098-772.02-2738). This retrospective observational study is in accordance with The World Medical Association, Decleration of Helsinki, Ethical Principles for Medical Research Involving Human Subjects. the Non-invasive Clinical Research Ethics Committee of Medipol University waived the need of informed consent as this is a retrospective study. Ethics approval (include appropriate approvals or waivers): The study was approved by the Non-invasive Clinical Research Ethics Committee of Medipol University (E-10840098-772.02-2738). Authors' contributions: Conceptualization: AM, OD, ÖE. Study Design: AM, OD, ÖE, İK, HA, SK, FC. Data collection: OD, SG, RD, RZ, SK, YG, İK, DY, CÜ, MK, LG, HK, KK, and Concortia. Data analysis: OD, ÖE. Manuscript writing: AM, OD, RD, HA, ÖE. Consent to participate: obtained. Consent for publication: obtained. References Bonomo RA, Burd EM, Conly J, et al. Carbapenemase-Producing Organisms: A Global Scourge. Clin Infect Dis [Internet]. 2018 Apr 3 [cited 2023 Oct 6];66(8):1290–7. Available from: https://pubmed.ncbi.nlm.nih.gov/29165604/ Poirel L, Héritier C, Tolün V, Nordmann P. Emergence of oxacillinase-mediated resistance to imipenem in Klebsiella pneumoniae. Antimicrob Agents Chemother [Internet]. 2004 Jan [cited 2023 Oct 6];48(1):15–22. Available from: https://pubmed.ncbi.nlm.nih.gov/14693513/ Genç S, Kolaylı F, Özçelik EY. Molecular characterization of carbapenemase producing Klebsiella pneumoniae strains by multiplex PCR and PFGE methods: The first K.pneumoniae isolates co-producing OXA-48/KPC and KPC/NDM in Turkey. J Infect Chemother [Internet]. 2022 Feb 1 [cited 2023 Oct 6];28(2):192–8. Available from: https://pubmed.ncbi.nlm.nih.gov/34711509/ Noval M, Banoub M, Claeys KC, Heil E. The Battle Is on: New Beta-Lactams for the Treatment of Multidrug-Resistant Gram-Negative Organisms. Curr Infect Dis Rep [Internet]. 2020 Jan 1 [cited 2023 Oct 6];22(1). Available from: https://pubmed.ncbi.nlm.nih.gov/31933158/ eucast: Clinical breakpoints and dosing of antibiotics [Internet]. [cited 2023 Oct 6]. Available from: https://www.eucast.org/clinical_breakpoints Shields RK, Nguyen MH, Chen L, et al. Ceftazidime-Avibactam Is Superior to Other Treatment Regimens against Carbapenem-Resistant Klebsiella pneumoniae Bacteremia. Antimicrob Agents Chemother [Internet]. 2017 Aug 1 [cited 2023 Oct 6];61(8). Available from: https://pubmed.ncbi.nlm.nih.gov/28559250/ Karaiskos I, Daikos GL, Gkoufa A, et al. Ceftazidime/avibactam in the era of carbapenemase-producing Klebsiella pneumoniae: experience from a national registry study. J Antimicrob Chemother [Internet]. 2021 Mar 1 [cited 2023 Oct 6];76(3):775–83. Available from: https://pubmed.ncbi.nlm.nih.gov/33249436/ Falcone M, Bassetti M, Tiseo G, et al. Time to appropriate antibiotic therapy is a predictor of outcome in patients with bloodstream infection caused by KPC-producing Klebsiella pneumoniae. Crit Care [Internet]. 2020 Jan 30 [cited 2023 Oct 6];24(1). Available from: /pmc/articles/PMC6993311/ Tumbarello M, Raffaelli F, Giannella M, et al. Ceftazidime-avibactam use for klebsiella pneumoniae carbapenemase-producing k. pneumoniae infections: A retrospective observational multicenter study. CLINICAL INFECTIOUS DISEASES [Internet]. 2022 Feb 22 [cited 2023 Oct 6];73(9):1664–76. Available from: https://iris.unipa.it/handle/10447/534238 Medeiros GS, Rigatto MH, Falci DR, Zavascki AP. Combination therapy with polymyxin B for carbapenemase-producing Klebsiella pneumoniae bloodstream infection. Int J Antimicrob Agents [Internet]. 2019 Feb 1 [cited 2023 Oct 6];53(2):152–7. Available from: https://pubmed.ncbi.nlm.nih.gov/30722960/ Balkan II, Aygün G, Aydin S, et al. Blood stream infections due to OXA-48-like carbapenemase-producing Enterobacteriaceae: treatment and survival. Int J Infect Dis [Internet]. 2014 [cited 2023 Oct 6];26. Available from: https://pubmed.ncbi.nlm.nih.gov/24998423/ Tzouvelekis LS, Markogiannakis A, Piperaki E, Souli M, Daikos GL. Treating infections caused by carbapenemase-producing Enterobacteriaceae. Clin Microbiol Infect [Internet]. 2014 Sep 1 [cited 2023 Oct 6];20(9):862–72. Available from: https://pubmed.ncbi.nlm.nih.gov/24890393/ Isler B, Özer B, Çınar G, et al. Characteristics and outcomes of carbapenemase harbouring carbapenem-resistant Klebsiella spp. bloodstream infections: a multicentre prospective cohort study in an OXA-48 endemic setting. Eur J Clin Microbiol Infect Dis . [Internet]. 2022[cited 2023 Dec 10];41(5):841-847. Available from: https://pubmed.ncbi.nlm.nih.gov/35301623/ Menekşe Ş, Çağ Y, Işık ME, 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. International Journal of Infectious Diseases. 2019 Sep 1;86:208–11. Falcone M, Bassetti M, Tiseo G, et al. Time to appropriate antibiotic therapy is a predictor of outcome in patients with bloodstream infection caused by KPC-producing Klebsiella pneumoniae. Crit Care . 