Carbapenem Therapy Research Articles

1809. Treatment Outcomes in Piperacillin-tazobactam Non-susceptible (TZP-NS)/Ceftriaxone Susceptible (CRO-S) Infections

Abstract Background Piperacillin-tazobactam-non-susceptible/ceftriaxone-susceptible (TZP-NS/CRO-S) Escherichia coli (Ec) and Klebsiella pneumoniae (Kp) phenotypes are hypothesized to be due to hyperproduction of TEM-1/2 and SHV-1 penicillinases. Limited available literature evaluating treatment outcomes in patients with TZP-NS/CRO-S infections may lead to unnecessary carbapenem use. Methods This was a retrospective study of non-critically ill adults hospitalized between 2013-2021, and treated for at least 48 hours for TZP-NS/CRO-S Ec or Kp infections. Patients with concomitant multi-drug resistant gram-negative infections were excluded. The primary composite endpoint included the need for escalation to intensive care unit (ICU), infection- or treatment-related readmission, mortality, and infection recurrence. Outcomes were compared between groups who received carbapenem (CG) vs carbapenem-sparing agents (CSG) as targeted therapy. Results Out of 1062 patients screened, 200 were included, with 51 in the CG and 149 in the CSG. Baseline characteristics, including Charlson Comorbidity Index (6 [IQR 3-10] vs 6 [4-9], p=0.64), were similar between groups, except for more immunocompromised patients in the CG (29% vs 11%, p=0.001). The most common infection sources were urinary (31% vs 57%, p=0.002), bloodstream (BSI) (18% vs 17%, p=0.887) and intra-abdominal (IAI) (20% vs 8%, p=0.023). Eighty-eight percent of the CG received meropenem, while the most common targeted therapy in the CSG was ceftriaxone (58%) followed by cefepime (24%). The primary composite endpoint was numerically higher in the CG (27% vs 17%, p=0.123), with no differences based on infection type (urine 25% vs 18%, p=0.495; BSI 33% vs 16%, p=0.348; IAI 40% vs 33%, p=1). More patients in the CSG were switched to oral therapy (15 [29%] vs 100 [67%], p< 0.001), with numerically 2 days shorter time to oral switch (6 [3-9] vs 4 [3-7] days, p=0.196). Out of those switched to oral therapy, most had a urinary source (8/15 [53%] vs 59/100 [59%]). Conclusion Our study did not find better clinical outcomes with carbapenem therapy for TZP-NS/CRO-S infections, thus CS agents may be considered to spare carbapenems in non-critically ill patients. Further studies are warranted to compare these outcomes in the critically ill. Disclosures All Authors: No reported disclosures.

Campylobacter Fetus Meningitis and Bacteremia in a Well-Controlled HIV Patient

We present a case of Campylobacter fetus meningitis and bacteremia in an HIV patient. He was initially admitted due to concern for meningitis. After brief observation, the patient was discharged—once infectious etiologies had been ruled out. Soon after discharge, he was readmitted due to late culture growth demonstrating Campylobacter fetus in his cerebrospinal fluid (CSF) and blood. Our patient declined initially despite being placed on an appropriate, susceptibility-proven antibiotic regimen. He was later treated successfully with carbapenem therapy. This outcome is in alignment with the few previous cases of treatment failure (despite an appropriate antibiotic regimen) and supports the argument that most patients respond best to a carbapenem regimen.

In vivo acquisition of blaKPC-2 with low biological cost in blaAFM-1-harboring ST463 hypervirulent Pseudomonas aeruginosa from a patient with hematologic malignancy

