Persistent bacteremia predicts poor outcomes among neutropenic patients with carbapenem-resistant gram-negative bloodstream infections receiving appropriate therapy

Persistent bacteremia predicts poor outcomes among neutropenic patients with carbapenem-resistant gram-negative bloodstream infections receiving appropriate therapy | 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 Short Report Persistent bacteremia predicts poor outcomes among neutropenic patients with carbapenem-resistant gram-negative bloodstream infections receiving appropriate therapy Abi Manesh S, Mithun Mohan George, Kundakarla Bhanuprasad, Grace Mary John, and 11 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-2064044/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 15 Feb, 2023 Read the published version in Annals of Clinical Microbiology and Antimicrobials → Version 1 posted 9 You are reading this latest preprint version Abstract Purpose Identifying persistent bacteremia early in patients with neutropenia may improve outcome. This study evaluated the role of follow-up blood cultures (FUBC) positivity in predicting outcomes among patients with neutropenia and carbapenem-resistant gram-negative bloodstream infections (CRGNBSI). Methods This retrospective cohort study conducted between December 2017 and April 2022 included patients more than 15 years old with neutropenia and CRGNBSI, who survived for ≥ 48 hours, receiving appropriate antibiotic therapy and had FUBCs. Patients with polymicrobial bacteremia within 30 days were excluded. The primary outcome was 30-day mortality. Persistent bacteremia, septic shock, recovery from neutropenia, prolonged or profound neutropenia, requirement of intensive care and dialysis, and initiation of appropriate empirical therapy were also studied. Results The 30-day mortality rate was 47.7%. Persistent bacteremia was common in our patient cohort (43.8%). The median time for sending a FUBC was 2 days (IQR, 1–3 days). Patients with persistent bacteremia had higher mortality than those without (56.76% versus 32.1%; p < 0.001). Appropriate initial empirical therapy was given to 70.9%. Recovery from neutropenia occurred in 57.4% while 25.8% had prolonged or profound neutropenia. Sixty-nine percent had septic shock and needed intensive care; 12.2% of patients required dialysis. Non-recovery from neutropenia (aHR, 4.28; 95% CI, 2.53–7.23), presence of septic shock (aHR, 4.42; 95%CI, 1.47–13.28), requirement of intensive care (aHR,3.12;95%CI, 1.23–7.93), and persistent bacteremia (aHR,1.74; 95%CI, 1.05–2.89) significantly predicted poor outcomes in multivariable analysis. Conclusion FUBC showing persistent bacteremia predicted poor outcomes among neutropenic patients with carbapenem-resistant gram-negative bloodstream infections (CRGNBSI) and should be routinely reported. Bloodstream infections Carbapenem resistance Neutropenia Persistent bacteremia Figures Figure 1 Introduction Carbapenem-resistant gram-negative bloodstream infections (CRGNBSI) have mortality rates of up to 50% and limited therapeutic options [ 1 ]. Neutropenic and other immunosuppressed patients have the poorest outcomes. Early identification of patients at risk for poor outcomes is important for optimal management and improving prognosis. However, available predictors,such as leucocyte counts, C-reactive protein (CRP), and procalcitonin, are often imprecise[ 2 ]. Persistent blood culture positivity at 48 to 72 hours despite optimal therapy is an established predictor of poor outcome, death, and metastatic infection among patients with methicillin-resistant Staphylococcus aureus (MRSA) bacteremia and candidemia [ 3 ]. However, their role in gram-negative bacteremia is uncertain [ 4 ]. Currently, the utilization of follow-up blood cultures (FUBC) is variable across hospitals and physicians. Further, the FUBC positivity varies according to the source of bacteremia and pathogen resistance phenotype. For example, bacteremia from a urinary source is usually transient. The role of FUBC in high-risk populations,such as patients with neutropenia and carbapenem-resistant infections, is not studied so far. As clear data is unavailable, recent guidelines from the Infectious Diseases Society of America and other international bodies do not have directives on the use of FUBC among patients with CRGNBSI [ 5 ]. This observational study was conducted to determine the role of FUBC in patients with neutropenia and CRGNBSI. Methods We performed a retrospective cohort study between December 2017 and April 2022 at the Christian Medical College, Vellore, a 3000-bedded academic center, among patients with neutropenia admitted to the hematology department with CRGNBSI. Patients over 15 years of age, who survived 48 hours or more after the bacteremia, were included in the study. Patients with polymicrobial bacteremia and who received inappropriate therapy were excluded. Only the first qualifying episode of bacteremia during the duration of hospital stay of an individual patient was included. The study was approved by the Institutional Review Board and Ethics committee. Patient data, including their comorbidities, treatment details, and outcomes, were documented from electronic medical records. All data was collected in a predesigned proforma developed for the study on an electronic data capture system.The date of positive blood culture growing carbapenem-resistant gram-negative bacteria was taken as the date of bacteremia (index date or day zero).The patient was followed up for 30 days from that date. Carbapenem resistance was defined as resistance to meropenem or imipenem according to Clinical Laboratory and Standards Institute guidelines. Persistent bacteremia was defined as a minimum of two positive blood cultures growing the same organisms with similar antibiograms at least 48 hours apart during the same infectious episode. Repeat blood cultures growing different organisms were not counted as persistent bacteremia. Neutropenia in our study was defined as an absolute neutrophil count (ANC) of less than 500 cells/µL before 48 hours to the date of bacteremia. Previous bacterial infections noted in the study which were identified 30 days prior to the index date were defined as serious bacterial infections. Concomitant bacterial infections were defined as any serious bacterial infections other than the current bacteremia which was isolated within 30 days after the index date. Cytomegalovirus reactivation among transplant patients was reported when CMV viremia with > 1000 copies/µl was present before or after seven days of bacterial isolation. Prolonged and profound neutropenia was documented if the neutropenic condition persisted for more than 7 days and ANC levels were ≤ 100 cells/µL. Achieving ANC levels > 500 cells/Μl during the follow-up period was marked as a recovery from neutropenia. Polymyxin-based therapy referred to treatment with polymyxin, either alone or with adjunct drugs, such as trimethoprim-sulfamethoxazole or tigecycline. Ceftazidime-avibactam-based therapy included ceftazidime-avibactam along with other adjunct drugs. When both polymyxin and ceftazidime-avibactam were given with or without adjunct drugs, it was recorded as polymyxin with ceftazidime-avibactam combination therapy. If the patient received treatment with drugs thatthe organism was not resistant to in the antibiogram done on the index date, they were considered to have received appropriate empiric therapy. The primary outcome of the study was 30-day mortality. Other outcomes of interest were persistent bacteremia, septic shock, recovery from neutropenia, prolonged and profound neutropenia, requirement of intensive care and dialysis after the index date, and initiation of appropriate empirical therapy.A telephonic follow-up to assess the primary outcome was done for participants who were discharged within the 30-day follow-up period. Baseline characteristics for all patients enrolled are presented as means with standard deviation (SD) or medians with interquartile range (IQR) for continuous variables and as frequencies with proportions for categorical variables. Statistical comparisons between groups for categorical variables were made using Pearson’s chi-square test or Fisher's exact test as applicable while Student’s t-test was used for comparing continuous variables between survivors and non-survivors. Univariate analysis was performed for all risk factors predicting 30-day mortality, and hazard ratio (HR) with 95% confidence interval (CI) was determined. Multicollinearity was checked between all variables by determining variance inflation factor (VIF). We performed multivariable Cox proportional hazards regression analysis using risk factors that were significant in the univariate analysis and determined the adjusted hazards ratio (aHR) with 95% CI. Age and sex were added to the multivariable model as natural confounders. Statistical significance was considered at a p-value of < 0.05. Survival curves were plotted to visualize the 30-day all-cause mortality among patients with persistent bacteremia and without. Censoring was not done as all study participants, unless dead, were followed-up for 30 days. Log-rank test was performed to evaluate statistical differences in survival estimates between groups. We used STATA 16 (StataCorp. 