2020;24(1):29. Published 2020 Jan 30. doi:10.1186/s13054-020-2742-9 Tables Table 1. Univariate analysis of 106 patients with CR-Klebsiella pneumonia bacteremia who received the CZA within 7 days of positive blood culture. Survived n=71 (67%) Fatal n=35 (33%) p Male gender 44 (62) 21 (60) 0.845 Mean Age 51 (sd: 17) 59 (sd: 18) 0.033 Mean Pitt bacteremia score 4.1 (sd: 3.2) 7 (sd: 2.6) <0.001 Charlson Comorbidity index 5.2 (sd: 11.6) 4.3 (sd: 2.7) 0.648 Severe neutropenia 12 (17) 9 (26) 0.284 Malignancy 27 (38) 14 (40) 0.845 Mean days of starting CAZ-AVI after culture 2.1 (sd: 1.9) 2.9 (sd: 1.85) 0.035 CAZ-AVI started on the same day of obtaining culture vs later days. 23 (32.3) 3 (8.5) 0.007 Table 2. Univariate and multivariate analysis (cox regression) for the predictors of fatality among the patients with Carbapenem-resistant Klebsiella pneumonia bacteremia (n=106 patients with BSI with CR-Kp, who received CAZ-AVI within 7 days after bacterial identification) Univariate Multivariate HR CI P HR CI p Male gender 0.89 0.45-1.75 0.743 0.91 0.45-1.81 0.796 Age 1.02 1.01-1.04 0.033 1.04 1.01-1.07 0.004 Charlson comorbidity index 0.99 0.94-1.03 0.771 0.96 0.83-1.11 0.599 Severe Neutropenia (neutrophil count<500) 1.54 0.72-3.29 0.264 4.4 1.60-12.56 0.004 CZA started on the same day of obtaining culture vs CZA started later days. 0.22 0.07-0.74 0.015 0.24 0.07-0.79 0.019 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 01 Nov, 2024 Read the published version in Scientific Reports → Version 1 posted Editorial decision: Revision requested 28 Jul, 2024 Reviews received at journal 13 Jul, 2024 Reviewers agreed at journal 11 Jul, 2024 Reviewers agreed at journal 11 Jul, 2024 Reviews received at journal 26 Jun, 2024 Reviewers agreed at journal 16 Jun, 2024 Reviewers invited by journal 13 Jun, 2024 Editor assigned by journal 13 Jun, 2024 Editor invited by journal 30 May, 2024 Submission checks completed at journal 27 May, 2024 First submitted to journal 12 Apr, 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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1","display":"","copyAsset":false,"role":"figure","size":30782,"visible":true,"origin":"","legend":"\u003cp\u003eThe role of Ceftazidim-avibactam (CZA) start on the same day of obtaining culture compared to CZA started later days in predicting 30-day fatality.\u003c/p\u003e","description":"","filename":"Fig1.png","url":"https://assets-eu.researchsquare.com/files/rs-4259788/v1/fbb0f398761bf610d756149c.png"},{"id":68206967,"identity":"eb3d1c6e-d5c6-4461-a442-1a110f8ddf03","added_by":"auto","created_at":"2024-11-04 16:34:10","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":390228,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4259788/v1/5dc17cdd-ce6c-4a9a-9285-a2683d478442.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Ceftazidime-Avibactam Use in Carbapenem-resistant Klebsiella pneumoniae Bloodstream Infections: A Retrospective Observational Multicenter Study in OXA-48 Endemic settings","fulltext":[{"header":"Introduction","content":"\u003cp\u003eEmergence of carbapenem resistance \u003cem\u003eKlebsiella pneumoniae\u003c/em\u003e (CR-Kp) is a significant global public health problem, but even more important in some areas including Turkey(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). In \u003cem\u003eK. pneumoniae\u003c/em\u003e infections, the most commonly reported carbapenemase type is OXA-48 in Turkey. The first isolate of \u003cem\u003eK. pneumoniae\u003c/em\u003e with OXA-48 was identified in Turkey in 2004(\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). Since then, hospital outbreaks from Turkey and all over the world (especially Europe, the Middle East, and Northern Africa) have been extensively reported(\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eAvibactam which is a novel non-beta-lactam beta-lactamase inhibitor inhibits OXA-48 carbapenemases. Ceftazidime-avibactam (CAZ-AVI) is used in the treatment of OXA-48 producing \u003cem\u003eK. pneumoniae\u003c/em\u003e bloodstream infections (OXA-48-Kp BSIs) of adult patients with limited treatment options(\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). Experience of use in this indication is limited. Therefore, we aimed to present the clinical outcomes of CR-Kp BSIs treated with CAZ-AVI in our country where OXA-48-producing \u003cem\u003eK. pneumoniae\u003c/em\u003e is endemic, and responsible from the vast majority of CRE.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy population\u003c/h2\u003e \u003cp\u003eWe conducted a multicenter, retrospective, observational study including patients with CR-Kp bacteremia who were treated with CAZ-AVI in 23 hospitals (academic and nonacademic) in Turkey, between 1 January 2017 and 31 September 2021. The study was approved by the Ethics Committees of Medipol University Ethics Committee (E-10840098-772.02-2738). This retrospective observational study is in accordance with The World Medical Association, Decleration of Helsinki, Ethical Principles for Medical Research Involving Human Subjects.We included adult patients (\u0026ge;\u0026thinsp;18 years older) who had blood culture-documented monomicrobial CAZ-AVI susceptible CR-Kp infections and received the CAZ-AVI within the first 7 days of blood culture positivity. Charlson comorbidity index was determined at admission.