scholarly journals 2251. Estimating the Need for Novel Gram-Negative Active Antibiotics in US Hospitals

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S769-S770 ◽  
Author(s):  
Jeffrey R Strich ◽  
Sarah Warner ◽  
Yi Ling Lai ◽  
Cumhur Y Demirkale ◽  
John H Powers ◽  
...  
Keyword(s):  
Day Treatment ◽  
Treatment Options ◽  
Unmet Need ◽  
Bloodstream Infections ◽  
Polymyxin B ◽  
Teaching Hospitals ◽  
Gram Negative ◽  
Urinary Infections ◽  
Days Of Therapy ◽  
Recursive Partition

Abstract Background Assessing the unmet need for novel antibiotics could inform appropriate utilization, enrollment in trials and ensure balance in aligning incentives and investments in therapeutic development. Methods The Cerner Healthfacts electronic health record repository was queried to identify inpatient treatment opportunities for Gram-negative active agents (GNAA) displaying either difficult-to-treat resistance (DTR; resistance to all β-lactams including carbapenems and fluoroquinolones) or extended-spectrum cephalosporin resistance (ECR). The former was quantified by aggregating episodes of confirmed DTR infection (i.e., DTR strain isolated and concomitant antibiotic(s) received) or suspected (i.e., 1–2 days of empiric colistin/polymyxin-B or aminoglycosides and no DTR pathogen isolated). Aggregate days of therapy (DOT) were reported as a range, multiplying episodes by site-specific or uniform 14-day treatment durations, respectively. Recursive partition and cluster analyses were performed for hospital characteristics and contributions of outbreaks to DTR treatment opportunities, respectively. Results Between 2009 and 2015, across 2,996,271 encounters, 1,352 episodes of potential targeted treatment were identified, which combined with empiric treatment episodes, represent 39–138 DOT/10,000 encounters for a DTR-GNAA. Similarly, 9,535 episodes of potential targeted therapy for an ECR-GNAA were identified (representing 211-466 DOT/10,000 encounters). The most common candidate site and pathogens for DTR-GNAA were lower respiratory and A. baumannii and P. aeruginosa respectively; DTR bloodstream infections displayed the highest crude mortality at 45%. Enterobacteriaceae urinary infections dominated the ECR group. Teaching hospitals with ≥100 beds were the most likely to encounter a DTR infection; potential outbreaks contributed to 10.6% of DTR treatment opportunities. Conclusion The candidate population for new antibacterials directed against highly resistant GN infections with limited treatment options is small but critical, indicating a role for non-revenue-based strategies to develop more effective antibiotics, as well as mechanisms to support trials that address real-world unmet needs. Disclosures All authors: No reported disclosures.

scholarly journals Implementation of a Rapid Phenotypic Susceptibility Platform for Gram-Negative Bloodstream Infections With Paired Antimicrobial Stewardship Intervention: Is the Juice Worth the Squeeze?

2021 ◽  
Author(s):  
Evan D Robinson ◽  
Allison M Stilwell ◽  
April E Attai ◽  
Lindsay E Donohue ◽  
Megan D Shah ◽  
...  
Keyword(s):  
Median Time ◽  
Antimicrobial Stewardship ◽  
A Priori ◽  
Bloodstream Infections ◽  
Standard Of Care ◽  
Post Intervention ◽  
Gram Negative ◽  
Stewardship Program ◽  
Days Of Therapy ◽  
The Impact

