Gram-negative Bloodstream Infections Research Articles

1320. Incidence and Outcome of Gram Negative Blood Stream Infections in Pediatric Intensive Care Unit: a Real Life Experience in a Pediatric Hospital in Italy

Abstract Background Antimicrobial resistance (AMR) among Gram Negative (GN) bacteria is a medical and economic concern. In the pediatric setting there is a paucity AMR data due to a lower surveillance in this population. Aim of this study is to describe incidence and outcomes of GN bloodstream infections (GN-BSI), especially caused by MDR among children admitted to intensive care unit of Istituto Giannina Gaslini Pediatric Hospital in Genoa from January 2017 to December 2021. Methods In this retrospective observational single-center study all pediatric patients admitted to ICU with GN-BSI were enrolled. We collected demographical and clinical data (such as underlying disease, empiric and targeted therapy, presence of devices, prior colonization due to MDR GN, prior treatments and surgery), and outcome and mortality at 7 and 30 days. Results Overall, 97 GN-BSI among 85 children admitted to PICU were included during the study period. Among all patients 40% (34/85) were male, with median age of 3 months (IQR: 1; 11; range: 0-292) and 75% (64/85) were aged < 1 years). Rates of GN BSI according to 1000 admission are showed in figure 1. The major causative agent was Klebsiella pneumoniae (28/97, 29%), followed by Escherichia coli (18/97, 18%), while 10 episodes (10%) were due to Pseudomonas aeruginosa (figure 2). A mechanism of resistance was found in 22/97 (23%), with a prevalence of ESBL producers (13/22, 59%), followed by AmpC (4/22, 18%) and KPC (2/22, 1%). 14/97 patients (14%) had a surveillance swab positive by the same bacteria causing BSI. The susceptibility to the 4 more used drugs for 4 more frequent pathogens are showed in figure 3. In 40% of GN-BSI the empiric therapy was piperacillin/tazobactam, followed by carbapenem in 28/98, 28% of episodes. Overall, 18 (21%) patients died, half of whom within 7 days of the BSI, including 3/6 of the onco/hematological patients. Figure 1Rates of GN BSI in PICU according to 1000 admissionFigure 2Species distributionFigure 3Susceptibility to the more used drugs for the more frequent pathogens. Conclusion This study confirmed the increasing role of GN in BSI and high mortality among children admitted to PICU, especially the youngest, with an increased rate in our Center. Carbapenem resistance isn’t common, but the empirical treatment with piperacillin/tazobactam often it might be useless. Disclosures All Authors: No reported disclosures.

906. Impact of Accelerate Rapid Diagnostic Technology on Time to Optimal Antimicrobial Therapy in Gram Negative Bloodstream Infection

Abstract Background Previous studies at our institution evaluating rapid diagnostic testing (RDT) for blood culture identification (BCID) did not show significant differences in time to optimal antimicrobial therapy for Gram negative bloodstream infections (GNBSI). Recent studies of Accelerate Pheno® system (Accelerate-PS) for blood culture identification and susceptibility have shown significant reduction in time to optimal antimicrobial therapy. This study evaluated the impact of Accelerate-PS compared to BCID RDT on time to optimal antimicrobial therapy for GNBSI. Methods A single center, retrospective, cohort study included adult patients with GNBSI from February 2017 to January 2018 (pre-implementation) and February 2020 to January 2021 (post-implementation). The primary outcome was time to optimal antimicrobial therapy for GNBSI, defined as time from positive blood cultures to time patient received optimal antimicrobial therapy. Secondary outcomes include duration of therapy, rate of antimicrobial-related adverse effects, hospital length of stay, in-hospital mortality, and infection-related readmission. Results The final cohort included 190 patients in pre-implementation group and 179 patients in post-implementation group. Escherichia coli and Klebsiella species were the most common pathogens and urinary tract was the most common source of bacteremia in both groups. More patients in the pre-implementation group had congestive heart failure while more patients in the post-implementation group had peripheral vascular disease. Patients in the post-implementation group had higher Pitt bacteremia scores (1.05 vs. 1.37, P=0.017). Patients in the post-implementation group had significantly shorter time to optimal therapy (mean 60.62 hours vs. 20.17 hours, P< 0.001) and shorter duration of therapy (mean 366.56 vs 310.24 hours, P < 0.001) than in the pre-implementation group. There were no differences in mortality or readmission at 30-days. Conclusion The results of this study indicate that incorporation of Accelerate-PS into microbiology lab workflow significantly reduces time to optimal antimicrobial therapy for GNBSI. Rapid diagnostic testing is a vital component of a robust antimicrobial stewardship program. Disclosures John Schrank, MD, Gilead: Speaker's Bureau.