\u003c/p\u003e \u003cp\u003eBacterial identification was performed with automated systems and MALDI-TOF. The routine antibiotic susceptibility testing was done by automated systems or broth microdilution method according to its own protocols in the microbiology laboratory of each center. All isolates were tested for susceptibility to CAZ-AVI with disc diffusion method, and susceptibility findings were interpreted in accordance with current EUCAST clinical breakpoints (EUCAST)(\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eCAZ-AVI was administered intravenously at the standard dose of 2/0.5 g every 8 hours as 2-hour-infusion. The dose was adjusted in cases of renal failure according to the manufacturer's instructions. CAZ-AVI was used as the initial treatment or as salvage therapy during the course of infection. Clinical cure was defined as resolution of all signs and symptoms of infection (assessed according to vital signs, and laboratory data) within 7 days of treatment initiation. Clinical success was defined as survival and absence of recurrence at 30 days following the onset of infection, resolution.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eCategorical and continuous variables are compared by using chi-square and Mann\u0026ndash;Whitney U tests, respectively. A \u0026ldquo;p\u0026rdquo; value of \u0026lt;\u0026thinsp;0.05 (2-sided test) was considered to indicate significance. To evaluate the prognostic value of significant variables, hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated by using logistic regression model. The Kaplan-Meier method was used for survival analysis.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eWe included 106 adults with CAZ-AVI susceptible, CR-Kp BSIs who received at least 72 hours of CAZ-AVI therapy. Demographic characteristics and univariate analysis of 106 patients with CR-Kp bacteremia who received the CAZ-AVI within 7 days of positive blood culture were presented in Table 1. Mean age was higher in fatal cases than the survived ones (59 vs 51, p=0.033). Mean Pittsburg bacteremia score was significantly higher among the fatal cases than the survived ones (7 vs 4.1, p\u0026lt;0.001), however no significant difference between fatal and survived cases was detected in Charlson comorbidity index, having malignancy, and having neutropenia (Table 1). \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMean days of starting CAZ-AVI after taking the blood culture was 2.1 days among the survived cases, whereas it was 2.9 days among the fatal cases (p=0.035). Starting CAZ-AVI on the same day of obtaining culture was significantly more common among the survived cases than the fatal cases (32.3% vs 8.5%, p=0.007) (Table 1). Mortality was found to be lower in those who started CAZ-AVI as first line treatment compared to those who switched treatment to CAZ-AVI [14.3% (n=3/21) vs 37.7% (n=32/85) (chi-square test p=0.04, and fisher exact test p=0.06)]. No development of resistance or relapse was detected in any of the cases.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn multivariate analysis for the prediction of the fatality, gender, age, Charlson comorbidity index, severe neutropenia (neutrophil count\u0026lt;500), starting CAZ-AVI on the same day of obtaining culture were included in the model (Table 2). Older age, and having severe neutropenia were found to be significantly associated with higher rate of fatality. Starting CAZ-AVI on the same day of obtaining culture compared to switching treatment from colistin-based-regimen to CAZ-AVI significantly reduced fatality (HR:0.25, CI: 0.07-0.84, p=0.025) (Table 2 and Figure 1).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe OXA-48-producing \u003cem\u003eKlebsiella pneumoniae\u003c/em\u003e is an endemic in Turkey. CR-Kp BSIs are associated with high mortality, and treatment options are limited. Clinical trial data on the management of CR-Kp BSIs is scarce. There are only 4 studies analyzing the clinical outcomes of CR-Kp BSIs treated with CAZ-AVI(\u003cspan additionalcitationids=\"CR7 CR8\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). The data from observational studies recommend the use of \u0026lsquo;last-resort\u0026rsquo; agents (eg,colistin, polymyxin-B, aminoglycosides, fosfomycin, tigecycline and/or carbapenems) only as a combined therapy when there is no access to CAZ-AVI and the bacteria is susceptible to the aforementioned agents (\u003cspan additionalcitationids=\"CR11\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). The studies show 30-day mortality rate in polymyxin-based regimens for KPC or OXA-48-Kp BSIs is around 50%(\u003cspan additionalcitationids=\"CR11\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). CAZ-AVI treatment in CR-Kp BSIs has been associated with lower mortality rates than the \u0026lsquo;last-resort\u0026rsquo; antibiotic regimens (~\u0026thinsp;25% vs\u0026thinsp;~\u0026thinsp;50%)(\u003cspan additionalcitationids=\"CR7 CR8 CR9 CR10 CR11\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). In our study, 30-day mortality rate of the patients was calculated at around 35%.