2019. Stata Statistical Software: Release 16 . College Station, TX: StataCorp LLC) for statistical analysis. Results We identified 208 patients with neutropenia above 15 years of age and had CRGNBSI. Twenty-nine patients died before 48 hours of bacteremia, twenty patients did not have FUBC, and four patients did not receive appropriate therapy for the bacteremia. The 155 patients who fulfilled the eligibility criteria were included in the final analysis, of whom 93(60%) were male. The mean age of patients was 36.65 years (SD, 13 years). Klebsiella species were the most commonly isolated organism (80%). All recruited patients had an underlying active hematological condition, of which, 120 (77.42%) were malignant in nature.The most common malignant conditions were acute myeloid leukemia (42.5%) and acute lymphoblastic leukemia (27.5%). Among benign conditions, aplastic anemia (71.43%) followed by myelodysplastic syndrome (17.14) were the most common. A sizable proportion of patients developed CRGNBSI after bone marrow transplant (35.4%). Among transplant patients, CMV reactivation along with CRGNBSIs was minimal (10.9%). Polymyxin resistance complicated more than a fifth of our patients (21.2%) (Table 1 ). Table 1 Baseline demographic and clinical characteristics Characteristics Total n = 155 Survivors n = 81 (%) Non-survivors n = 74 (%) p-value Age(Mean ± SD) 36.65 ± 12.93 35.96 ± 13.17 37.42 ± 12.71 0.485 Gender: Male 93 46(56.79) 47(63.51) 0.393 Polymyxin resistance(n = 146) 31 14(21.21) 17(21.25) 0.996 Risk factors Hematologic condition: Benign Acute myeloid leukemia Acute lymphoblastic leukemia Other malignant conditions 35 51 33 36 14(17.28) 31(38.27) 17(20.99) 19(23.46) 21(28.38) 20(27.03) 16(21.62) 17(22.97) 0.307 No recovery from neutropenia 66 15(18.52) 51(68.92) < 0.001 Prolonged and profound neutropenia a 40 24(29.63) 16(21.62) 0.255 Transplant 55 33(40.74) 22(29.73) 0.152 Intensive care requirement 106 38(46.91) 68(91.89) < 0.001 Presence of septic shock 107 37(45.68) 70(94.59) < 0.001 Dialysis requirement 19 3(3.7) 16(21.62) 0.001 Infection details Primary organism: Klebsiella 124 66(81.48) 58(78.38) 0.063 Previous bacterial infections 44 22(27.16) 22(29.73) 0.723 Concomitant bacterial infections 34 13(16.05) 21(28.38) 0.064 Cytomegalovirus reactivation b (n = 55) 6 2(6.06) 4(18.18) 0.158 Source of bacteremia: Gut translocation 109 58(71.6) 51(68.92) 0.715 Previous exposure to polymyxin 94 46(56.79) 48(64.86) 0.304 Previous exposure to carbapenem 142 74(91.36) 68(91.89) 0.905 Persistent bacteremia 68 26(32.1) 42(56.76) 0.002 Treatment details Polymyxin-based therapy Ceftazidime-avibactam-based therapy Polymyxin with ceftazidime-avibactam combination Alternate agents 75 20 53 7 34(41.98) 10(12.35) 33(40.74) 4(4.94) 41(55.41) 10(13.51) 20(27.03) 3(4.05) 0.299 No appropriate empirical therapy received 45 31(38.27) 14(18.92) 0.008 a Prolonged and profound Neutropenia is defined as absolute neutrophil count < 100 cells/mm3 and a duration of 7 days. b Cytomegalovirus reactivation- More than 1000 copies of cytomegalovirus present 7 days before or after bacterial isolation. Our cohort of patients was very ill with septic shock (69%) and required intensive care. Nineteen (12.2%) patients required dialysis, of whom sixteen died within the follow-up period. More than half of our patients (60.6%) received polymyxins in the 30 days preceding the CRGNBSI. Almost all patients (91.6%) were exposed to carbapenems over the same time period. Over a quarter of our patients (28.3%) had laboratory confirmed bacterial infection in the last 30 days prior to index date, and 21.9% developed a concomitant bacterial infection,other than the infectious episode on index date, within their follow-up period. Gut translocation was identified as the major source of bacteremia in our patients (70.3%). Other sources included catheter, lung, skin, and soft tissue infections. Source control was achieved in our patients whenever clinically applicable. Persistent bacteremia was common in our patient cohort (43.8%). The median time for sending a FUBC was 2 days (IQR, 1–3 days). The median duration of persistent bacteremia was 4 days (IQR, 3–7.5 days). The overall mortality rate was 47.7%, and mortality was significantly higher among individuals with persistent bacteremia (56.76%, p < 0.001) than among those without (32.10%). Among our cohort of patients, 40 (25.8%) had prolonged or profound neutropenia while 89 (57.4%) recovered from neutropenia. Among patients who survived during the follow-up period, 81.48% recovered from neutropenia. About half of the patients received a polymyxin-based therapy (48.4%), and 34.2% received polymyxin and ceftazidime-avibactam combination therapy. Other types of therapy included ceftazidime-avibactam-based treatment or alternate drugs, such as tigecycline. The majority of our patients received an appropriate empirical therapy (70.9%),of whom over half (54.5%) had poor outcomes at the 30-day follow-up. We performed univariate analysis on all patients to determine risk factors associated with 30-day mortality. Non-recovery from neutropenia (HR,5.42;95%CI, 3.28–8.93), requirement of intensive care (HR,7.84;95%CI, 3.39–18.12), septic shock (HR,12.34; 95%CI, 4.5–33.88), requirement of dialysis (HR,2.75; 95%CI, 1.57–4.81) and persistent bacteremia (HR,2.15; 95%CI, 1.35–3.41) were significantly associated with 30-day mortality in univariate analysis. Not receiving appropriate empirical therapy did not predict mortality in our group of patients (HR,0.5; 95%CI, 0.28–0.89). The mean VIF among the factors significant on univariable analysis was 1.26 with no critical correlation among the factors. When adjusted to all the significant risk factors along with age and sex as natural confounders, non-recovery from neutropenia (aHR,4.28; 95%CI, 2.53–7.23), requirement of intensive care (aHR,3.12;95%CI, 1.23–7.93),presence of septic shock (aHR,4.42; 95%CI, 1.47–13.28), and persistent bacteremia (aHR,1.74; 95%CI, 1.05–2.89) emerged as significant associations that predicted poor outcomes in multivariable analysis (Table 2 ). Table 2 Risk factors predicting 30-day mortality Characteristics Univariate analysis Multivariable analysis Hazards ratio(95% CI) P value Adjusted Hazards ratio(95% CI) P value Age 1.01 (0.99,1.02) 0.573 1(0.98,1.02) 0.772 Male gender 1.19(0.74,1.92) 0.463 1.4(0.83,2.34) 0.207 Polymyxin resistance 0.96 (0.53,1.74) 0.904 Hematologic condition: Acute myeloid leukemia Acute lymphoblastic leukemia Other malignant conditions Benign 0.56(0.30,1.04) 0.73(0.38,1.40) 0.74(0.39,1.40) Reference 0.065 0.34 0.353 - No recovery from neutropenia 5.42(3.28,8.93) < 0.001 4.28(2.53,7.23) < 0.001 Prolonged and profound neutropenia a 0.65(0.37,1.13) 0.13 Transplant 0.67(0.41,1.11) 0.121 Intensive care requirement 7.84(3.39,18.12) < 0.001 3.12(1.23,7.93) 0.017 Presence of septic shock 12.34(4.5,33.88) < 0.001 4.42(1.47,13.28) 0.008 Dialysis requirement 2.75(1.57,4.81) < 0.001 1.68(0.92,3.05) 0.091 Primary organism: Klebsiella 0.87(0.50,1.52) 0.625 Previous bacterial infections 1.06(0.64,1.75) 0.818 Concomitant bacterial infections 1.6(0.96,2.66) 0.069 Cytomegalovirus reactivation b 2.31(0.78,6.85) 0.132 Source of bacteremia: Gut translocation 0.89(0.54,1.45) 0.639 Previous exposure to polymyxin 1.22(0.75,1.96) 0.421 Previous exposure to carbapenem 0.99(0.43,2.28) 0.983 Persistent bacteremia 2.15(1.35,3.41) 0.001 1.74(1.05,2.89) 0.031 Treatment details : Ceftazidime-avibactam-based therapy Polymyxin with Ceftazidime-avibactam combination Alternate agents Polymyxin based therapy 0.82(0.41,1.63) 0.61(0.36,1.04) 0.75(0.23,2.41) Reference 0.569 0.067 0.624 - No appropriate empirical therapy received 0.50(0.28,0.89) 0.019 0.77(0.42,1.41) 0.389 a Prolonged and profound Neutropenia is defined as absolute neutrophil count < 100 cells/mm3 and a duration of 7 days. b Cytomegalovirus reactivation- More than 1000 copies of cytomegalovirus present 7 days before or after bacterial isolation. Kaplan Meier survival curve (Fig. 1 ) demonstrates the survival among patients with and without persistent bacteremia in the 30-day follow-up period. Probability of survival was higher in patients without persistent bacteremia (63.2%) as