964. Physicians' acceptable treatment failure rates and interpretation of antibiogram for Gram-negative infections: A pilot survey study of infectious diseases specialists

Abstract Background The recommendations of many clinical guidelines include an antibiogram as a key component when making empiric therapy decisions. However, little is known about how clinicians interpret antibiograms. We aim to characterize the threshold of the acceptable risk of selecting inappropriate antibiotics among clinicians through clinical case-based questionnaires. Methods We conducted an online survey of infectious diseases (ID) specialists at the University of Iowa, as an internal pilot study. We created realistic clinical case scenarios and asked clinicians to provide the desired minimum percentage of susceptible isolates on an antibiogram for them to feel comfortable with selecting that agent for empiric therapy. We included four scenarios in the questionnaire: i) a patient with urinary tract infection (UTI) in an outpatient setting, ii) a patient with UTI in an inpatient setting, iii) a patient with Gram-negative rod bloodstream infection (GNR-BSI) in an intensive care unit (ICU) setting, iv) a patient with GNR-BSI in a non-ICU setting. Results Of the 16 of 26 providers (62%) who responded, 15 were considered effective responses. ID Physicians reported wide ranges in thresholds of minimum percentage to feel comfortable with prescribing a hypothetical antibiotic and higher thresholds for patients with more severe illnesses (outpatient with UTI: 85% [range: 75-100%]; inpatient with UTI: 95% [range: 50-99%]; inpatient with GNR-BSI in non-ICU settings: 90% [range: 80-95%]; inpatient with GNR-BSI in ICU: 95% [range: 88-100%]) (Figure 1). Figure 1.The distribution of physicians’ acceptable likelihood of susceptibility in four realistic clinical case-scenarios. Abbreviations: GNR-BSI, Gram-negative rod bloodstream infection; ICU, intensive care unit; UTI, urinary tract infection. Conclusion There were wide ranges in thresholds for interpretation of antibiogram among frontline clinicians, especially for less severe infections. Understanding physicians’ antibiogram usage can be helpful to determine how and if antibiogram guides clinicians toward more appropriate empiric therapy decisions. As this was a preliminary study, we plan to conduct a study with a larger sample size to better characterize the use of antibiogram among clinicians from diverse practice settings. Disclosures Michihiko Goto, MD MSCI, Merck & Co.: Grant/Research Support.

735. Contribution of the Oral Cavity and Gastrointestinal Microbiome on Bloodstream Infections inLeukemia Patients

Abstract Background Blood stream infections (BSI) are a common cause of morbidity and mortality in immunocompromised patients. It was previously reported that intestinal domination (defined as occupation of ≥ 30% of the microbiota by a single bacterial taxon) by Enterococcus and Proteobacteria often preceded enterococcal and gram-negative BSI. Methods 16s rRNA sequencing was used to analyze the saliva and stool of 73 acute leukemia patients with BSIs to determine the correlation between the taxa present ( > 0% relative abundance), colonizing ( > 3%) or dominating ( > 30%) a patient’s microbiome and the BSI agent. Species level confirmation of these findings was performed via digital droplet PCR (ddPCR) and LEfSe analysis was used to determine enrichment of infectious taxa at either collection site. Whole genome sequencing and antimicrobial susceptibilities on all BSI isolates. Results We collected simultaneous patient stool and blood isolates from 11 Pseudomonas aeruginosa, 14 Escherichia coli, 4 Klebsiella sp., 8 Enterococcus sp., 18 viridans group streptococci (VGS), 13 Staphylococcus epidermidis, and 5 Staphylococcus aureus BSIs. Mann-Whitney testing confirmed that individuals with P. aeruginosa (oral P =.004, stool P < .001), E. coli (stool P < .001), and VGS infections (oral P =.001) had significantly higher relative abundance of those respective genera compared to other BSI patients, and this appeared to be site specific. LEfSe analysis confirmed enrichment of Pseudomonas in the saliva and stool, Escherichia in the stool, and Streptococcus in the saliva of respective infections. However, while 64 patients showed presence of the infectious genera in the stool and/or saliva at time of BSI, only 7 exhibited domination. ddPCR was used to confirm not only species specificity, but the detection of those antibiotic resistance determinants (CTX-14, CTX-15, Van A and CfrA) found in the BSI isolates within concurrent stool samples. Conclusion It appears that GI domination by the infecting organism was not present at the time of most BSIs. However, in scenarios where the etiological agent was detectable in the saliva or stool, so were the antibiotic resistant determinants. Furthermore, certain infections exhibited a significant difference in oral or stool presence by the same bacteria they were infected with. Disclosures All Authors: No reported disclosures.

1816. Bloodstream Infection Following Arterial Aneurysm Repair: A Population-Based Study

Abstract Background Bloodstream infection (BSI) following arterial aneurysm repair may signify vascular graft infection (VGI). The incidence of BSI and its implications in patients with arterial grafts have received scant attention with limited contemporary study. Therefore, the aim of the current investigation is to describe the incidence and epidemiology of BSI following arterial aneurysm repair in a population-based cohort. Methods Retrospective case-cohort study using the expanded Rochester Epidemiology Project (e-REP) to identify all arterial aneurysm repairs performed in adults (>18 years) residing in eight counties in southern Minnesota between January 1, 2010 and December 31, 2020. All repairs were performed at Mayo Clinic Rochester. Electronic health records were screened for initial BSI episode following aneurysm repair and complicating VGI. Results Overall, 643 patients underwent 708 aneurysm repairs: 417 endovascular and 291 open surgical repairs. Forty-two patients developed BSI during 2,992 cumulative person-years of follow-up. The median time from repair to BSI was 3.1 [interquartile range 0.5, 6.4] years. The BSI incidence rate, in cases per 1000 person-years, was 14.0 (95% CI 10.1-19.0) overall, including 18.2 (95% CI 11.9-26.7) following open surgical repair and 10.2 (95% CI 5.8-16.6) following endovascular repair (p=0.148). Thirty-nine (92.9%) of the BSI cases were monomicrobial, with 18 (46.2%) due to Gram-positive organisms and 21 (53.8%) due to Gram-negative organisms. Of the 42 patients with BSI, 10 (23.8%) had VGI. VGI occurred in 8/18 (44.4%) monomicrobial Gram-positive BSI as compared to 2/21 (9.5%) monomicrobial Gram-negative BSI (p=0.013). The 3-year mortality rate following BSI was 52.3%. Conclusion There was no statistically significant difference in incidence rates of BSI following open surgical repair and endovascular repair. Higher rates of VGI were seen with Gram-positive BSI as compared to Gram-negative BSI. Disclosures Larry M. Baddour, M.D., Boston Scientific: Advisor/Consultant|Botanix Pharmaceuticals: Advisor/Consultant|Roivant Sciences: Advisor/Consultant|UpToDate, Inc.: Royalty payments - authorship duties.