\u003c/p\u003e \u003cp\u003eIn a recent multicentered study from Turkey, OXA-48-like carbapenemases comprised the largest carbapenemase group with 75% of CR-Kp bloodstream isolates and 16% of them were accompanied with NDM type beta lactamases (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). Likewise, the OXA-48 and NDM-1 positivity rates were found to be as 81% and 19% among carbapenem and colistin resistant Kp in Turkey, respectively(\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eFalcone et al. showed that shorter median time to appropriate antibiotic treatment improved survival in Cr-Kp-BSIs (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). Our finding were consistent with Falcone et al.\u003c/p\u003e \u003cp\u003eResistance may develop during treatment with CAZ-AVI. It is reported that 1.4\u0026ndash;3.6% resistance has developed in studies of CR-Kp BSIs since the introduction of CAZ-AVI (\u003cspan additionalcitationids=\"CR8\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). In our cohort, no resistance was observed during CAZ-AVI treatment. It is also reported that the prevalence of resistance to the \u0026lsquo;last-resort\u0026rsquo; antibiotics in CRE has been increasing. As a result of the increasing prevalence of resistance, CAZ-AVI emerges as a first line therapy for CRE infections.\u003c/p\u003e \u003cp\u003eMain risk factors predicting the mortality in patients of CR-Kp BSIs treated with CAZ-AVI are Charlson comorbidity index\u0026thinsp;\u0026ge;\u0026thinsp;2, presence at infection onset of septic shock, neutropenia, an INCREMENT score\u0026thinsp;\u0026ge;\u0026thinsp;8, lower respiratory tract infection (LRTI), CAZ-AVI dose adjustment for renal function(\u003cspan additionalcitationids=\"CR8\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). Prolonging CAZ-AVI infusions to \u0026ge;\u0026thinsp;3 hours have been shown to reduce mortality in one study (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). In our chort, according to Cox Regression analyses, age, severe neutropenia and CAZ-AVI started on the same day of obtaining culture were independent clinical determinants of mortality.\u003c/p\u003e \u003cp\u003eThere were several limitations of our study. The observational retrospective character of the study and non-determination of carbapenemase types were intrinsic study limitations. Whether BSIs are primary or secondary or as catheter related has not been identified.\u003c/p\u003e \u003cp\u003eIn conclusion, this multicenter retrospective cohort showed that the mortality was ~\u0026thinsp;30% and CAZ-AVI monotherapy is an important treatment option in OXA-48- Kp BSIs. In addition, our study confirmed that early initiation of CAZ-AVI is more appropriate than conversion to CAZ-AVI from a colistin-based regimen.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eFunding: The study was not funded.\u003c/p\u003e\n\u003cp\u003eConflicts of interest/Competing interests: All the authors declare no conflict of interest.\u003cbr\u003e \u003c/p\u003e\n\u003cp\u003eData availability statement: The datasets used and analysed during the current study available from the corresponding author on reasonable request.\u003cbr\u003e \u003c/p\u003e\n\u003cp\u003eCode availability: Yes, the analysis was performed by STATA.\u003c/p\u003e\n\n\u003cp\u003eInformed Consent Statement: The study was approved by the Non-invasive Clinical Research Ethics Committee of Medipol University(E-10840098-772.02-2738). This retrospective observational study is in accordance with The World Medical Association, Decleration of Helsinki, Ethical Principles for Medical Research Involving Human Subjects. the Non-invasive Clinical Research Ethics Committee of Medipol University waived the need of informed consent as this is a retrospective study.\u003c/p\u003e\n\n\u003cp\u003eEthics approval (include appropriate approvals or waivers): The study was approved by the Non-invasive Clinical Research Ethics Committee of Medipol University\u003c/p\u003e\n\u003cp\u003e(E-10840098-772.02-2738).\u003cbr\u003e \u003c/p\u003e\n\u003cp\u003eAuthors\u0026apos; contributions:\u003c/p\u003e\n\n\u003cp\u003eConceptualization: AM, OD, \u0026Ouml;E.\u003c/p\u003e\n\n\u003cp\u003eStudy Design: AM, OD, \u0026Ouml;E, İK, HA, SK, FC.\u003c/p\u003e\n\n\u003cp\u003eData collection: OD, SG, RD, RZ, SK, YG, İK, DY, C\u0026Uuml;, MK, LG, HK, KK, and Concortia.\u003c/p\u003e\n\n\u003cp\u003eData analysis: OD, \u0026Ouml;E.