compared to those with persistent bacteremia(38.2%). The difference observed in survival functions was statistically significant with p < 0.001. Discussion In this study, we highlight the need for doing FUBC in patients with neutropenia and CRGNBSI. While most gram-negative bloodstream infections encountered in routine clinical practice are transient, patients with neutropenia and CRGNBSI may benefit from FUBC. Persistent bacteremia in these patients may serve as a biomarker to consider modification of treatment strategy, adequate source control, and evaluation for metastatic infections. Non-recovery of neutropenia, shock and requirement of critical care are other well known risk factors of mortality. So far, most studies evaluating the use of FUBC in gram-negative bacteremia did not find support for their routine use [ 6 – 8 ]. This was because they predominantly included patients with transient bacteremia from sources like pyelonephritis, which is usually caused by organisms susceptible to most antibiotics. However, newer studies including sicker patients with resistant infections support the results of this study. Gianella et al. reported significantly higher rates of persistent bacteremia among patients with central line-related infections and bacteremia with carbapenem-resistant organisms [ 9 ]. However, overall mortality in their study was low, and persistent bacteremia was not associated with 30-day mortality. In another single-center large prospective study including 1702 patients with gram-negative bacteremia, two-thirds of whom had FUBC, persistent bacteremia was associated with increased mortality. Persistent bacteremia was more common with delayed initiation of effective therapy, indwelling devices, immunosuppression, and Serratia spp. bloodstream infections [ 10 ]. This study has potential clinical implications. If the inability to clear bacteremia promptly is associated with mortality, strategies to promote clearance need to be studied. While neutropenia and immunosuppression contribute to persistent bacteremia, often they cannot be promptly reversed. Treatment modifications like switching to another agent or to combination therapies may be considered in these patients. Evaluation for occult metastatic infections also may be warranted in them. The ability of individual or combination antibiotics to clear the bacteremia in correlation with treatment outcomes needs to be prospectively studied. Comparing time-to-culture negativity may also aid clinicians in assessing response to treatment. Persistent bacteremia is not routinely reported in large-scale prospective CRGNBSI studies. The PANORAMA study reported persistent bacteremia in 17% [ 11 ]. Persistent bacteremia may also serve as an important tool for assessing the efficacy of bacterial regimens in clinical trials. The duration of bacteremia may serve as an early predictor of treatment success while comparing regimens. This study had several limitations. It is a single-center study from a country with a significant burden of CRGNBSI. Due to the retrospective design, the timing of FUBC was not standardized, although most patients had FUBCs within 96 hours of bacteremia. The results may not be generalizable to patients with causes of immunosuppression other than neutropenia. A proportion of central line related bacteremias may be misclassified, as some patients did not have paired cultures from the central line and peripheral poke. In summary, we propose that FUBC showing persistent bacteremia is a simple clinical tool that predicts outcomes in patients with neutropenia and CRGNBSI. Potentially, this identifies the subgroup of patients who require treatment modifications or adequate source control. FUBC should be routinely considered in these patients. Declarations Ethical Approval This study was approved by the institutional review board and ethics committee of Christian Medical College, Vellore. Informed consent Informed consent was obtained from all participants which included consent to participate in the study and consent to publish the study findings in any scientific journal. Competing interests The authors have no competing interests to declare that are relevant to the content of this article. Authors' contributions A.M.S, G.M.V and B.G contributed to the study conception and design. Material preparation, data collection and analysis were performed by M.M.G, G.M.J and K.B. Statistical analysis was performed by M.M.G and P.S.P. The first draft of the manuscript was written by A.M.S, G.M.V and M.M.G and all authors commented on previous versions of the manuscript and provided critical reviews and editing. All authors read and approved the final manuscript. Funding No funds, grants, or other support was received. Availability of data and materials All data used in the manuscript can be accessed upon request to the corresponding author. References Righi E, Peri AM, Harris PN, Wailan AM, Liborio M, Lane SW, et al. Global prevalence of carbapenem resistance in neutropenic patients and association with mortality and carbapenem use: systematic review and meta-analysis. J AntimicrobChemother. 2017;72:668–77. GoodletKJ CameronEA. NailorMD. Low Sensitivity of Procalcitonin for Bacteremia at an Academic Medical Center: A Cautionary Tale for Antimicrobial Stewardship. 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Canzoneri CN, Akhavan BJ, Tosur Z, Andrade PEA, Aisenberg GM. Follow-up Blood Cultures in Gram-Negative Bacteremia: Are They Needed? Clin Infect Dis. 2017;65:1776–9. doi: 10.1093/cid/cix648 . Jung J, Song KH, Jun KI, Kang CK, Kim NH, Choe PG, et al. Predictive scoring models for persistent gram-negative bacteremia that reduce the need for follow-up blood cultures: a retrospective observational cohort study. BMC Infect Dis. 2020;20:680. doi: 10.1186/s12879-020-05395-8 . Bedside risk prediction for positive follow-up blood culture in Gram-negative bacilli bacteremia: for whom is follow-up blood culture useful? | SpringerLink [Internet]. [cited 2022 Sep 12]. Available from: https://link.springer.com/article/10.1007/s 15010-021-01742-2. Giannella M, Pascale R, Pancaldi L, Monari C, Ianniruberto S, Malosso P, et al. Follow-up blood cultures are associated with improved outcome of patients with gram-negative bloodstream infections: retrospective observational cohort study. Clin Microbiol Infect. 2020;26:897–903. Maskarinec SA, Park LP, Ruffin F, Turner NA, Patel N, Eichenberger EM, et al. Positive follow-up blood cultures identify high mortality risk among patients with Gram-negative bacteraemia. Clin Microbiol Infect. 2020;26:904–10. Stewardson AJ, Marimuthu K, Sengupta S, Allignol A, El-Bouseary M, Carvalho MJ, et al. Effect of carbapenem resistance on outcomes of bloodstream infection caused by Enterobacteriaceae in low-income and middle-income countries (PANORAMA): a multinational prospective cohort study. Lancet Infect Dis. 2019;19:601–10. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 15 Feb, 2023 Read the published version in Annals of Clinical Microbiology and Antimicrobials → Version 1 posted Editorial decision: Major revision 20 Dec, 2022 Reviews received at journal 20 Dec, 2022 Reviews received at journal 25 Oct, 2022 Reviewers agreed at journal 05 Oct, 2022 Reviewers agreed at journal 04 Oct, 2022 Reviewers invited by journal 02 Oct, 2022 Editor assigned by journal 30 Sep, 2022 Submission checks completed at journal 14 Sep, 2022 First submitted to journal 14 Sep, 2022 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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College","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Binila","middleName":"","lastName":"Chacko","suffix":""},{"id":136802603,"identity":"ef8ddda0-46e7-494c-a4a3-348554722468","order_by":11,"name":"K Subramani","email":"","orcid":"","institution":"Christian Medical College","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"K","middleName":"","lastName":"Subramani","suffix":""},{"id":136802604,"identity":"018d4bc1-d91d-4b4b-85f4-6aa2d6ca0c47","order_by":12,"name":"George M Varghese","email":"","orcid":"","institution":"Christian Medical College","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"George","middleName":"M","lastName":"Varghese","suffix":""},{"id":136802605,"identity":"9ceb86dc-b6af-4044-8661-3bbcf31a33ac","order_by":13,"name":"V Balaji","email":"","orcid":"","institution":"Christian Medical College","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"V","middleName":"","lastName":"Balaji","suffix":""},{"id":136802606,"identity":"001cd7a3-3efe-4fe9-a02e-6d6513aed62d","order_by":14,"name":"Biju