168. Closing Time: A Quasi-experiment Comparing Time to Optimal Therapy using Traditional Identification and Susceptibility Methods, Rapid Identification, or Rapid Identification with Phenotype for Gram-negative Bloodstream Infections

Abstract Background Bloodstream infections (BSI) are a major cause of morbidity and mortality. Compared to traditional microbiology methods, rapid diagnostic testing (RDT) provides prompt organism identification and antibiotic susceptibility results. This leads to earlier opportunities to optimize therapy, which may improve patient outcomes. Methods This was a single center quasi-experimental study of hospitalized adults with Gram-negative (GN) BSI, comparing the management and outcomes across three periods: pre-RDT (traditional identification and susceptibilities with BD Phoenix®, December 2014 to September 2016), RDT1 (Nanosphere Verigene®, December 2016 to December 2019), and RDT2 (Accelerate Pheno™, February 2020 to September 2021). The primary outcome was time to optimal therapy (TTOT). Secondary outcomes included time to oral antibiotic step-down, hospital length of stay (LOS), incidence of Clostridioides difficile infection, and 30-day inpatient mortality. Chi-squared and Kruskal-Wallis tests were used to compare categorical and continuous variables. Significance values for the primary endpoint were adjusted with Bonferroni correction to account for multiple pairwise comparisons. Results Of 296 included patients, 100 were in the pre-RDT, 98 in the RDT1, and 98 in the RDT2 arms. The most common organisms were Escherichia coli (64.5%) and Klebsiella species (20.3%). The TTOT (median, interquartile range) in the pre-RDT, RDT1, and RDT2 groups were 46 (7-61), 30 (0-53), and 12 (0-28) hours (P< 0.001), respectively. The time to oral antibiotic step-down and hospital LOS was similar between groups. There was no difference in C. difficile infection or 30-day inpatient mortality (Table 1). Table 1.Comparison of Outcomes Conclusion In patients with GN BSI the TTOT in RDT1 was shorter when compared to traditional susceptibility methods. Compared to both rapid identification alone and traditional identification and susceptibility methods, RDT2 improved time to optimal therapy. Larger, controlled studies are needed to examine the clinical impact of different RDT methods for Gram negative bloodstream infections. Disclosures Rachel Perry, PharmD, Accelerate Diagnostics: Investigator initiated funding for research presentation; no funding for study design or data analysis Minkey Wungwattana, PharmD, BCIDP, Accelerate Diagnostics: Investigator initiated funding for research presentation; no funding for study design or data analysis.

152. Molecular Epidemiological Analysis of Relapsed Gram-negative Bloodstream Infection Isolates

Abstract Background Gram-negative bacterial bloodstream infections (GNB-BSI) are common and frequently lethal. Many patients experience multiple episodes of GNB-BSI for unclear reasons. This study examines the genetic differences between initial and subsequent isolates of recurrent GNB-BSI. Methods We used a prospective cohort of patients with GNB-BSI at Duke Hospital to identify patients with >1 episode of GNB-BSI due to the same bacterial species. We performed pulsed field gel electrophoresis (PFGE) on paired isolates to determine if the events were Reinfection (paired isolates different) or Relapse (paired isolates genetically identical). We then used whole genome sequencing (WGS) to verify the PFGE findings and explore the genetic similarity between initial and relapsed GNB-BSI isolates. Results Among 1,423 unique patients with GNB-BSI, 60 (4%) experienced recurrent GNB-BSI with the same bacterial species. We performed genotyping (PFGE, followed by WGS) on the paired bacterial isolates from the index and recurrent bloodstream infections for the four most common species in our study population (Escherichia coli, Klebsiella species, Pseudomonas aeruginosa, and Serratia marcescens) (n=48 pairs). We determined that 63% (30/48) of recurrent GNB-BSI episodes were due to relapse and 37% (18/48) were due to reinfection. PFGE correctly identified relapse versus reinfection in 98% (47/48) of cases. The WGS data illustrated the microevolution of relapsed GNB-BSI isolates within patients. When comparing initial to relapsed isolates, we calculated a median of 5 single-nucleotide polymorphisms (SNPs) in relapsed E. coli isolates and 2 SNPs in Klebsiella spp. isolates. Of these SNPs, 37% (E. coli) and 12% (Klebsiella) were non-synonymous changes in coding regions, most commonly genes associated with antimicrobial resistance (AMR), energy metabolism and stress response. Alterations in the AMR profile was common, with 20/30 relapsed isolates demonstrating either loss or acquisition of AMR. Figure 1:Time from initial to recurrent episode of gram-negative bloodstream infection. Relapse (i.e., same bacterial strain noted by green circle) versus reinfection (i.e., different bacterial strain noted by red circle) was determined by pulse field gel electrophoresis followed by WGS. Whole genome sequencing was performed on the initial and recurrent isolate from patients with relapsed GNB-BSI. We identified single nucleotide polymorphisms (SNPs) present in the recurrent isolate, which were not present in the initial isolate. We identified the function of genes containing SNPs in E. coli (n=28 SNPs) and Klebsiella spp. (n=13 SNPs). Synonymous mutations, insertions, deletions, and non-synonymous mutations in hypothetical proteins were excluded. Conclusion Most recurrent GNB-BSI with same species are due to relapse. PFGE has comparable accuracy to WGS to determine reinfection versus relapse. Multiple mutations in genes involved in stress response, AMR and metabolism were identified in relapsed isolates. Disclosures Vance G. Fowler, Jr, MD, MHS, Affinergy: Grant/Research Support|Affinergy: Honoraria|Affinium: Honoraria|Amphliphi Biosciences: Honoraria|ArcBio: Stocks/Bonds|Basilea: Grant/Research Support|Basilea: Honoraria|Bayer: Honoraria|C3J: Honoraria|Cerexa/Forest/Actavis/Allergan: Grant/Research Support|Contrafect: Grant/Research Support|Contrafect: Honoraria|Cubist/Merck: Grant/Research Support|Debiopharm: Grant/Research Support|Deep Blue: Grant/Research Support|Destiny: Honoraria|Genentech: Grant/Research Support|Genentech: Honoraria|Integrated Biotherapeutics: Honoraria|Janssen: Grant/Research Support|Janssen: Honoraria|Karius: Grant/Research Support|Medicines Co.: Honoraria|MedImmune: Grant/Research Support|MedImmune: Honoraria|NIH: Grant/Research Support|Novartis: Grant/Research Support|Novartis: Honoraria|Pfizer: Grant/Research Support|Regeneron: Grant/Research Support|Regeneron: Honoraria|Sepsis diagnostics: Sepsis diagnostics patent pending|UpToDate: Royalties|Valanbio: Stocks/Bonds.