\u003c/p\u003e\n\n\u003cp\u003eManuscript writing: AM, OD, RD, HA, \u0026Ouml;E.\u003c/p\u003e\n\n\u003cp\u003eConsent to participate: obtained.\u003c/p\u003e\n\n\u003cp\u003eConsent for publication: obtained.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eBonomo RA, Burd EM, Conly J, et al. Carbapenemase-Producing Organisms: A Global Scourge. Clin Infect Dis [Internet]. 2018 Apr 3 [cited 2023 Oct 6];66(8):1290\u0026ndash;7. Available from: https://pubmed.ncbi.nlm.nih.gov/29165604/\u003c/li\u003e\n\u003cli\u003ePoirel L, H\u0026eacute;ritier C, Tol\u0026uuml;n V, Nordmann P. Emergence of oxacillinase-mediated resistance to imipenem in Klebsiella pneumoniae. Antimicrob Agents Chemother [Internet]. 2004 Jan [cited 2023 Oct 6];48(1):15\u0026ndash;22. Available from: https://pubmed.ncbi.nlm.nih.gov/14693513/\u003c/li\u003e\n\u003cli\u003eGen\u0026ccedil; S, Kolaylı F, \u0026Ouml;z\u0026ccedil;elik EY. Molecular characterization of carbapenemase producing Klebsiella pneumoniae strains by multiplex PCR and PFGE methods: The first K.pneumoniae isolates co-producing OXA-48/KPC and KPC/NDM in Turkey. J Infect Chemother [Internet]. 2022 Feb 1 [cited 2023 Oct 6];28(2):192\u0026ndash;8. Available from: https://pubmed.ncbi.nlm.nih.gov/34711509/\u003c/li\u003e\n\u003cli\u003eNoval M, Banoub M, Claeys KC, Heil E. The Battle Is on: New Beta-Lactams for the Treatment of Multidrug-Resistant Gram-Negative Organisms. Curr Infect Dis Rep [Internet]. 2020 Jan 1 [cited 2023 Oct 6];22(1). Available from: https://pubmed.ncbi.nlm.nih.gov/31933158/\u003c/li\u003e\n\u003cli\u003eeucast: Clinical breakpoints and dosing of antibiotics [Internet]. [cited 2023 Oct 6]. Available from: https://www.eucast.org/clinical_breakpoints\u003c/li\u003e\n\u003cli\u003eShields RK, Nguyen MH, Chen L, et al. Ceftazidime-Avibactam Is Superior to Other Treatment Regimens against Carbapenem-Resistant Klebsiella pneumoniae Bacteremia. Antimicrob Agents Chemother [Internet]. 2017 Aug 1 [cited 2023 Oct 6];61(8). Available from: https://pubmed.ncbi.nlm.nih.gov/28559250/\u003c/li\u003e\n\u003cli\u003eKaraiskos I, Daikos GL, Gkoufa A, et al. Ceftazidime/avibactam in the era of carbapenemase-producing Klebsiella pneumoniae: experience from a national registry study. J Antimicrob Chemother [Internet]. 2021 Mar 1 [cited 2023 Oct 6];76(3):775\u0026ndash;83. Available from: https://pubmed.ncbi.nlm.nih.gov/33249436/\u003c/li\u003e\n\u003cli\u003eFalcone M, Bassetti M, Tiseo G, et al. Time to appropriate antibiotic therapy is a predictor of outcome in patients with bloodstream infection caused by KPC-producing Klebsiella pneumoniae. Crit Care [Internet]. 2020 Jan 30 [cited 2023 Oct 6];24(1). Available from: /pmc/articles/PMC6993311/\u003c/li\u003e\n\u003cli\u003eTumbarello M, Raffaelli F, Giannella M, et al. Ceftazidime-avibactam use for klebsiella pneumoniae carbapenemase-producing k. pneumoniae infections: A retrospective observational multicenter study. CLINICAL INFECTIOUS DISEASES [Internet]. 2022 Feb 22 [cited 2023 Oct 6];73(9):1664\u0026ndash;76. Available from: https://iris.unipa.it/handle/10447/534238\u003c/li\u003e\n\u003cli\u003eMedeiros GS, Rigatto MH, Falci DR, Zavascki AP. Combination therapy with polymyxin B for carbapenemase-producing Klebsiella pneumoniae bloodstream infection. Int J Antimicrob Agents [Internet]. 2019 Feb 1 [cited 2023 Oct 6];53(2):152\u0026ndash;7. Available from: https://pubmed.ncbi.nlm.nih.gov/30722960/\u003c/li\u003e\n\u003cli\u003eBalkan II, Ayg\u0026uuml;n G, Aydin S, et al. Blood stream infections due to OXA-48-like carbapenemase-producing Enterobacteriaceae: treatment and survival. Int J Infect Dis [Internet]. 2014 [cited 2023 Oct 6];26. Available from: https://pubmed.ncbi.nlm.nih.gov/24998423/\u003c/li\u003e\n\u003cli\u003eTzouvelekis LS, Markogiannakis A, Piperaki E, Souli M, Daikos GL. Treating infections caused by carbapenemase-producing Enterobacteriaceae. Clin Microbiol Infect [Internet]. 2014 Sep 1 [cited 2023 Oct 6];20(9):862\u0026ndash;72. Available from: https://pubmed.ncbi.nlm.nih.gov/24890393/\u003c/li\u003e\n\u003cli\u003eIsler B, \u0026Ouml;zer B, \u0026Ccedil;ınar G, et al. Characteristics and outcomes of carbapenemase harbouring carbapenem-resistant Klebsiella spp. bloodstream infections: a multicentre prospective cohort study in an OXA-48 endemic setting. \u003cem\u003eEur J Clin Microbiol Infect Dis\u003c/em\u003e. [Internet]. 2022[cited 2023 Dec 10];41(5):841-847. Available from: https://pubmed.ncbi.nlm.nih.gov/35301623/\u003c/li\u003e\n\u003cli\u003eMenekşe Ş, \u0026Ccedil;ağ Y, Işık ME, 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. International Journal of Infectious Diseases. 2019 Sep 1;86:208\u0026ndash;11. \u003c/li\u003e\n\u003cli\u003eFalcone M, Bassetti M, Tiseo G, et al. Time to appropriate antibiotic therapy is a predictor of outcome in patients with bloodstream infection caused by KPC-producing Klebsiella pneumoniae. \u003cem\u003eCrit Care\u003c/em\u003e. 2020;24(1):29. Published 2020 Jan 30. doi:10.1186/s13054-020-2742-9\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1. Univariate analysis of 106 patients with CR-Klebsiella pneumonia bacteremia who received the CZA within 7 days of positive blood culture.