George","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA5klEQVRIiWNgGAWjYBACA2aGBIYPYCZz4wGY6AEcquFaGGeAmYwNRGoBGc+DrgUvMGdneCZtU7NN3uB4Y8OBj3tsGPjbDzAeLsCjxbKZIU0659htww1nDjYcnPEsjUHiTALD4Rn4HHYYqCW34XaC5IzEhsM8Bw4zMNxgYDjMQ0iLJUjL/IcgLf8Z5InSwgjUwi/BCNJygMGAkBagX5Ite4B+6edJBPrlQDKP4RmQC/FoMec/k3jjR81teTb2wwcffDhgJyd3/PDhz/i0MDDwJKByQRGEVwMDA/sBAgpGwSgYBaNgxAMAqD9RaakTlwcAAAAASUVORK5CYII=","orcid":"","institution":"Christian Medical College","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Biju","middleName":"","lastName":"George","suffix":""}],"badges":[],"createdAt":"2022-09-14 08:59:20","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-2064044/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-2064044/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12941-023-00561-7","type":"published","date":"2023-02-15T18:56:59+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":26581814,"identity":"f322cc6f-ff90-4df8-8c13-9a394950ccb7","added_by":"auto","created_at":"2022-09-16 20:56:45","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":39588,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eKaplan-Meier survival curves for patients with persistent bacteremia versus cleared bacteremia\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-2064044/v1/3c884f87d16462ca5397e396.jpg"},{"id":44719838,"identity":"37cd5718-0eb3-436e-b3ae-2a556ec2acc5","added_by":"auto","created_at":"2023-10-16 19:02:33","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":445369,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-2064044/v1/85cc1496-e2ca-42b9-88de-f7c5302e2c11.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Persistent bacteremia predicts poor outcomes among neutropenic patients with carbapenem-resistant gram-negative bloodstream infections receiving appropriate therapy","fulltext":[{"header":"Introduction","content":"\u003cp\u003eCarbapenem-resistant gram-negative bloodstream infections (CRGNBSI) have mortality rates of up to 50% and limited therapeutic options [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Neutropenic and other immunosuppressed patients have the poorest outcomes. Early identification of patients at risk for poor outcomes is important for optimal management and improving prognosis. However, available predictors,such as leucocyte counts, C-reactive protein (CRP), and procalcitonin, are often imprecise[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e \u003cp\u003ePersistent blood culture positivity at 48 to 72 hours despite optimal therapy is an established predictor of poor outcome, death, and metastatic infection among patients with methicillin-resistant \u003cem\u003eStaphylococcus aureus\u003c/em\u003e (MRSA) bacteremia and candidemia [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. However, their role in gram-negative bacteremia is uncertain [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Currently, the utilization of follow-up blood cultures (FUBC) is variable across hospitals and physicians. Further, the FUBC positivity varies according to the source of bacteremia and pathogen resistance phenotype. For example, bacteremia from a urinary source is usually transient. The role of FUBC in high-risk populations,such as patients with neutropenia and carbapenem-resistant infections, is not studied so far.\u003c/p\u003e \u003cp\u003eAs clear data is unavailable, recent guidelines from the Infectious Diseases Society of America and other international bodies do not have directives on the use of FUBC among patients with CRGNBSI [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. This observational study was conducted to determine the role of FUBC in patients with neutropenia and CRGNBSI.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eWe performed a retrospective cohort study between December 2017 and April 2022 at the Christian Medical College, Vellore, a 3000-bedded academic center, among patients with neutropenia admitted to the hematology department with CRGNBSI. Patients over 15 years of age, who survived 48 hours or more after the bacteremia, were included in the study. Patients with polymicrobial bacteremia and who received inappropriate therapy were excluded. Only the first qualifying episode of bacteremia during the duration of hospital stay of an individual patient was included. The study was approved by the Institutional Review Board and Ethics committee.\u003c/p\u003e \u003cp\u003ePatient data, including their comorbidities, treatment details, and outcomes, were documented from electronic medical records. All data was collected in a predesigned proforma developed for the study on an electronic data capture system.The date of positive blood culture growing carbapenem-resistant gram-negative bacteria was taken as the date of bacteremia (index date or day zero).The patient was followed up for 30 days from that date. Carbapenem resistance was defined as resistance to meropenem or imipenem according to Clinical Laboratory and Standards Institute guidelines. Persistent bacteremia was defined as a minimum of two positive blood cultures growing the same organisms with similar antibiograms at least 48 hours apart during the same infectious episode. Repeat blood cultures growing different organisms were not counted as persistent bacteremia. Neutropenia in our study was defined as an absolute neutrophil count (ANC) of less than 500 cells/\u0026micro;L before 48 hours to the date of bacteremia. Previous bacterial infections noted in the study which were identified 30 days prior to the index date were defined as serious bacterial infections. Concomitant bacterial infections were defined as any serious bacterial infections other than the current bacteremia which was isolated within 30 days after the index date. Cytomegalovirus reactivation among transplant patients was reported when CMV viremia with \u0026gt;\u0026thinsp;1000 copies/\u0026micro;l was present before or after seven days of bacterial isolation. Prolonged and profound neutropenia was documented if the neutropenic condition persisted for more than 7 days and ANC levels were \u0026le;\u0026thinsp;100 cells/\u0026micro;L. Achieving ANC levels\u0026thinsp;\u0026gt;\u0026thinsp;500 cells/Μl during the follow-up period was marked as a recovery from neutropenia. Polymyxin-based therapy referred to treatment with polymyxin, either alone or with adjunct drugs, such as trimethoprim-sulfamethoxazole or tigecycline. Ceftazidime-avibactam-based therapy included ceftazidime-avibactam along with other adjunct drugs. When both polymyxin and ceftazidime-avibactam were given with or without adjunct drugs, it was recorded as polymyxin with ceftazidime-avibactam combination therapy. If the patient received treatment with drugs thatthe organism was not resistant to in the antibiogram done on the index date, they were considered to have received appropriate empiric therapy.\u003c/p\u003e \u003cp\u003eThe primary outcome of the study was 30-day mortality. Other outcomes of interest were persistent bacteremia, septic shock, recovery from neutropenia, prolonged and profound neutropenia, requirement of intensive care and dialysis after the index date, and initiation of appropriate empirical therapy.A telephonic follow-up to assess the primary outcome was done for participants who were discharged within the 30-day follow-up period.\u003c/p\u003e \u003cp\u003eBaseline characteristics for all patients enrolled are presented as means with standard deviation (SD) or medians with interquartile range (IQR) for continuous variables and as frequencies with proportions for categorical variables. Statistical comparisons between groups for categorical variables were made using Pearson\u0026rsquo;s chi-square test or Fisher's exact test as applicable while Student\u0026rsquo;s t-test was used for comparing continuous variables between survivors and non-survivors. Univariate analysis was performed for all risk factors predicting 30-day mortality, and hazard ratio (HR) with 95% confidence interval (CI) was determined. Multicollinearity was checked between all variables by determining variance inflation factor (VIF). We performed multivariable Cox proportional hazards regression analysis using risk factors that were significant in the univariate analysis and determined the adjusted hazards ratio (aHR) with 95% CI. Age and sex were added to the multivariable model as natural confounders. Statistical significance was considered at a p-value of \u0026lt;\u0026thinsp;0.05. Survival curves were plotted to visualize the 30-day all-cause mortality among patients with persistent bacteremia and without. Censoring was not done as all study participants, unless dead, were followed-up for 30 days. Log-rank test was performed to evaluate statistical differences in survival estimates between groups. We used STATA 16 (StataCorp. 2019. \u003cem\u003eStata Statistical Software: Release 16\u003c/em\u003e. College Station, TX: StataCorp LLC) for statistical analysis.