Abstract Background Implementation of the Accelerate PhenoTM Gram-negative platform (RDT) paired with antimicrobial stewardship program (ASP) intervention projects to improve time to institutional-preferred antimicrobial therapy (IPT) for Gram-negative bacilli (GNB) bloodstream infections (BSIs). However, few data describe the impact of discrepant RDT results from standard of care (SOC) methods on antimicrobial prescribing. Methods A single-center, pre-/post-intervention study of consecutive, nonduplicate blood cultures for adult inpatients with GNB BSI following combined RDT + ASP intervention was performed. The primary outcome was time to IPT. An a priori definition of IPT was utilized to limit bias and to allow for an assessment of the impact of discrepant RDT results with the SOC reference standard. Results Five hundred fourteen patients (PRE 264; POST 250) were included. Median time to antimicrobial susceptibility testing (AST) results decreased 29.4 hours (P < .001) post-intervention, and median time to IPT was reduced by 21.2 hours (P < .001). Utilization (days of therapy [DOTs]/1000 days present) of broad-spectrum agents decreased (PRE 655.2 vs POST 585.8; P = .043) and narrow-spectrum beta-lactams increased (69.1 vs 141.7; P < .001). Discrepant results occurred in 69/250 (28%) post-intervention episodes, resulting in incorrect ASP recommendations in 10/69 (14%). No differences in clinical outcomes were observed. Conclusions While implementation of a phenotypic RDT + ASP can improve time to IPT, close coordination with Clinical Microbiology and continued ASP follow up are needed to optimize therapy. Although uncommon, the potential for erroneous ASP recommendations to de-escalate to inactive therapy following RDT results warrants further investigation.

scholarly journals 149. Short vs. Long Course of Antibiotics for Uncomplicated Gram-Negative Bacteremia

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S101-S102
Author(s):  
James Go ◽  
Sarah Cotner ◽  
Donna R Burgess ◽  
David Burgess ◽  
Katie Wallace ◽  
...  
Keyword(s):  
Bloodstream Infections ◽  
Data Bank ◽  
The United States ◽  
Duration Of Treatment ◽  
Gram Negative ◽  
Short Course ◽  
Days Of Therapy ◽  
Significant Difference ◽  
Gram Negative Bacteremia ◽  
Long Course

Abstract Background Bloodstream infections (BSI) continue to be a major cause of morbidity and mortality in the United States; thus, the correct choice of antibiotics for an appropriate duration is imperative. However, there are limited recommendations on adequate duration of treatment of bacteremia caused by Gram-negative organisms. Therefore, treating an infection for an adequate duration to prevent complications while preventing adverse effects from unnecessary antibiotic exposure remains a balancing act. This study aims to compare clinical outcomes between patients treated with a short (7–10 days) vs. long (11–20 days) course of antibiotics for uncomplicated gram-negative bacteremia. Methods This single-center retrospective cohort study evaluated adult patients admitted between January 2007 to October 2018 with a blood culture positive for gram-negative bacteria. Data came from the University of Kentucky Microbiological Laboratory and Center for Clinical and Translational Science (CCTS) Data Bank. Patients included must have received appropriate antibiotics for at least 7 days. Appropriate antibiotics were defined as those to which the organism is susceptible with day one of therapy as the first day of appropriate antibiotic therapy. Patients were excluded if they were treated with aminoglycoside monotherapy, had polymicrobial bacteremia, or if treated for longer than 20 days of therapy. Results A total of 466 patients were identified (208 in the short-course group and 258 in the long course group). Gender and ethnicity were similar across both groups. The patients in the long course group had more ICU admissions compared with the short-course group (52.7% vs. 43.3%, P = 0.0426), tended to be older (57 ± 16.7 vs. 53 ± 15.9 years, P = 0.0119), had a higher Charlson Comorbidity Index (5.7 ± 3.6 vs. 4.6 ± 3.6, P = 0.0009) and remained admitted to the hospital longer (23.2 ± 25.6 vs. 15.8 ± 17.5 days, P = 0.0002). However, patients treated with a long course had no difference in 30-day mortality compared with the short-course group (3.9% vs. 3.4%, P = 0.7701). Conclusion Patients with an uncomplicated gram-negative BSI treated with a short course (7–10 days) of antibiotics do not appear to have a significant difference in 30-day mortality compared with those patients treated with a long course (11–20 days). Disclosures All authors: No reported disclosures.

scholarly journals Treatment of Bloodstream Infections Due to Gram-Negative Bacteria with Difficult-to-Treat Resistance