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"586\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"31.11111111111111%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.811965811965813%\" valign=\"top\"\u003e\n \u003cp\u003eSurvived\u003c/p\u003e\n \u003cp\u003en=71 (67%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.811965811965813%\" valign=\"top\"\u003e\n \u003cp\u003eFatal\u003c/p\u003e\n \u003cp\u003en=35 (33%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.264957264957264%\" valign=\"top\"\u003e\n \u003cp\u003ep\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"31.11111111111111%\" valign=\"top\"\u003e\n \u003cp\u003eMale gender\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.811965811965813%\" valign=\"top\"\u003e\n \u003cp\u003e44 (62)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.811965811965813%\" valign=\"top\"\u003e\n \u003cp\u003e21 (60)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.264957264957264%\" valign=\"top\"\u003e\n \u003cp\u003e0.845\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"31.11111111111111%\" valign=\"top\"\u003e\n \u003cp\u003eMean Age\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.811965811965813%\" valign=\"top\"\u003e\n \u003cp\u003e51 (sd: 17)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.811965811965813%\" valign=\"top\"\u003e\n \u003cp\u003e59 (sd: 18)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.264957264957264%\" valign=\"top\"\u003e\n \u003cp\u003e0.033\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"31.11111111111111%\" valign=\"top\"\u003e\n \u003cp\u003eMean Pitt bacteremia score\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.811965811965813%\" valign=\"top\"\u003e\n \u003cp\u003e4.1 (sd: 3.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.811965811965813%\" valign=\"top\"\u003e\n \u003cp\u003e7 (sd: 2.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.264957264957264%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"31.11111111111111%\" valign=\"top\"\u003e\n \u003cp\u003eCharlson Comorbidity index\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.811965811965813%\" valign=\"top\"\u003e\n \u003cp\u003e5.2 (sd: 11.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.811965811965813%\" valign=\"top\"\u003e\n \u003cp\u003e4.3 (sd: 2.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.264957264957264%\" valign=\"top\"\u003e\n \u003cp\u003e0.648\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"31.11111111111111%\" valign=\"top\"\u003e\n \u003cp\u003eSevere neutropenia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.811965811965813%\" valign=\"top\"\u003e\n \u003cp\u003e12 (17)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.811965811965813%\" valign=\"top\"\u003e\n \u003cp\u003e9 (26)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.264957264957264%\" valign=\"top\"\u003e\n \u003cp\u003e0.284\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"31.11111111111111%\" valign=\"top\"\u003e\n \u003cp\u003eMalignancy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.811965811965813%\" valign=\"top\"\u003e\n \u003cp\u003e27 (38)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.811965811965813%\" valign=\"top\"\u003e\n \u003cp\u003e14 (40)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.264957264957264%\" valign=\"top\"\u003e\n \u003cp\u003e0.845\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"31.11111111111111%\" valign=\"top\"\u003e\n \u003cp\u003eMean days of starting CAZ-AVI after culture\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.811965811965813%\" valign=\"top\"\u003e\n \u003cp\u003e2.1 (sd: 1.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.811965811965813%\" valign=\"top\"\u003e\n \u003cp\u003e2.9 (sd: 1.85)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.264957264957264%\" valign=\"top\"\u003e\n \u003cp\u003e0.035\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"31.11111111111111%\" valign=\"top\"\u003e\n \u003cp\u003eCAZ-AVI started on the same day of obtaining culture vs later days.\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.811965811965813%\" valign=\"top\"\u003e\n \u003cp\u003e23 (32.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.811965811965813%\" valign=\"top\"\u003e\n \u003cp\u003e3 (8.