Klebsiella pneumoniae carbapenemase (KPC)-producing sequence type (ST) 463 Pseudomonas aeruginosa are increasingly prevalent in China. This study aims to investigate how blaKPC-2 is acquired in ST463 P. aeruginosa during antimicrobial therapy. Two extensively drug-resistant P. aeruginosa strains, B1122 and U1121, were respectively isolated from blood and urine of a patient during carbapenem therapy. Whole-genome sequences were obtained, and minimum inhibitory concentrations (MICs) were determined. Plasmid transferability and stability were examined. Bacterial growth kinetics, biofilm formation, and virulence level was assessed. U1121 and B1122 were only susceptible to amikacin and intermediately susceptible to colistin. They were isogenic ST463 P. aeruginosa strains and shared the same chromosome-encoded resistance genes, including blaAFM-1. This is the first report of chromosomal integration of blaAFM-1 in P. aeruginosa mediated by ISCR29. pU1121 and pB1122, which shared almost identical backbone, were the sole plasmids in U1121 and B1122, respectively, differing by an insertion region containing two copies of blaKPC-2 genes observed on pU1121. Sequence alignment revealed that pU1121 might evolve in vivo from pB1122 via IS26-mediated continuous genetic rearrangement in response to selective challenge from carbapenem. pU1121 was not self-transmissible and could be stably maintained in the host in the absence of antibiotic. Both U1121 and B1122 were hypervirulent, and no differences on virulence were recorded between them. However, U1121 exhibited significant impaired growth in comparison with B1122. ST463 P. aeruginosa can capture blaKPC-2 through horizontal transfer of insertion sequence under antibiotic selection pressure, which does decrease the fitness but does not impair the virulence of the ancestor.

In Vitro Activity of Single and Combined Antibiotics against Carbapenem Resistant Enterobacteriaceae Clinical Isolates in Relation to their Resistance Genes

Background: Mortality due to infection with carbapenem-resistant Enterobacteriaceae (CRE) is reported globally and carbapenemase production is the main mechanism of resistance in these isolates. The detection and treatment of carbapenemase-producing Enterobacteriaceae (CPE) is a major challenge in health care facilities.
 Objectives: The aim of the current study was to evaluate the in-vitro effect of different single and combined antibiotic agents against CRE clinical isolates.
 Methodology: Fifty CRE isolates were detected using disk diffusion test as a screening test. Species identification and antibiotic susceptibility testing was done using Vitek 2 system. Carbapenemase enzyme production was confirmed by Carba NP test. Multiplex PCR was done to detect carbapenem resistance genes. Antibiotics were tested in the form of single agents (colistin and tigecycline) and combined (tigecycline/ colistin, doripenem/ colistin and dual carbapenem therapy (ertapenem and doripenem) against CRE isolates using E-test method.
 Results: Most of the CRE isolates were K. pneumoniae, 68%, followed by E. coli, 22%, S. marcescens, 4%, E. cloacae, 4% and C. freundii, 2%. CPE was confirmed in 46 isolates by multiplex PCR; blaNDM-like was the main carbapenem resistance gene in (84%) of the isolates, followed by blaOXA-48-like (6%) and blaKPC-like (2%). Carba NP test detected 90% of CPE isolates. Single use of colistin and tigecycline showed 100% sensitivity against all tested CRE isolates except in blaNDM-like (83%). Combination of colistin/tigecycline showed synergetic activity in 18% of CRE that was correlated to their carbapenemase R genes showing a significant increase in blaOXA-48-like and blaKPC-like positive isolates (100%) compared to blaNDM-like (7%). Other combinations showed indifferent effect whereas antagonism was not detected in any of the tested combinations.
 Conclusions: blaNDM-like is the main carbapenemase-producing gene detected among our CPE isolates followed by blaOXA-48-like. Colistin and tigecycline are still effective when used as single agents, and may offer effective treatment options when used in combination for CRE infections. Characterization of carbapenemases is crucial in determining treatment options. There is urgent demand for the development of novel therapeutic agents against NDM-producing CPE isolates.

Investigation of the Effect of Double Carbapenem Therapy on Clinical Outcomes in Patients with Klebsiella pneumoniae Bacteremia

Investigation of the Effect of Double Carbapenem Therapy on Clinical Outcomes in Patients with Klebsiella pneumoniae Bacteremia

Clinical Characteristics, Outcomes, and Risk Factors for Mortality in Patients with Stenotrophomonas maltophilia Bacteremia.