1206: BETA-LACTAM DOSING IN PATIENTS WITH SEPSIS AND AKI: A MULTICENTER OBSERVATIONAL STUDY

Introduction: Beta-lactam antibiotics are the backbone of therapy for critically ill patients with sepsis; however, these patients experience pharmacokinetic changes that alter beta-lactam exposure. Adjusting doses for acute kidney injury during the first 48 hours of admission to the ICU may result in suboptimal drug exposure and subject patients to inadequate therapy. We evaluated the association of beta-lactam antibiotic dose adjustment within the first 48 hours of therapy, on shock-free days in critically ill patients with acute kidney injury and septic shock secondary to gram-negative bloodstream infections. Methods: Multi-center, retrospective, observational cohort study of adult ICU patients with septic shock secondary to gram-negative bloodstream infections who received empiric, in vitro active cefepime, piperacillin-tazobactam, or meropenem. Primary outcome was shock-free days at 28 days which was modeled with linear regression. Secondary outcomes were ventilator-free days at 28 days, ICU mortality, and analysis of outcomes in patients with CrCL < 50ml/min at the time of beta-lactam initiation. Results: A total of 179 patients were included in the final analysis (103 in the adjusted group, 76 in the unadjusted group). Dose adjusting the beta-lactam was not associated with a difference in shock-free days at 28 days (β 2.25, [95% CI -2.04, 6.54], p=0.30. There was no difference in ventilator-free days at 28 days, or overall mortality. Conclusions: In patients with gram negative bacteremia and shock, there was no difference in clinical outcomes in patients who had their beta-lactams renally dose adjusted verses those who did not. Prospective, randomized interventional studies are needed to test if renal dose adjustments impact outcomes in patients with septic shock.

Epidemiology of Escherichia coli as a Critical Pathogen of Bloodstream Infection Patients in Tertiary Referral Hospital

Bloodstream infections (BSI), caused primarily by multidrug-resistant Escherichia coli, are a significant cause of morbidity and mortality worldwide. This study aims to evaluate the epidemiology of E. coli as a critical pathogen in patients with bloodstream infections in a tertiary referral hospital. This is a retrospective study using a descriptive observational research design. This study used a medical record instrument for bloodstream patients in Dr. Soetomo Hospital's inpatient ward with Gram-negative bacteria results of blood cultures in the Clinical Microbiology Laboratory from April 2021 to September 2021. The observed variables include; antimicrobial sensitivity, patient clinical characteristics, demographic data, clinical diagnosis, and clinical outcome. In 6 months, 276 Gram-negative bloodstream infection patients were treated at Dr. Soetomo Hospital. The proportion of E. coli was 17 %. The main characteristics of patients were over 60 years old (28%), and 54% were female. 63% of E. coli were ESBL, and 9% were carbapenem-resistant microorganisms. High antimicrobial resistance was found in quinolones (100%), ampicillin (93%), piperacillin (74%), tetracycline (72%), ceftriaxone (66%), cefotaxime (65%), ceftazidime (60%), cefazolin (65%), and trimethoprim-sulfamethoxazole (65%). The most common potential determinant profile discovered was linked to immunocompromised status due to malignancy. The high number of antimicrobial-resistant bacteria showed the importance of strict infection control and updated epidemiology data as a guide for empirical antimicrobial therapy.