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.264957264957264%\" valign=\"top\"\u003e\n \u003cp\u003e0.007\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTable 2. Univariate and multivariate analysis (cox regression) for the predictors of fatality among the patients with Carbapenem-resistant Klebsiella pneumonia bacteremia (n=106 patients with BSI with CR-Kp, who \u0026nbsp; received CAZ-AVI within 7 days after bacterial identification)\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"604\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"34.3801652892562%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"31.239669421487605%\" colspan=\"3\" valign=\"top\"\u003e\n \u003cp\u003eUnivariate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"34.3801652892562%\" colspan=\"3\" valign=\"top\"\u003e\n \u003cp\u003eMultivariate\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"34.3801652892562%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.768595041322314%\" valign=\"top\"\u003e\n \u003cp\u003eHR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.049586776859504%\" valign=\"top\"\u003e\n \u003cp\u003eCI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.421487603305785%\" valign=\"top\"\u003e\n \u003cp\u003eP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.421487603305785%\" valign=\"top\"\u003e\n \u003cp\u003eHR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.702479338842975%\" valign=\"top\"\u003e\n \u003cp\u003eCI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.256198347107437%\" valign=\"top\"\u003e\n \u003cp\u003ep\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"34.3801652892562%\" valign=\"top\"\u003e\n \u003cp\u003eMale gender\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.768595041322314%\" valign=\"top\"\u003e\n \u003cp\u003e0.89\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.049586776859504%\" valign=\"top\"\u003e\n \u003cp\u003e0.45-1.75\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.421487603305785%\" valign=\"top\"\u003e\n \u003cp\u003e0.743\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.421487603305785%\" valign=\"top\"\u003e\n \u003cp\u003e0.91\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.702479338842975%\" valign=\"top\"\u003e\n \u003cp\u003e0.45-1.81\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.256198347107437%\" valign=\"top\"\u003e\n \u003cp\u003e0.796\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"34.3801652892562%\" valign=\"top\"\u003e\n \u003cp\u003eAge\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.768595041322314%\" valign=\"top\"\u003e\n \u003cp\u003e1.02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.049586776859504%\" valign=\"top\"\u003e\n \u003cp\u003e1.01-1.04\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.421487603305785%\" valign=\"top\"\u003e\n \u003cp\u003e0.033\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.421487603305785%\" valign=\"top\"\u003e\n \u003cp\u003e1.04\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.702479338842975%\" valign=\"top\"\u003e\n \u003cp\u003e1.01-1.07\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.256198347107437%\" valign=\"top\"\u003e\n \u003cp\u003e0.004\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"34.3801652892562%\" valign=\"top\"\u003e\n \u003cp\u003eCharlson comorbidity index\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.768595041322314%\" valign=\"top\"\u003e\n \u003cp\u003e0.99\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.049586776859504%\" valign=\"top\"\u003e\n \u003cp\u003e0.94-1.03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.421487603305785%\" valign=\"top\"\u003e\n \u003cp\u003e0.771\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.421487603305785%\" valign=\"top\"\u003e\n \u003cp\u003e0.96\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.702479338842975%\" valign=\"top\"\u003e\n \u003cp\u003e0.83-1.11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.256198347107437%\" valign=\"top\"\u003e\n \u003cp\u003e0.599\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"34.3801652892562%\" valign=\"top\"\u003e\n \u003cp\u003eSevere Neutropenia (neutrophil count\u0026lt;500)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.768595041322314%\" valign=\"top\"\u003e\n \u003cp\u003e1.54\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.049586776859504%\" valign=\"top\"\u003e\n \u003cp\u003e0.72-3.29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.421487603305785%\" valign=\"top\"\u003e\n \u003cp\u003e0.264\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.421487603305785%\" valign=\"top\"\u003e\n \u003cp\u003e4.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.702479338842975%\" valign=\"top\"\u003e\n \u003cp\u003e1.60-12.56\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.256198347107437%\" valign=\"top\"\u003e\n \u003cp\u003e0.004\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"34.3801652892562%\" valign=\"top\"\u003e\n \u003cp\u003eCZA started on the same day of obtaining culture vs CZA started later days.