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eWe identified 208 patients with neutropenia above 15 years of age and had CRGNBSI. Twenty-nine patients died before 48 hours of bacteremia, twenty patients did not have FUBC, and four patients did not receive appropriate therapy for the bacteremia. The 155 patients who fulfilled the eligibility criteria were included in the final analysis, of whom 93(60%) were male. The mean age of patients was 36.65 years (SD, 13 years). \u003cem\u003eKlebsiella\u003c/em\u003e species were the most commonly isolated organism (80%). All recruited patients had an underlying active hematological condition, of which, 120 (77.42%) were malignant in nature.The most common malignant conditions were acute myeloid leukemia (42.5%) and acute lymphoblastic leukemia (27.5%). Among benign conditions, aplastic anemia (71.43%) followed by myelodysplastic syndrome (17.14) were the most common. A sizable proportion of patients developed CRGNBSI after bone marrow transplant (35.4%). Among transplant patients, CMV reactivation along with CRGNBSIs was minimal (10.9%). Polymyxin resistance complicated more than a fifth of our patients (21.2%) (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline demographic and clinical characteristics\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\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=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharacteristics\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTotal\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;155\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSurvivors\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;81 (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNon-survivors\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;74 (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge(Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e36.65\u0026thinsp;\u0026plusmn;\u0026thinsp;12.93\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e35.96\u0026thinsp;\u0026plusmn;\u0026thinsp;13.17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e37.42\u0026thinsp;\u0026plusmn;\u0026thinsp;12.71\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.485\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGender: Male\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e93\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e46(56.79)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e47(63.51)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.393\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePolymyxin resistance(n\u0026thinsp;=\u0026thinsp;146)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14(21.21)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e17(21.25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.996\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eRisk factors\u003c/b\u003e\u003c/p\u003e \u003cp\u003eHematologic condition:\u003c/p\u003e \u003cp\u003eBenign\u003c/p\u003e \u003cp\u003eAcute myeloid leukemia\u003c/p\u003e \u003cp\u003eAcute lymphoblastic leukemia\u003c/p\u003e \u003cp\u003eOther malignant conditions\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e35\u003c/p\u003e \u003cp\u003e51\u003c/p\u003e \u003cp\u003e33\u003c/p\u003e \u003cp\u003e36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14(17.28)\u003c/p\u003e \u003cp\u003e31(38.27)\u003c/p\u003e \u003cp\u003e17(20.99)\u003c/p\u003e \u003cp\u003e19(23.46)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e21(28.38)\u003c/p\u003e \u003cp\u003e20(27.03)\u003c/p\u003e \u003cp\u003e16(21.62)\u003c/p\u003e \u003cp\u003e17(22.97)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.307\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo recovery from neutropenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e66\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15(18.52)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e51(68.92)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eProlonged and profound neutropenia \u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e24(29.63)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e16(21.62)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.255\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTransplant\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e33(40.74)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e22(29.73)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.152\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIntensive care requirement\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e106\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e38(46.91)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e68(91.89)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePresence of septic shock\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e107\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e37(45.68)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e70(94.59)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDialysis requirement\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3(3.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e16(21.62)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eInfection details\u003c/b\u003e\u003c/p\u003e \u003cp\u003ePrimary organism: \u003cem\u003eKlebsiella\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e124\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e66(81.48)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e58(78.38)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.063\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrevious bacterial infections\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e22(27.16)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e22(29.73)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.723\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eConcomitant bacterial infections\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13(16.05)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e21(28.38)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.064\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCytomegalovirus reactivation \u003csup\u003eb\u003c/sup\u003e (n\u0026thinsp;=\u0026thinsp;55)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2(6.06)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4(18.18)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.158\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSource of bacteremia: Gut translocation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e109\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e58(71.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e51(68.92)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.715\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrevious exposure to polymyxin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e94\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e46(56.79)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e48(64.86)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.304\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrevious exposure to carbapenem\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e142\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e74(91.36)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e68(91.89)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.905\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePersistent bacteremia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e68\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e26(32.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e42(56.76)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.002\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTreatment details\u003c/b\u003e\u003c/p\u003e \u003cp\u003ePolymyxin-based therapy\u003c/p\u003e \u003cp\u003eCeftazidime-avibactam-based therapy\u003c/p\u003e \u003cp\u003ePolymyxin with ceftazidime-avibactam combination\u003c/p\u003e \u003cp\u003eAlternate agents\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e75\u003c/p\u003e \u003cp\u003e20\u003c/p\u003e \u003cp\u003e53\u003c/p\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e34(41.98)\u003c/p\u003e \u003cp\u003e10(12.35)\u003c/p\u003e \u003cp\u003e33(40.74)\u003c/p\u003e \u003cp\u003e4(4.94)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e41(55.41)\u003c/p\u003e \u003cp\u003e10(13.51)\u003c/p\u003e \u003cp\u003e20(27.03)\u003c/p\u003e \u003cp\u003e3(4.05)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.299\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo appropriate empirical therapy received\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e31(38.27)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e14(18.92)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.008\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 \u003csup\u003ea\u003c/sup\u003e Prolonged and profound Neutropenia is defined as absolute neutrophil count\u0026thinsp;\u0026lt;\u0026thinsp;100 cells/mm3 and a duration of 7 days.