A descriptive pharmacokinetic/pharmacodynamic analysis of continuous infusion ceftazidime-avibactam in a case series of critically ill renal patients treated for documented carbapenem-resistant Gram-negative bloodstream infections and/or ventilator-associated pneumonia

ObjectivesTo describe the pharmacokinetic/pharmacodynamic (PK/PD) behaviour of continuous infusion (CI) ceftazidime-avibactam and the microbiological outcome in a case series of critically ill renal patients treated for documented carbapenem-resistant Gram-negative (CR-GN) bloodstream infections (BSI) and/or ventilator-associated pneumonia (VAP). MethodsCritically ill patients with different degrees of renal function who were treated with CI ceftazidime-avibactam for documented CR-GN infections, and who underwent therapeutic drug monitoring from April 2021 to March 2022, were retrospectively assessed. Ceftazidime and avibactam concentrations were determined at steady-state, and the free fraction (fCss) was calculated. The joint PK/PD target of ceftazidime-avibactam was considered as optimal when both Css/MIC ratio for ceftazidime ≥4 (equivalent to 100%fT>4xMIC) and Css/CT ratio for avibactam >1 (equivalent to 100% fT>CT of 4.0 mg/L) were simultaneously achieved (quasi-optimal if only one of the two was achieved, and suboptimal if neither of the two was achieved). The relationship between ceftazidime-avibactam PK/PD targets and microbiological outcome was assessed. ResultsTen patients with documented CR-GN infections (5 BSIs, 4 VAP, 1 BSI+VAP) were retrieved. The joint PK/PD targets of ceftazidime-avibactam were optimal and quasi-optimal in eight and two cases, respectively. Microbiological failure occurred in two patients (one with VAP, one with BSI+VAP), one of whom developed ceftazidime-avibactam resistance. Both underwent renal replacement therapy, and failed despite attaining optimal joint PK/PD target and receiving fosfomycin co-treatment. ConclusionCI administration may enable optimal joint PK/PD targets of ceftazidime-avibactam to be achieved in most critical renal patients with CR-GN infections, and may help to minimize the risk of microbiological failure.

Quantifying Gram-Negative Resistance to Empiric Treatment After Repeat ExpoSure To AntimicRobial Therapy (RESTART).

Antibiotic exposure is a primary predictor of subsequent antibiotic resistance; however, development of cross-resistance between antibiotic classes is also observed. The impact of changing to a different antibiotic from that of previous exposure is not established. This was a retrospective, single-center cohort study of hospitalized adult patients previously exposed to an antipseudomonal β-lactam (APBL) for at least 48 hours in the 90 days prior to the index infection with a gram-negative bloodstream or respiratory infection. Susceptibility rates to empiric therapy were compared between patients receiving the same (repeat group) versus a different antibiotic from prior exposure (change group). A total of 197 patients were included (n = 94 [repeat group] and n = 103 [change group]). Pathogen susceptibility to empiric therapy was higher in the repeat group compared to the change group (76.6% vs 60.2%; P = .014). After multivariable logistic regression, repeat APBL was associated with an increased likelihood of pathogen susceptibility (adjusted odds ratio, 2.513; P = .012). In contrast, there was no difference in susceptibility rates between the repeat group and the subgroup of change patients who received an empiric APBL (76.6% vs 78.5%; P = .900). Longer APBL exposure duration (P = .012) and chronic kidney disease (P = .002) were associated with higher nonsusceptibility to the exposure APBL. In-hospital mortality was not significantly different between the repeat and change groups (18.1% vs 23.3%; P = .368). The common practice of changing to a different APBL from that of recent exposure may not be warranted.

Impact of Fluoroquinolone Prophylaxis on Neutropenic Fever, Infections, and Antimicrobial Resistance in Newly Diagnosed AML Patients.

Fluoroquinolone prophylaxis is recommended during induction chemotherapy for patients with acute myeloid leukemia (AML) to reduce risk of neutropenic fever and systemic bacterial infections. We evaluated the effectiveness of primary fluoroquinolone prophylaxis in an area with high fluoroquinolone resistance. We performed a retrospective chart review of newly diagnosed adult AML patients who received frontline therapy at Mount Sinai Hospital in New York, NY, between 2012 and 2019. Primary outcome was development of neutropenic fever. Secondary outcomes were development of systemic bacterial infections and infections with multidrug-resistant organisms and Clostridioides difficile. Infectious outcomes were collected through 6 months after therapy initiation. We estimated the effect of fluoroquinolone prophylaxis with a time-dependent Cox proportional hazards model. Of 121 included patients, 87 received antibiotic prophylaxis and 34 did not. There was no difference in baseline characteristics, although the prophylaxis group had longer neutropenia duration (median 30 vs. 23 days, P=.013). The prophylaxis group had a reduced risk of neutropenic fever (hazard ratio 0.59, P=.039). The prophylaxis group had fewer gram-positive (P=.043) and gram-negative (P=.049) bloodstream infections and fewer clinically documented infections during frontline therapy (P=.005) and follow-up (P=.026). There was no difference in incidence of C. difficile or infection with fluoroquinolone-resistant or multidrug-resistant organisms. There was no mortality difference between groups. In an area with high fluoroquinolone resistance, primary fluoroquinolone prophylaxis in newly diagnosed AML patients reduced the risk of neutropenic fever and systemic bacterial infections without increased antimicrobial resistance. Prospective, randomized studies are needed to confirm these observations.

Prognostic Risk Factors of Carbapenem-Resistant Gram-Negative Bacteria Bloodstream Infection in Immunosuppressed Patients: A 7-Year Retrospective Cohort Study.