Antibiotics ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 632 ◽  
Author(s):  
Matteo Bassetti ◽  
Antonio Vena ◽  
Chiara Sepulcri ◽  
Daniele Roberto Giacobbe ◽  
Maddalena Peghin
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Antibiotic Resistance ◽  
Treatment Options ◽  
Bloodstream Infections ◽  
Gram Negative Bacteria ◽  
Beta Lactamase ◽  
Gram Negative ◽  
Extended Spectrum Beta Lactamase ◽  
Carbapenem Resistant ◽  
Rising Incidence

The rising incidence of bloodstream infections (BSI) due to Gram-negative bacteria (GNB) with difficult-to-treat resistance (DTR) has been recognized as a global emergency. The aim of this review is to provide a comprehensive assessment of the mechanisms of antibiotic resistance, epidemiology and treatment options for BSI caused by GNB with DTR, namely extended-spectrum Beta-lactamase-producing Enterobacteriales; carbapenem-resistant Enterobacteriales; DTR Pseudomonas aeruginosa; and DTR Acinetobacter baumannii.

scholarly journals 1274. Activity of Ceftolozane/Tazobactam, Imipenem/Relebactam, and Comparators Against Pseudomonas aeruginosa Isolates from Patients with Bloodstream and Other Infection Types—SMART United States/Canada 2018-2019

2021 ◽  
Vol 8 (Supplement_1) ◽  
pp. S725-S726
Author(s):  
Sibylle Lob ◽  
Meredith Hackel ◽  
C Andrew DeRyke ◽  
Kelly Harris ◽  
Katherine Young ◽  
...  
Keyword(s):  
Treatment Options ◽  
Bloodstream Infections ◽  
Independent Contractor ◽  
Gram Negative ◽  
The Us ◽  
Gram Negative Organisms ◽  
Infection Types ◽  
Tract Infections ◽  
Hospital Acquired ◽  
Intraabdominal Infections

Abstract Background Ceftolozane/tazobactam (C/T), an antipseudomonal cephalosporin combined with a β-lactamase inhibitor, was approved for treatment of complicated urinary tract (cUTI) and intraabdominal infections (cIAI), and hospital-acquired/ventilator-associated bacterial pneumonia (HAP/VAP). Imipenem/relebactam (IMI/REL) is a combination of imipenem/cilastatin with relebactam, an inhibitor of class A and C β-lactamases. IMI/REL was approved for HAP/VAP and for infections due to aerobic gram-negative organisms in adults with limited treatment options (e.g., cUTI, cIAI). We compared the activity of C/T and IMI/REL against P. aeruginosa from bloodstream infections (BSI) to those from other infection types. Methods As part of the SMART program, 24 hospitals in the US and 8 in Canada each collected up to 250 consecutive gram-negative isolates per year in 2018-2019 from patients with BSI, lower respiratory tract infections (LRTI), IAI, and UTI. A total of 2351 Pa isolates were collected. MICs were determined using CLSI broth microdilution and breakpoints. Results Pa isolates from BSI tended to show higher susceptibility than IAI, UTI, and especially LRTI isolates (Table). Susceptibility to the tested comparator β-lactams was 11-12 percentage points lower among LRTI than BSI isolates, while C/T and IMI/REL susceptibility was only 2-5% lower. Even among BSI isolates, the comparator β-lactams were active against only 75-88% of isolates, while C/T and IMI/REL were active against >95%. Only amikacin showed higher activity. Analyzing coverage by either C/T or IMI/REL, 98.7% of Pa isolates from BSI were susceptible to one or both agents. C/T and IMI/REL maintained activity against 89% and 69% of meropenem-nonsusceptible (MEM-NS) Pa isolates from BSI (n=36), respectively, and 87% and 76% of piperacillin/tazobactam (P/T)-NS Pa (n=38). Results Table Conclusion Even among BSI isolates, which were generally more susceptible than those from other infection types, Pa susceptibility to commonly used β-lactams like MEM and P/T was < 90%, 7-23% lower than C/T and IMI/REL. Given the desirability of β-lactams among clinicians and the >98% coverage by either C/T or IMI/REL of Pa isolates from BSI, both agents represent important options in the treatment of patients with BSI. Disclosures Sibylle Lob, PhD, IHMA (Employee)Pfizer, Inc. (Independent Contractor) Meredith Hackel, PhD MPH, IHMA (Employee)Pfizer, Inc. (Independent Contractor) C. Andrew DeRyke, PharmD, Merck & Co., Inc. (Employee, Shareholder) Kelly Harris, PharmD, BCPS, Merck & Co. Inc (Employee) Katherine Young, MS, Merck (Employee) Mary Motyl, PhD, Merck & Co., Inc. (Employee, Shareholder) Daniel F. Sahm, PhD, IHMA (Employee)Pfizer, Inc. (Independent Contractor)