\u003c/p\u003e \u003cp\u003e \u003csup\u003eb\u003c/sup\u003e Cytomegalovirus reactivation- More than 1000 copies of cytomegalovirus present 7 days before or after bacterial isolation.\u003c/p\u003e \u003cp\u003eOur cohort of patients was very ill with septic shock (69%) and required intensive care. Nineteen (12.2%) patients required dialysis, of whom sixteen died within the follow-up period. More than half of our patients (60.6%) received polymyxins in the 30 days preceding the CRGNBSI. Almost all patients (91.6%) were exposed to carbapenems over the same time period. Over a quarter of our patients (28.3%) had laboratory confirmed bacterial infection in the last 30 days prior to index date, and 21.9% developed a concomitant bacterial infection,other than the infectious episode on index date, within their follow-up period. Gut translocation was identified as the major source of bacteremia in our patients (70.3%). Other sources included catheter, lung, skin, and soft tissue infections. Source control was achieved in our patients whenever clinically applicable. Persistent bacteremia was common in our patient cohort (43.8%). The median time for sending a FUBC was 2 days (IQR, 1\u0026ndash;3 days). The median duration of persistent bacteremia was 4 days (IQR, 3\u0026ndash;7.5 days).\u003c/p\u003e \u003cp\u003eThe overall mortality rate was 47.7%, and mortality was significantly higher among individuals with persistent bacteremia (56.76%, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) than among those without (32.10%). Among our cohort of patients, 40 (25.8%) had prolonged or profound neutropenia while 89 (57.4%) recovered from neutropenia. Among patients who survived during the follow-up period, 81.48% recovered from neutropenia. About half of the patients received a polymyxin-based therapy (48.4%), and 34.2% received polymyxin and ceftazidime-avibactam combination therapy. Other types of therapy included ceftazidime-avibactam-based treatment or alternate drugs, such as tigecycline. The majority of our patients received an appropriate empirical therapy (70.9%),of whom over half (54.5%) had poor outcomes at the 30-day follow-up.\u003c/p\u003e \u003cp\u003eWe performed univariate analysis on all patients to determine risk factors associated with 30-day mortality. Non-recovery from neutropenia (HR,5.42;95%CI, 3.28\u0026ndash;8.93), requirement of intensive care (HR,7.84;95%CI, 3.39\u0026ndash;18.12), septic shock (HR,12.34; 95%CI, 4.5\u0026ndash;33.88), requirement of dialysis (HR,2.75; 95%CI, 1.57\u0026ndash;4.81) and persistent bacteremia (HR,2.15; 95%CI, 1.35\u0026ndash;3.41) were significantly associated with 30-day mortality in univariate analysis. Not receiving appropriate empirical therapy did not predict mortality in our group of patients (HR,0.5; 95%CI, 0.28\u0026ndash;0.89). The mean VIF among the factors significant on univariable analysis was 1.26 with no critical correlation among the factors. When adjusted to all the significant risk factors along with age and sex as natural confounders, non-recovery from neutropenia (aHR,4.28; 95%CI, 2.53\u0026ndash;7.23), requirement of intensive care (aHR,3.12;95%CI, 1.23\u0026ndash;7.93),presence of septic shock (aHR,4.42; 95%CI, 1.47\u0026ndash;13.28), and persistent bacteremia (aHR,1.74; 95%CI, 1.05\u0026ndash;2.89) emerged as significant associations that predicted poor outcomes in multivariable analysis (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eRisk factors predicting 30-day mortality\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\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 \u003cdiv align=\"char\" char=\".\" 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\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eCharacteristics\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eUnivariate analysis\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e \u003cp\u003eMultivariable analysis\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"1\" nameend=\"c7\" namest=\"c7\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHazards ratio(95% CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAdjusted Hazards ratio(95% CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"1\" nameend=\"c7\" namest=\"c7\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.01 (0.99,1.02)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.573\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1(0.98,1.02)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c7\" namest=\"c5\"\u003e \u003cp\u003e0.772\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale gender\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.19(0.74,1.92)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.463\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.4(0.83,2.34)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.207\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePolymyxin resistance\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.96 (0.53,1.74)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.904\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHematologic condition:\u003c/p\u003e \u003cp\u003eAcute myeloid leukemia\u003c/p\u003e \u003cp\u003eAcute lymphoblastic leukemia\u003c/p\u003e \u003cp\u003eOther malignant conditions\u003c/p\u003e \u003cp\u003eBenign\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.56(0.30,1.04)\u003c/p\u003e \u003cp\u003e0.73(0.38,1.40)\u003c/p\u003e \u003cp\u003e0.74(0.39,1.40)\u003c/p\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.065\u003c/p\u003e \u003cp\u003e0.34\u003c/p\u003e \u003cp\u003e0.353\u003c/p\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo recovery from neutropenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e5.42(3.28,8.93)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e4.28(2.53,7.23)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eProlonged and profound neutropenia \u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.65(0.37,1.13)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTransplant\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.67(0.41,1.11)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.121\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIntensive care requirement\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e7.84(3.39,18.12)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e3.12(1.23,7.93)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.017\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePresence of septic shock\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e12.34(4.5,33.88)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e4.42(1.47,13.28)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.008\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDialysis requirement\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2.75(1.57,4.81)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.68(0.92,3.05)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.091\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrimary organism: \u003cem\u003eKlebsiella\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.87(0.50,1.52)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.625\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrevious bacterial infections\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.06(0.64,1.75)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.818\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eConcomitant bacterial infections\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.6(0.96,2.66)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.069\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCytomegalovirus reactivation \u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2.31(0.78,6.85)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.132\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSource of bacteremia: Gut translocation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.89(0.54,1.45)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.639\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrevious exposure to polymyxin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.22(0.75,1.96)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.421\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrevious exposure to