Carbapenem-resistant Gram-negative bacteria bloodstream infection (CRGNB-BSI) has gradually become a major threat worldwide due to its treatment difficulty and high mortality. This study aimed to determine the risk factors for CRGNB-BSI in immunosuppressed patients. A total of 427 immunosuppressed patients with CRGNB-BSI were retrospectively investigated from 2015 to 2021. Both univariate and multivariate logistic regression analyses were applied to evaluate independent risk factors for CRGNB-BSI. The most common etiology was Klebsiella Pneumoniae (50.59%; 216/427), while the Acinetobacillus baumannii infection was associated with the highest mortality (58.25%) among all etiologies. The 60-day mortality of immunosuppressed patients with CRGNB-BSI was 52.48% (224/427). Procalcitonin (PCT) > 0.5 μg/L (OR = 2.32, 95% CI: 1.28-4.19, P = 0.005) and age > 55 years (OR = 2.06, 95% CI: 1.17-3.64, P = 0.012) were found to be predictors of 60-day mortality of CRGNB-BSI, and tigecycline regimen (OR = 3.20, 95% CI: 1.81-5.67, P < 0.001) was associated with higher mortality. Multivariate analysis also revealed that patients who developed acute kidney injury (AKI) (OR = 2.19, 95% CI: 1.11-4.30, P = 0.023), gastrointestinal bleeding (OR = 3.18, 95% CI: 1.10-9.16, P = 0.032), multiple organ dysfunction syndrome (MODS) (OR = 12.11, 95% CI: 2.61-56.19, P = 0.001), and septic shock (OR = 3.24, 95% CI: 1.77-5.94, P < 0.001) showed worse outcomes. The risk factors were also significantly associated with mortality in the different subgroups. This study demonstrated that PCT > 0.5 μg/L, age > 55 years, and the tigecycline regimen were significantly associated with higher 60-day mortality among immunosuppressed patients with CRGNB- BSI. Patients developing MODS, septic shock, or AKI had worse clinical outcomes. .

The progression of sepsis from physiologic systemic inflammatory response to immune dysregulation due to life-threatening infections

Sepsis was defined in 1991 by the systemic inflammatory response syndrome (SIRS) criteria which consisted mostly of physiologic responses to infection or inflammation (fever, tachycardia, tachypnea, and leukocytosis). These criteria were initially proposed to identify patients with gram-negative bloodstream infection (BSI). However, most patients with BSI are not critically ill at initial presentation using objective clinical scores for acute severity of illness, such as the Pitt bacteremia score (PBS). Lack of specificity and low positive predictive value (PPV) are other pitfalls of the SIRS criteria. Moreover, the implementation of sepsis interventions based on this outdated definition failed to improve patients’ outcomes and in some settings was associated with increased use of broad-spectrum antibiotics and Clostridioides difficile (C. difficile) infection. In 2016, sepsis was redefined as a dysregulatory host response to life-threatening infections using quick sequential organ failure assessment (qSOFA) score. The presence of two of three bedside clinical variables (hypotension, respiratory distress, and altered mental status) that have consistently predicted mortality in patients with infections now constitutes sepsis. The scientific debate continues in the medical literature regarding the performance of the new criteria. Some medical professionals and quality organizations consider these changes to the sepsis definition too revolutionary and are resistant to altering existing medical practice. This narrative review presents infection as a continuum from localized to systemic infection (pre-sepsis) with the potential progression into sepsis and septic shock if appropriate antibiotic therapy and source control are delayed. The review assesses host and microbial factors that may influence the rate of progression through the sepsis cascade and proposes diagnostic considerations and management decisions at each step of the way. It emphasizes the need to utilize precision medicine concepts in selecting empirical antibiotic therapy based on patient-specific risk factors for infections due to resistant bacteria and potential benefits from appropriate therapy across the sepsis spectrum.

Highly versus less bioavailable oral antibiotics in the treatment of gram-negative bloodstream infections: a propensity-matched cohort analysis

ObjectivesIn this study, we evaluated the clinical outcomes associated with the use of highly bioavailable oral antibiotics (fluoroquinolones and trimethoprim-sulfamethoxazole) compared with the less-bioavailable oral antibiotics (β-lactams) in gram-negative bloodstream infections (BSIs). MethodsAmong hospitalized older adult patients in Ontario, Canada, discharged home on oral treatment for gram-negative BSI between 1 January 2017 and 31 December 2019, we used a matched cohort design to compare outcomes among those receiving highly versus less-bioavailable agents; hard-matching 1:1 on sex, BSI pathogen (Escherichia coli vs. non–E. coli), and infection source (urinary vs. non-urinary/unknown source) along with a propensity score, incorporating specific pathogen, patient, and infection characteristics. The primary outcome was the composite of 90-day all-cause mortality, recurrent BSI with the same pathogen (genus and species), and re-admission to any Ontario hospital. ResultsA total of 2012 patients were included in the study (1006 in each bioavailability category). Those who received highly (compared with less) bioavailable antibiotics at discharge had lower rates of the composite outcome (171/1006 [17.0%] vs. 216/1006 [21.5%]), adjusted odds ratio being 0.74 (95% CI, 0.60–0.92). Recurrent BSI at 90 days was the main driver for the composite outcome occurring in 64 (5.4%) and 107 (9.4%) patients of the highly and less-bioavailable groups, respectively (p < 0.001) (adjusted odds ratio, 0.56; 95% CI, 0.40–0.78). DiscussionUse of highly (compared with less) bioavailable antibiotics at discharge was associated with significantly better clinical outcomes among patients with gram-negative BSIs.