This study aimed to establish the clinical features, outcomes, and factors associated with mortality in patients with Stenotrophomonas maltophilia (S. maltophilia) septicemia. The characteristics and outcome data used in this retrospective study were collected from medical records at Songklanagarind Hospital. Risk factors for survival were analyzed using χ2-tests, Kaplan–Meier curves, and Cox regression. A total of 117 patients with S. maltophilia bacteremia were analyzed. The patients’ median age was 45 years, 77 (70%) were male, 105 (90%) had comorbidities, 112 (96%) had previously undergone carbapenem therapy, and over half of the patients were on invasive medical devices. Trimethoprim-sulfamethoxazole (TMP-SMX) and fluoroquinolone showed high susceptibility rates to S. maltophilia, with 93% and 88% susceptibility, respectively. Patients who received appropriate empirical antibiotic treatment had significantly reduced 14-day, 30-day, and in-hospital mortality rates than those who did not (p < 0.001). The days of hospital stay and costs for those who received appropriate and inappropriate empirical antimicrobial treatment were 21 and 34 days (p < 0.001) and 142,463 and 185,663 baht, respectively (p < 0.002). Our results suggest that an appropriate empirical antibiotic(s) is significantly associated with lower 30-day mortality in hospitalized patients with S. maltophilia septicemia.

Evaluation of Carbapenem Use Before and After Implementation of an Antimicrobial Stewardship-Led Carbapenem-Sparing Strategy in a Lebanese Tertiary Hospital: A Retrospective Study.

PurposeThe use of carbapenem before and after implementation of an antimicrobial stewardship-led carbapenem-sparing strategy at a tertiary care center in Lebanon was evaluated.MethodsA retrospective, observational chart review was performed on all hospitalized pediatric and adult patients who received carbapenem therapy during January 2019 and January 2020. Patients who started their regimen before January or received carbapenems for less than 24 hours were excluded. Primary outcomes included the appropriateness of physician prescribing patterns and pharmacists’ interventions, as well as appropriateness and response rates of the latter. Secondary outcomes included the carbapenem defined daily dose (DDD) and days of therapy (DOT). Descriptive statistics were used in the analysis and a p-value < 0.05 was considered to be statistically significant.ResultsA total of 157 and 150 patients charts were reviewed in January 2019 and January 2020, respectively. There was no difference in baseline characteristics except for inpatient services and rates of isolated multidrug-resistant organisms. When comparing the two timelines, the appropriateness of physicians’ prescribing patterns increased in terms of empirical therapy, targeted therapy, and duration of therapy but the results were not statistically significant. Pharmacists’ interventions significantly increased with regards to the duration of therapy (p= <0.001), dose adjustment (p<0.001), de-escalation to a narrower spectrum antibiotic (p=0.007), and use of extended infusion (p=0.042). The DDD and DOT were higher for ertapenem and lower for anti-pseudomonal carbapenems in January 2020.ConclusionThe carbapenem-sparing strategy adopted by the antimicrobial stewardship program contributed to an increase in the number of interventions made by pharmacists on carbapenem therapy, including their appropriateness, and response rate. Despite an improvement in the physician-prescribing patterns, more awareness and education may be needed to achieve a better impact.

Feasibility of a "Salvage Regimen" Using Home-based Intravenous Meropenem Therapy With a Delamanid/Bedaquilline Containing Regimen in the Management of MDR/XDR Pediatric Tuberculosis.

The prevalence of multidrug resistant (MDR) tuberculosis (TB) with additional resistance to fluoroquinolones or second-line injectables (MDRFQ/SLI)/extensively drug-resistant TB (XDR-TB) in children is high in Mumbai. There are limited therapeutic options available in management of such children. Carbapenems, although approved for this indication, requires 2 to 3 daily injections, which are cumbersome. Bedaquilline (Bdq) and Delamanid (Dlm), the new antitubercular drugs still remain inaccessible to this subset of patients caused by conditional approvals. Hence, newer strategies to combat MDRFQ/SLI/XDR-TB needs to be explored. To study feasibility and interim outcomes of a "salvage regimen" using home-based carbapenem therapy through peripherally inserted central catheter as part of a longer (18-20 months) optimized background regimen including Dlm or Bdq or both in pediatric MDRFQ/SLI/XDR-TB patients who failed a standard MDR-TB regimen under the National Tuberculosis Elimination Programme in Mumbai, India. Retrospective descriptive analysis study. National Tuberculosis Elimination Programme medical records of all MDRFQ/SLI/XDR-TB patients enrolled at the pediatric TB clinic at BJ Wadia Hospital for Children, Mumbai who were initiated on such "salvage regimen" during the period between April 2018 and December 2020 were retrospectively studied. Treatment outcomes and adverse events were described. Of the 15 patients enrolled, mean age of the patient population was 12.53 ± 2.47 years and the female:male ratio was 13:2. Seven patients had XDR-TB while 8 patients had MDRFQ/SLI. Most common adverse event noted was dyselectrolytemia (3 patients). Catheter-related complications were reported in 5 patients and included catheter blockage, leak, and thrombosis. Sputum culture conversion was reported in all of the patients. One child mortality was reported and 2 patients were lost to follow up during study period. Home-based meropenem therapy using peripherally inserted central catheter is feasible with few adverse effects. This can be a promising strategy in the management of MDRFQ/SLI/XDR-TB when an effective oral regimen cannot be otherwise constituted and needs to be explored further.