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.768595041322314%\" valign=\"top\"\u003e\n \u003cp\u003e0.22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.049586776859504%\" valign=\"top\"\u003e\n \u003cp\u003e0.07-0.74\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.421487603305785%\" valign=\"top\"\u003e\n \u003cp\u003e0.015\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.421487603305785%\" valign=\"top\"\u003e\n \u003cp\u003e0.24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.702479338842975%\" valign=\"top\"\u003e\n \u003cp\u003e0.07-0.79\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.256198347107437%\" valign=\"top\"\u003e\n \u003cp\u003e0.019\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\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":"[email protected]","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":"Ceftazidime-avibactam, carbapenemases, OXA-48 producing Klebsiella pneumoniae, Bloodstream infections","lastPublishedDoi":"10.21203/rs.3.rs-4259788/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4259788/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground.\u003c/h2\u003e \u003cp\u003eExperience of ceftazidime-avibactam (CAZ-AVI) use in OXA-48 producing \u003cem\u003eK. pneumoniae\u003c/em\u003e bloodstream infections (OXA-48-Kp BSIs) is limited. We aimed to describe the clinical outcomes of OXA-48-Kp BSIs treated with CAZ-AVI in hospital settings, where OXA-48-producing \u003cem\u003eK. pneumoniae\u003c/em\u003e is endemic.\u003c/p\u003e\u003ch2\u003eMethods.\u003c/h2\u003e \u003cp\u003eA multicenter retrospective observational study was conducted between January 2017 and September 2021. The aim of the study is to describe the clinical data that affects outcome, the 30-day mortality and relapse. The predictors of 30-day mortality are detected by using cox regression model.\u003c/p\u003e\u003ch2\u003eResults.\u003c/h2\u003e \u003cp\u003eWe included 106 adults with CAZ-AVI-susceptible, carbapenem-resistant \u003cem\u003eK. pneumoniae\u003c/em\u003e (CR-Kp) BSIs who received at least 72 hours of CAZ-AVI therapy. Mortality was found to be lower in those who started CAZ-AVI from the initial treatment compared to those who switched from colistin-based-regimen to CAZ-AVI[14.3% (n\u0026thinsp;=\u0026thinsp;3/21) vs 37.7%(n\u0026thinsp;=\u0026thinsp;32/85), p\u0026thinsp;=\u0026thinsp;0.04].In multivariate analysis older age, having severe neutropenia were found to be significantly associated with the higher rate of mortality. Same-day CAZ-AVI start lowers mortality risk significantly.(HR:0.25, CI: 0.07\u0026ndash;0.84, p\u0026thinsp;=\u0026thinsp;0.025).\u003c/p\u003e\u003ch2\u003eConclusions.\u003c/h2\u003e \u003cp\u003eData of our cohort showed that CAZ-AVI monotherapy is an important treatment option in OXA-48-Kp BSIs. In addition, the study confirmed that early initiation of CAZ-AVI is more appropriate than switch to CAZ-AVI from a colistin-based-regimen.\u003c/p\u003e","manuscriptTitle":"Ceftazidime-Avibactam Use in Carbapenem-resistant Klebsiella pneumoniae Bloodstream Infections: A Retrospective Observational Multicenter Study in OXA-48 Endemic settings","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-06-12 09:08:38","doi":"10.21203/rs.3.rs-4259788/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-07-29T03:36:28+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-07-13T14:54:28+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"287127365702963942633656478608645523072","date":"2024-07-12T01:04:12+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"19297059090624385487442639088004083179","date":"2024-07-11T07:50:47+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-06-27T00:11:17+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"128120587908524578202533566816745637875","date":"2024-06-16T07:23:22+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-06-13T23:47:31+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-06-13T23:42:16+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2024-05-30T15:52:33+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-05-27T15:12:27+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2024-04-12T22:01:34+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","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":"2f680941-41a3-4c20-82f0-3a6b4e079543","owner":[],"postedDate":"June 12th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":33100672,"name":"Health sciences/Diseases/Infectious diseases/Bacterial infection"},{"id":33100673,"name":"Biological sciences/Microbiology/Antimicrobials/Antimicrobial resistance"}],"tags":[],"updatedAt":"2024-11-04T16:23:43+00:00","versionOfRecord":{"articleIdentity":"rs-4259788","link":"https://doi.org/10.1038/s41598-024-77259-z","journal":{"identity":"scientific-reports","isVorOnly":false,"title":"Scientific Reports"},"publishedOn":"2024-11-01 16:05:11","publishedOnDateReadable":"November 1st, 2024"},"versionCreatedAt":"2024-06-12 09:08:38","video":"","vorDoi":"10.1038/s41598-024-77259-z","vorDoiUrl":"https://doi.org/10.1038/s41598-024-77259-z","workflowStages":[]},"version":"v1","identity":"rs-4259788","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4259788","identity":"rs-4259788","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}