Antimicrobial susceptibility to polymyxin B and other comparators against Gram-negative bacteria isolated from bloodstream infections in China: Results from CARVIS-NET program.

ObjectiveTo investigate the bacterial distribution and antimicrobial resistance profile of clinical isolates from Gram-negative bacteria bloodstream infections (GNBSI) in China.MethodsThe clinical bacterial strains isolated from blood culture were collected during April 2019 to December 2021 in 21 member hospitals of China Bloodstream Gram-negative Pathogens Antimicrobial Resistance and Virulence Surveillance Network (CARVIS-NET). Antibiotic susceptibility test was conducted by broth microdilution method recommended by Clinical and Laboratory Standards Institute (CLSI, United States). WHONET 2021 and SPSS 22.0 were used to analyze data.ResultsDuring the study period, 1939 Gram-negative bacteria were collected from 21 hospitals, among which 1,724 (88.9%) were Enterobacteriaceae, 207 (10.7%) were non-fermenting Gram-negative bacteria and 8 (0.4%) were others. The top five bacterial species were Escherichia coli (46.2%), Klebsiella pneumoniae (31.6%), Pseudomonas aeruginosa (4.9%), Acinetobacter baumannii (4.2%) and Enterobacter cloacae (3.0%). For K. pneumoniae, antibiotic resistance was mainly prevalent in hospital-associated bloodstream infections, while for A. baumannii, antibiotic resistance was mainly prevalent in community-associated bloodstream infections. It is worth mentioning that 94.1% of the 1939 Gram-negative isolates were susceptible to polymyxin B. The sensitivity of the strains involved in our investigation to polymyxin B is highly correlated with their sensitivity to colistin.ConclusionThe surveillance results in CARVIS-NET-2021 showed that the main pathogens of GNBSI in China were Enterobacteriaceae, while E. coli was the most common pathogen. The resistance rates of K. pneumonia, P. aeruginosa, A. baumannii, and E. cloacae to multiple antibiotics kept on a high level. In many cases, polymyxin B and colistin has become the last-resort agents to combat bloodstream infections caused by multidrug-resistant (MDR) Gram-negative bacteria.

Antibiotic Stewardship (ABS) im Kontext schwerer Infektionen

HintergrundSchwere Infektionen stellen aufgrund der häufigen Komplikationen und hohen Sterblichkeit eine große klinische Herausforderung dar.Ziel der Arbeit (Fragestellung)Am Beispiel der Sepsis, gramnegativer Blutstrominfektionen und COVID-19 sollen Anwendung und Bedeutung von Antibiotic Stewardship(ABS)-Strategien im Kontext schwerer Infektionen erläutert werden.Material und MethodeEs erfolgen die Zusammenfassung der aktuellen Literatur und Empfehlungen mit Fokus auf klinische ABS-Implikationen bei schweren Infektionen wie Sepsis, gramnegativen Blutstrominfektionen und COVID-19.ErgebnisseDie aktualisierte Sepsis-Leitlinie schlägt ein differenziertes Vorgehen zum Beginn der Antibiotikatherapie bei Patient*innen mit Sepsis, aber ohne Schock vor. Bei unsicherer Diagnose und bei fehlendem Schock kann der Zeitraum bis zur Einleitung der Antibiotikatherapie auf 3 h ausgedehnt werden. In dieser Zeit gilt es, die Differenzialdiagnostik und ein adäquates mikrobiologisches Sampling zu komplettieren, um eine Antibiotikatherapie aufgrund belastbarer Befunde zu initiieren oder alternativ zu verwerfen. Bei unkomplizierten gramnegativen Blutstrominfektionen ist eine 7‑tägige antibiotische Therapie ausreichend. Eine regelhafte Kombinationstherapie bei Blutstrominfektionen mit Pseudomonas aeruginosa ist aufgrund der bisher vorliegenden Daten nicht erforderlich. Bakterielle Koinfektionen bei COVID-19 sind selten. Eine prophylaktische antibiotische Therapie ist daher nicht gerechtfertigt. Bakterielle Sekundärinfektionen (> 48 h nach Hospitalisierung) treten v. a. bei kritisch kranken COVID-19-Patient*innen auf. Bei pulmonalen Ko- oder Sekundärinfektion ist ein therapeutisches Vorgehen entsprechend den Pneumonie-Leitlinien geboten.SchlussfolgerungenTrotz der Schwere und Komplexität der genannten Infektionen gelten die grundlegenden Prinzipien des Antibiotic Stewardship (ABS) im Sinne einer rationalen Antiinfektivaverordnung hinsichtlich Substanz, Dosis und Dauer der Therapie.