carbapenem\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.99(0.43,2.28)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.983\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePersistent bacteremia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2.15(1.35,3.41)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e1.74(1.05,2.89)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.031\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTreatment details\u003c/b\u003e:\u003c/p\u003e \u003cp\u003eCeftazidime-avibactam-based therapy\u003c/p\u003e \u003cp\u003ePolymyxin with Ceftazidime-avibactam combination\u003c/p\u003e \u003cp\u003eAlternate agents\u003c/p\u003e \u003cp\u003ePolymyxin based therapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.82(0.41,1.63)\u003c/p\u003e \u003cp\u003e0.61(0.36,1.04)\u003c/p\u003e \u003cp\u003e0.75(0.23,2.41)\u003c/p\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.569\u003c/p\u003e \u003cp\u003e0.067\u003c/p\u003e \u003cp\u003e0.624\u003c/p\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo appropriate empirical therapy received\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.50(0.28,0.89)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.019\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.77(0.42,1.41)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.389\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003e\u003csup\u003ea\u003c/sup\u003e Prolonged and profound Neutropenia is defined as absolute neutrophil count\u0026thinsp;\u0026lt;\u0026thinsp;100 cells/mm3 and a duration of 7 days.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003e\u003csup\u003eb\u003c/sup\u003e Cytomegalovirus reactivation- More than 1000 copies of cytomegalovirus present 7 days before or after bacterial isolation.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eKaplan Meier survival curve (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e) demonstrates the survival among patients with and without persistent bacteremia in the 30-day follow-up period. Probability of survival was higher in patients without persistent bacteremia (63.2%) as compared to those with persistent bacteremia(38.2%). The difference observed in survival functions was statistically significant with p\u0026thinsp;\u0026lt;\u0026thinsp;0.001.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this study, we highlight the need for doing FUBC in patients with neutropenia and CRGNBSI. While most gram-negative bloodstream infections encountered in routine clinical practice are transient, patients with neutropenia and CRGNBSI may benefit from FUBC. Persistent bacteremia in these patients may serve as a biomarker to consider modification of treatment strategy, adequate source control, and evaluation for metastatic infections. Non-recovery of neutropenia, shock and requirement of critical care are other well known risk factors of mortality.\u003c/p\u003e \u003cp\u003eSo far, most studies evaluating the use of FUBC in gram-negative bacteremia did not find support for their routine use [\u003cspan additionalcitationids=\"CR7\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. This was because they predominantly included patients with transient bacteremia from sources like pyelonephritis, which is usually caused by organisms susceptible to most antibiotics. However, newer studies including sicker patients with resistant infections support the results of this study. Gianella et al. reported significantly higher rates of persistent bacteremia among patients with central line-related infections and bacteremia with carbapenem-resistant organisms [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. However, overall mortality in their study was low, and persistent bacteremia was not associated with 30-day mortality. In another single-center large prospective study including 1702 patients with gram-negative bacteremia, two-thirds of whom had FUBC, persistent bacteremia was associated with increased mortality. Persistent bacteremia was more common with delayed initiation of effective therapy, indwelling devices, immunosuppression, and \u003cem\u003eSerratia spp.\u003c/em\u003e bloodstream infections [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThis study has potential clinical implications. If the inability to clear bacteremia promptly is associated with mortality, strategies to promote clearance need to be studied. While neutropenia and immunosuppression contribute to persistent bacteremia, often they cannot be promptly reversed. Treatment modifications like switching to another agent or to combination therapies may be considered in these patients. Evaluation for occult metastatic infections also may be warranted in them. The ability of individual or combination antibiotics to clear the bacteremia in correlation with treatment outcomes needs to be prospectively studied. Comparing time-to-culture negativity may also aid clinicians in assessing response to treatment.\u003c/p\u003e \u003cp\u003ePersistent bacteremia is not routinely reported in large-scale prospective CRGNBSI studies. The PANORAMA study reported persistent bacteremia in 17% [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Persistent bacteremia may also serve as an important tool for assessing the efficacy of bacterial regimens in clinical trials. The duration of bacteremia may serve as an early predictor of treatment success while comparing regimens.\u003c/p\u003e \u003cp\u003eThis study had several limitations. It is a single-center study from a country with a significant burden of CRGNBSI. Due to the retrospective design, the timing of FUBC was not standardized, although most patients had FUBCs within 96 hours of bacteremia. The results may not be generalizable to patients with causes of immunosuppression other than neutropenia. A proportion of central line related bacteremias may be misclassified, as some patients did not have paired cultures from the central line and peripheral poke.\u003c/p\u003e \u003cp\u003eIn summary, we propose that FUBC showing persistent bacteremia is a simple clinical tool that predicts outcomes in patients with neutropenia and CRGNBSI. Potentially, this identifies the subgroup of patients who require treatment modifications or adequate source control. FUBC should be routinely considered in these patients.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthical Approval\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThis study was approved by the institutional review board and ethics committee of Christian Medical College, Vellore.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInformed consent\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eInformed consent was obtained from all participants which included consent to participate in the study and consent to publish the study findings in any scientific journal.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe authors have no competing interests to declare that are relevant to the content of this article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eA.M.S, G.M.V and B.G contributed to the study conception and design. Material preparation, data collection and analysis were performed by M.M.G, G.M.J and K.B. Statistical analysis was performed by M.M.G and P.S.P. The first draft of the manuscript was written by A.M.S, G.M.V and M.M.G and all authors commented on previous versions of the manuscript and provided critical reviews and editing. All authors read and approved the final manuscript.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo funds, grants, or other support was received.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAll data used in the manuscript can be accessed upon request to the corresponding author.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eRighi E, Peri AM, Harris PN, Wailan AM, Liborio M, Lane SW, et al. Global prevalence of carbapenem resistance in neutropenic patients and association with mortality and carbapenem use: systematic review and meta-analysis. J AntimicrobChemother. 2017;72:668\u0026ndash;77.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGoodletKJ CameronEA. NailorMD. Low Sensitivity of Procalcitonin for Bacteremia at an Academic Medical Center: A Cautionary Tale for Antimicrobial Stewardship. Open Forum Infectious Diseases. 2020. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://academic.oup.com/ofid/article/7/4/ofaa096/5807488?login=true\u003c/span\u003e\u003cspan address=\"https://academic.oup.com/ofid/article/7/4/ofaa096/5807488?login=true\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. Accessed on 18 Aug 2022.