scholarly journals Evaluation of Intraventricular/Intrathecal Antimicrobial Therapy in the Treatment of Nosocomial Meningitis Caused by Multidrug-Resistant Gram-Negative Bacteria after Central Nervous System Surgery

2021 ◽  
Vol 2021 ◽  
pp. 1-6
Author(s):  
Nagehan Didem Sari ◽  
Sevim Baltali ◽  
Istemi Serin ◽  
Veysel Antar
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Clinical Success ◽  
Day Treatment ◽  
Treatment Options ◽  
Multidrug Resistant ◽  
Gram Negative Bacteria ◽  
Gram Negative ◽  
Mortality And Morbidity ◽  
Postoperative Meningitis

Introduction. Postoperative meningitis (POM) is an infection with high mortality and morbidity following central nervous system surgery due to trauma or tumor. Intrathecal/intraventricular (IT/IVT) antibiotic administrations have been considered as the last treatment options for multidrug-resistance (MDR) Gram-negative bacteria that do not respond to intravenous (IV) regimens. IT/IVT can bypass the blood-brain barrier, obtain a more effective antibiotic concentration in CSF, and reduce systemic side effects. We aimed to determine the characteristics of postoperative patients who were diagnosed with MDR POM during follow-up in our intensive care unit (ICU). Material and Methods. In this study, POM patients who were followed up in ICU after the central nervous system intervention between January 2016 and December 2019 and whose MDR Gram-negative bacteria were isolated from CSF were evaluated. As soon as the patients were diagnosed with POM, a catheter was inserted and treatment was started. Results. Microbiological eradication was achieved in 3 ± 0.8 days with 30 mg/day amikacin treatment in POM due to K. pneumoniae and 3.7 ± 1.95 days with colistin sodium 10 mg/day treatment in POM due to A. baumannii via IT/IVT catheter. IT/IVT treatment was utilized for a median of 10 days and continued until the defined cure criteria were achieved. While cure was achieved in 6 of 14 POM cases, 8 of them were exitus. Discussion and Conclusion. To avoid the severe consequences of postoperative meningitis, acting fast and adding IT/IVT methods to parenteral administration routes by considering the distribution of MDR microorganisms within the hospital while planning effective treatment will increase the clinical success.

scholarly journals 192. Augmenting Utility of Rapid Diagnostic Testing in Treatment of Gram-Negative Bacteremia with Stewardship Intervention

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S115-S116
Author(s):  
Jessica Gerges ◽  
Karan Raja ◽  
Mitesh Patel ◽  
Ruben Patel ◽  
Brandon Chen ◽  
...  
Keyword(s):  
Treatment Failure ◽  
Diagnostic Testing ◽  
Intervention Group ◽  
Bloodstream Infections ◽  
Resistance Marker ◽  
Post Intervention ◽  
Predictive Values ◽  
Gram Negative ◽  
E Coli ◽  
Days Of Therapy