Intravenous to oral transition of antibiotics for gram-negative bloodstream infection at a University hospital in Thailand: Clinical outcomes and predictors of treatment failure

BackgroundLimited studies evaluate the outcome of intravenous antibiotics to oral transition in Gram-negative bloodstream infection (GN-BSI), particularly GN-BSI originating outside the urinary tract. This study aimed to evaluate treatment success in patients with GN-BSI treated with either intravenous therapy or intravenous to oral transition and to identify factors associated with treatment failure in those undergoing intravenous to oral transition.MethodsA retrospective cohort study was conducted at King Chulalongkorn Memorial Hospital, Thailand. Patients were included if they were ≥18 years of age, hospitalized in general medical wards with GN-BSI between August 1, 2015, to July 31, 2020, received intravenous antibiotic agents and had a functioning gastrointestinal tract.ResultsOf 955 patients, 545 (57.1%) were in the intravenous to oral transition group. The urinary tract was the most common source of infection (38.8%). Ciprofloxacin was the most prescribed oral antibiotic (53%). Treatment success occurred in 94.3% in the intravenous antibiotic to oral transition group. There was no significant difference in treatment success between the two groups (P = 0.790) with a concordant result after using propensity score matching (P = 0.223). Independent predictors of treatment failure in the intravenous to oral transition group included metastatic solid cancer (aOR = 4.355), HIV infection with CD4 < 200 cells/mm3 (aOR = 8.452), qSOFA score ≥ 2 (aOR = 2.545), multidrug-resistant infection (aOR = 2.849), and respiratory tract infection (aOR = 8.447). Hospital length of stay in the intravenous to oral transition group was shorter than in the intravenous group (P < 0.001).ConclusionsIntravenous to oral transition may be a practical approach in GN-BSI. Patients with Gram-negative bacteremia who have HIV infection with CD4 < 200 cells/mm3, multidrug-resistant infections, and respiratory tract sources of infection may not be ideal candidates for this approach. Future research is needed from a randomized controlled trial.

Association of Follow-up Blood Cultures With Mortality in Patients With Gram-Negative Bloodstream Infections

Obtaining follow-up blood cultures (FUBCs) in patients with Staphylococcus aureus bloodstream infection (BSI) is standard practice, although its utility in patients with gram-negative bacterial BSI (GN-BSI) is unclear. To examine whether obtaining FUBCs is associated with decreased mortality (key question [KQ] 1) and whether positive vs negative FUBCs are associated with increased mortality (KQ2). MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Web of Science, and gray literature were searched from inception to March 11, 2022. Two investigators used predefined eligibility criteria to independently screen titles, abstracts, and relevant full texts. Randomized clinical trials or observational studies that matched or statistically adjusted for differences in, at minimum, level of acute illness between patients in the intervention (eg, FUBCs obtained) and control (eg, FUBCs not obtained) groups were included in primary analyses. Articles published in languages other than English were excluded. Data abstraction and quality assessments were performed by one investigator and verified by a second investigator. Risk of bias was assessed with the Newcastle-Ottawa Scale. Effect sizes were pooled using random-effects models. The study followed the Meta-analysis of Observational Studies in Epidemiology (MOOSE) reporting guideline. Mortality before hospital discharge or up to 30 days from the index blood culture. From 3495 studies, 15 were included (all nonrandomized). In the 5 studies (n = 4378 patients) that met criteria for the KQ1 primary analysis, obtaining FUBCs was associated with decreased mortality (hazard ratio, 0.56; 95% CI, 0.45-0.71). For KQ2, 2 studies met criteria for the primary analysis (ie, matched or statistically adjusted for differences in patients with positive vs negative FUBCs), so an exploratory meta-analysis of all 9 studies that investigated KQ2 (n = 3243 patients) was performed. Positive FUBCs were associated with increased mortality relative to negative blood cultures (odds ratio, 2.27; 95% CI, 1.54-3.34). Limitations of the literature included a lack of randomized studies and few patient subgroup analyses. In this systematic review and meta-analysis, obtaining FUBCs in patients with GN-BSI was associated with decreased mortality. The benefit of FUBCs may stem from identification of patients with positive FUBCs, which was a poor prognostic marker.

Impact of a Multistep Bundles Intervention in the Management and Outcome of Gram-Negative Bloodstream Infections: A Single-Center "Proof-of-Concept" Study.

BackgroundThis is a “proof-of-concept” study aiming to evaluate the impact of a multistep bundles intervention in the management and outcomes of patients with gram-negative bloodstream infections (GN-BSIs).MethodsThis was a single-center, quasi-experimental design study. In the pre-phase (January 2019 to May 2020), patients were retrospectively enrolled. During the post-phase (June 2020 to September 2021), all patients were prospectively enrolled in a nonmandatory 3-step bundles intervention arm including (i) step 1: imaging to detect deep foci of infection, follow-up blood cultures and procalcitonin monitoring; (ii) step 2: early targeted antibiotic treatment and surgical source control; (iii) step 3: discontinuation of antibiotics within 7–10 days in case of uncomplicated BSI. Patients were followed up to 28 days from BSI onset. The primary outcome was 28-day mortality.ResultsA total of 271 patients were enrolled: 127 and 144 in the pre- vs post-phase, respectively. Full application of step 1 (67% vs 42%; P < .001), step 2 (83% vs 72%; P = .031), and step 3 (54% vs 2%; P < .001) increased in the post-phase. Overall, the intervention reduced 28-day mortality (22% vs 35%, respectively; P = .016) and the median duration of total (11 vs 15 days; P < .001) and targeted (8 vs 12 days; P = .001) antibiotic therapy. Finally, the multivariate Cox regression confirmed the independent protective effect of adherence to step 1 (adjusted hazard ratio [aHR], 0.36; 95% CI, 0.20–0.63) and step 2 (aHR, 0.48; 95% CI, 0.29–0.81) on risk of 28-day mortality.ConclusionsClinical management and outcomes of patients with GN-BSIs may be improved by providing a pre-established multistep bundles intervention.