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKuehl R, Morata L, Boeing C, Subirana I, Seifert H, Rieg S, et al. International Staphylococcus aureus collaboration study group and the ESCMID Study Group for Bloodstream Infections, Endocarditis and Sepsis. Defining persistent Staphylococcus aureus bacteraemia: secondary analysis of a prospective cohort study. Lancet Infect Dis. 2020;20:1409\u0026ndash;17.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCogliatiDezza F, Curtolo A, Volpicelli L, Ceccarelli G, Oliva A, Venditti M. Are Follow-Up Blood Cultures Useful in the Antimicrobial Management of Gram Negative Bacteremia? A Reappraisal of Their Role Based on Current Knowledge. Antibiotics. 2020;9:895.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTamma PD, Aitken SL, Bonomo RA, Mathers AJ, van Duin D, Clancy CJ. IDSA Guidance on the Treatment of Antimicrobial-Resistant Gram-Negative Infections: Version 1.0. IDSA. 2022. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.idsociety.org/practice-guideline/amr-guidance\u003c/span\u003e\u003cspan address=\"https://www.idsociety.org/practice-guideline/amr-guidance\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. Accessed on2 May 2022.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCanzoneri CN, Akhavan BJ, Tosur Z, Andrade PEA, Aisenberg GM. Follow-up Blood Cultures in Gram-Negative Bacteremia: Are They Needed? Clin Infect Dis. 2017;65:1776\u0026ndash;9. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1093/cid/cix648\u003c/span\u003e\u003cspan address=\"10.1093/cid/cix648\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJung J, Song KH, Jun KI, Kang CK, Kim NH, Choe PG, et al. Predictive scoring models for persistent gram-negative bacteremia that reduce the need for follow-up blood cultures: a retrospective observational cohort study. BMC Infect Dis. 2020;20:680. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1186/s12879-020-05395-8\u003c/span\u003e\u003cspan address=\"10.1186/s12879-020-05395-8\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBedside risk prediction for positive follow-up blood culture in Gram-negative bacilli bacteremia: for whom is follow-up blood culture useful? | SpringerLink [Internet]. [cited 2022 Sep 12]. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://link.springer.com/article/10.1007/s\u003c/span\u003e\u003cspan address=\"https://link.springer.com/article/10.1007/s\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e15010-021-01742-2.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGiannella M, Pascale R, Pancaldi L, Monari C, Ianniruberto S, Malosso P, et al. Follow-up blood cultures are associated with improved outcome of patients with gram-negative bloodstream infections: retrospective observational cohort study. Clin Microbiol Infect. 2020;26:897\u0026ndash;903.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMaskarinec SA, Park LP, Ruffin F, Turner NA, Patel N, Eichenberger EM, et al. Positive follow-up blood cultures identify high mortality risk among patients with Gram-negative bacteraemia. Clin Microbiol Infect. 2020;26:904\u0026ndash;10.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eStewardson AJ, Marimuthu K, Sengupta S, Allignol A, El-Bouseary M, Carvalho MJ, et al. Effect of carbapenem resistance on outcomes of bloodstream infection caused by Enterobacteriaceae in low-income and middle-income countries (PANORAMA): a multinational prospective cohort study. Lancet Infect Dis. 2019;19:601\u0026ndash;10.\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":"[email protected]","identity":"annals-of-clinical-microbiology-and-antimicrobials","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"cmam","sideBox":"Learn more about [Annals of Clinical Microbiology and Antimicrobials](http://ann-clinmicrob.biomedcentral.com/)","snPcode":"12941","submissionUrl":"https://submission.nature.com/new-submission/12941/3","title":"Annals of Clinical Microbiology and Antimicrobials","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Bloodstream infections, Carbapenem resistance, Neutropenia, Persistent bacteremia","lastPublishedDoi":"10.21203/rs.3.rs-2064044/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-2064044/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e \u003cp\u003eIdentifying persistent bacteremia early in patients with neutropenia may improve outcome. This study evaluated the role of follow-up blood cultures (FUBC) positivity in predicting outcomes among patients with neutropenia and carbapenem-resistant gram-negative bloodstream infections (CRGNBSI).\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThis retrospective cohort study conducted between December 2017 and April 2022 included patients more than 15 years old with neutropenia and CRGNBSI, who survived for \u0026ge;\u0026thinsp;48 hours, receiving appropriate antibiotic therapy and had FUBCs. Patients with polymicrobial bacteremia within 30 days were excluded. The primary outcome was 30-day mortality. Persistent bacteremia, septic shock, recovery from neutropenia, prolonged or profound neutropenia, requirement of intensive care and dialysis, and initiation of appropriate empirical therapy were also studied.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eThe 30-day mortality rate was 47.7%. Persistent bacteremia was common in our patient cohort (43.8%). The median time for sending a FUBC was 2 days (IQR, 1\u0026ndash;3 days). Patients with persistent bacteremia had higher mortality than those without (56.76% versus 32.1%; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Appropriate initial empirical therapy was given to 70.9%. Recovery from neutropenia occurred in 57.4% while 25.8% had prolonged or profound neutropenia. Sixty-nine percent had septic shock and needed intensive care; 12.2% of patients required dialysis. Non-recovery from neutropenia (aHR, 4.28; 95% CI, 2.53\u0026ndash;7.23), presence of septic shock (aHR, 4.42; 95%CI, 1.47\u0026ndash;13.28), requirement of intensive care (aHR,3.12;95%CI, 1.23\u0026ndash;7.93), and persistent bacteremia (aHR,1.74; 95%CI, 1.05\u0026ndash;2.89) significantly predicted poor outcomes in multivariable analysis.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eFUBC showing persistent bacteremia predicted poor outcomes among neutropenic patients with carbapenem-resistant gram-negative bloodstream infections (CRGNBSI) and should be routinely reported.\u003c/p\u003e","manuscriptTitle":"Persistent bacteremia predicts poor outcomes among neutropenic patients with carbapenem-resistant gram-negative bloodstream infections receiving appropriate therapy","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2022-09-16 20:56:43","doi":"10.21203/rs.3.rs-2064044/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revision","date":"2022-12-20T10:51:10+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2022-12-20T09:58:55+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2022-10-25T18:12:54+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"65e6cac6-ac95-4735-82a9-cf9649f69d99","date":"2022-10-05T17:52:23+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"7c3aba74-9328-44cf-aba2-8726d7f32583","date":"2022-10-04T17:14:52+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2022-10-02T11:29:56+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2022-09-30T08:45:16+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2022-09-15T03:50:03+00:00","index":"","fulltext":""},{"type":"submitted","content":"Annals of Clinical Microbiology and Antimicrobials","date":"2022-09-14T08:47:57+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"annals-of-clinical-microbiology-and-antimicrobials","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"cmam","sideBox":"Learn more about [Annals of Clinical Microbiology and Antimicrobials](http://ann-clinmicrob.biomedcentral.com/)","snPcode":"12941","submissionUrl":"https://submission.nature.com/new-submission/12941/3","title":"Annals of Clinical Microbiology and Antimicrobials","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"2b52a9dc-d40e-487b-808d-ebf00e079b30","owner":[],"postedDate":"September 16th, 2022","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2023-10-16T19:00:17+00:00","versionOfRecord":{"articleIdentity":"rs-2064044","link":"https://doi.org/10.1186/s12941-023-00561-7","journal":{"identity":"annals-of-clinical-microbiology-and-antimicrobials","isVorOnly":false,"title":"Annals of Clinical Microbiology and Antimicrobials"},"publishedOn":"2023-02-15 18:56:59","publishedOnDateReadable":"February 15th, 2023"},"versionCreatedAt":"2022-09-16 20:56:43","video":"","vorDoi":"10.1186/s12941-023-00561-7","vorDoiUrl":"https://doi.org/10.1186/s12941-023-00561-7","workflowStages":[]},"version":"v1","identity":"rs-2064044","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-2064044","identity":"rs-2064044","version":["v1"]},"buildId":"7rjqhiLT3MXkJMwkYKINL","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}