Abstract Background Rapid diagnostic tests (RDT) can identify pathogens in bloodstream infections (BSI) in less than 24 hours. Our institution utilizes an RDT for blood cultures (BCx) that can detect various organisms and resistance determinants. A retrospective evaluation conducted in our institution calculated the negative predictive values (NPV) of various Gram-negative pathogens and susceptibility to target antimicrobials in the absence of detected resistance markers. Resultant NPV >90% for E. coli and K. pneumoniae to ceftriaxone support use of RDT with stewardship intervention for more rapid de-escalation of antimicrobial therapy in patients with resistance marker-negative BSI. Methods In our facility, all positive BCx are processed through RDT. In the post-intervention group, pharmacists monitored RDT results and provided recommendations. Our IRB-approved, prospective study assessed time to antimicrobial de-escalation in treatment of resistance marker-negative E. coli and K. pneumoniae BSI before (January 1 to December 31, 2018) and after Stewardship intervention (January 1 to March 31, 2019). Secondary outcomes included days of therapy (DOT) of target narrow-spectrum β-lactams, carbapenems, and non-carbapenem anti-pseudomonal (NCAP) β-lactams, length of stay (LOS), and treatment failure. Data were analyzed using the Fisher exact or Chi-square and t-test for categorical and continuous data, respectively. Results Of the 12,893 evaluated RDT results in the pre-intervention group and 2,238 post intervention, 41 and 12 patients met inclusion criteria, respectively. Baseline characteristics were similar in both groups. Time to de-escalation to a target agent was decreased by 24 hours after stewardship intervention (50 v 74.6 hours) (P = 0.14). There were no statistically significant differences in DOTs for target agents (5.19 v 5.25 DOT; P = 0.48), carbapenems (1.29 v 1.08 DOT; P = 0.41), or NCAP β-lactams (1.73 v 2.33; P = 0.25). Treatment failure (2 in each group; P = 0.17) and LOS (10.9 v 11.9 days; P = 0.4) were similar between groups. Protocol compliance and intervention acceptance rate was approximately 60%. Conclusion Appreciation of NPVs and utilization of stewardship intervention allowed for early de-escalation of empiric therapy in patients with resistance marker-negative E. coli and K. pneumoniae bacteremia. Disclosures All authors: No reported disclosures.

scholarly journals Clinical Outcomes Associated with Polymyxin B Dose in Patients with Bloodstream Infections Due to Carbapenem-Resistant Gram-Negative Rods

2015 ◽  
Vol 59 (11) ◽  
pp. 7000-7006 ◽  
Author(s):  
Brian C. Nelson ◽  
Daniel P. Eiras ◽  
Angela Gomez-Simmonds ◽  
Angela S. Loo ◽  
Michael J. Satlin ◽  
...  
Keyword(s):  
Renal Impairment ◽  
Clinical Outcomes ◽  
Clinical Cure ◽  
Multivariable Analysis ◽  
Kidney Injury ◽  
Bloodstream Infections ◽  
Total Body Weight ◽  
Polymyxin B ◽  
Gram Negative ◽  
Carbapenem Resistant

ABSTRACTThere is significant variation in the use of polymyxin B (PMB), and optimal dosing has not been defined. The purpose of this retrospective study was to evaluate the relationship between PMB dose and clinical outcomes. We included patients with bloodstream infections (BSIs) due to carbapenem-resistant Gram-negative rods who received ≥48 h of intravenous PMB. The objective was to evaluate the association between PMB dose and 30-day mortality, clinical cure at day 7, and development of acute kidney injury (AKI). A total of 151 BSIs were included. The overall 30-day mortality was 37.8% (54 of 151), and the median PMB dosage was 1.3 mg/kg (of total body weight)/day. Receipt of PMB dosages of <1.3 mg/kg/day was significantly associated with 30-day mortality (46.5% versus 26.3%;P= 0.02), and this association persisted in multivariable analysis (odds ratio [OR] = 1.58; 95% confidence interval [CI] = 1.05 to 1.81;P= 0.04). Eighty-two percent of patients who received PMB dosages of <1.3 mg/kg/day had baseline renal impairment. Clinical cure at day 7 was not significantly different between dosing groups. AKI was more common in patients receiving PMB dosages of ≥250 mg/day (66.7% versus 32.0%;P= 0.03), and this association persisted in multivariable analysis (OR = 4.32; 95% CI = 1.15 to 16.25;P= 0.03). PMB dosages of <1.3 mg/kg/day were administered primarily to patients with renal impairment, and this dosing was independently associated with 30-day mortality. However, dosages of ≥250 mg/day were independently associated with AKI. These data support the use of PMB without dose reduction in the setting of renal impairment.

US Food and Drug Administration (FDA): Benefit-Risk Considerations for Cefiderocol (Fetroja®)

2020 ◽  
Author(s):  
Shabnam Naseer ◽  
Edward A Weinstein ◽  
Daniel B Rubin ◽  
Kalavati Suvarna ◽  
Xiaohui Wei ◽  
...  
Keyword(s):  
Drug Administration ◽  
Nosocomial Pneumonia ◽  
Food And Drug Administration ◽  
Treatment Options ◽  
Bloodstream Infections ◽  
Gram Negative Bacteria ◽  
Open Label ◽  
Double Blind ◽  
Gram Negative ◽  
Tract Infections

Abstract In November 2019, the Food and Drug Administration (FDA) approved cefiderocol for the treatment of complicated urinary tract infections (cUTI) including pyelonephritis caused by susceptible gram-negative bacteria in adults with limited to no alternative treatment options based on a randomized, double-blind, noninferiority cUTI trial (APEKS-cUTI). In a randomized, open-label trial (CREDIBLE-CR) in patients with cUTI, nosocomial pneumonia, bloodstream infections, or sepsis due to carbapenem-resistant gram-negative bacteria, an increase in all-cause mortality was observed in patients treated with cefiderocol as compared to best available therapy. The cause of the increased mortality was not established, but some deaths were attributed to treatment failure. Preliminary data from a randomized, double-blind trial (APEKS-NP) in patients with nosocomial pneumonia due to carbapenem-susceptible gram-negative bacteria showed a similar rate of mortality as compared to meropenem. We describe the uncertainties and challenges in the interpretation of the CREDIBLE-CR trial and some benefit-risk considerations for the use of cefiderocol in clinical practice. Clinical Trials Registration NCT02714595.

scholarly journals Impact of an Antimicrobial Stewardship Intervention on Within- and Between-Patient Daptomycin Resistance Evolution in Vancomycin-Resistant Enterococcus faecium

2019 ◽  
Vol 63 (4) ◽  
Author(s):  
Clare L. Kinnear ◽  
Twisha S. Patel ◽  
Carol L. Young ◽  
Vincent Marshall ◽  
Duane W. Newton ◽  
...  
Keyword(s):  
Antimicrobial Stewardship ◽  
Enterococcus Faecium ◽  
Treatment Options ◽  
Bloodstream Infections ◽  
Prescribing Patterns ◽  
Interrupted Time Series Analysis ◽  
Content Type ◽  
Days Of Therapy ◽  
Vancomycin Resistant ◽  
The Impact

ABSTRACT Vancomycin-resistant Enterococcus (VRE) is a leading cause of hospital-acquired infection, with limited treatment options. Resistance to one of the few remaining drugs, daptomycin, is a growing clinical problem and has previously been described in this hospital. In response to increasing resistance, an antimicrobial stewardship intervention was implemented to reduce hospital-wide use of daptomycin. To assess the impact of the intervention, daptomycin prescribing patterns and clinically reported culture results from vancomycin-resistant Enterococcus faecium (VREfm) bloodstream infections (BSIs) from 2011 through 2017 were retrospectively extracted and the impact of the intervention was estimated using interrupted time series analysis (ITS). We corrected for a change in MIC determination methodology by retesting 262 isolates using Etest and broth microdilution. Hospital-wide and within-patient resistance patterns of corrected daptomycin MICs are reported. Our data show that daptomycin prescriptions decreased from an average of 287 days of therapy/month preintervention to 151 days of therapy/month postintervention. Concurrently, the proportion of patients experiencing an increase in daptomycin MIC during an infection declined from 14.6% (7/48 patients) in 2014 to 1.9% (1/54 patients) in 2017. Hospital-wide resistance to daptomycin also decreased in the postintervention period, but this was not maintained. This study shows that an antimicrobial stewardship-guided intervention reduced daptomycin use and improved individual level outcomes but had only transient impact on the hospital-level trend.

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