Re-evaluation of cefepime or piperacillin-tazobactam to decrease use of carbapenems in extended-spectrum beta-lactamase-producing Enterobacterales bloodstream infections (REDUCE-BSI).

To re-examine the use of noncarbapenems (NCBPs), specifically piperacillin-tazobactam (PTZ) and cefepime (FEP), for extended-spectrum beta-lactamase-producing Enterobacterales bloodstream infections (ESBL-E BSIs). Retrospective cohort study. Tertiary-care, academic medical center. The study included patients hospitalized between May 2016 and May 2019 with a positive blood culture for ESBL-E. Patients were excluded if they received treatment with antibiotics other than meropenem, ertapenem, PTZ, or FEP. Patients were also excluded if they were aged <18 years, received antibiotics for <24 hours, were treated for polymicrobial BSI, or received concomitant antibiotic therapy for a separate gram-negative infection. We compared CBPs with FEP or PTZ for the treatment of ESBL-E BSI. The primary outcome was in-hospital mortality. Secondary outcomes included clinical cure, microbiologic cure, infection recurrence, and resistance development. Data from 114 patients were collected and analyzed; 74 (65%) patients received carbapenem (CBP) therapy and 40 (35%) patients received a NCBP (30 received FEP and 10 received PTZ). The overall in-hospital mortality was 6% (N = 7), with a higher death rate in the CBP arm than in the N-CBP arm, (8% vs 3%; P = .42). No difference in mortality was detected between subgroups with Pitt bacteremia score ≥4, those requiring ICU admission, those whose infections were cause by a nongenitourinary source or causative organism (ie, 76 had Escherichia coli and 38 had Klebsiella spp). We detected no differences in secondary outcomes between the groups. Compared to CBPs, FEP and PTZ did not result in greater mortality or decreased clinical efficacy for the treatment of ESBL-E BSI caused by susceptible organisms.

Intravenous Drug Use: a Significant Risk Factor for Serratia Bacteremia.

Background:Serratia is an opportunistic pathogen known to cause an array of infectious presentations. Aside from case reports, intravenous (IV) drug use has not been adequately quantified as a major risk factor for Serratia infection.Methods:A retrospective cohort study of 103 adult patients admitted to four community hospitals in Ohio from January 2014 to December 2018 with a positive blood culture for Serratia species. A complete data set of 103 patients was analyzed for demographics, comorbidities, initial diagnosis, treatment, and outcomes. Outcomes were recurrence of infection, in hospital mortality, 90-day mortality, length of hospital stay (LOS), complications (endocarditis, osteomyelitis, abscess), and evaluation for resistance to third-generation cephalosporins and extended-spectrum beta-lactamase (ESBL) activity. Descriptive statistics were performed using frequencies for discrete variables and median [interquartile range (IQR)] for continuous variables.Results:Serratia marcescens was the predominate species 94 (91%). Demographics were White 88 (85%) and male 63 (62%); 42 (42%) were IV drug users. IV drug users were younger than non-IV drug users with a median (IQR) age of 40 [33–50] versus 71 years [41–72] and likely to have hepatitis C virus (HCV) infection 37 (88%) versus 3 (5%), p < 0.0001. Culture and susceptibility analysis revealed 36% of isolates with possible or confirmed ESBL production. The most common complications were endocarditis (12%) and osteomyelitis (10%). In-hospital mortality was 2%, 90-day mortality (2%), with 90-day readmission (21%). The median (IQR) LOS is 7 [3.25–14.75].Conclusion:This is the largest study to our knowledge evaluating non-nosocomial Serratia bacteremia. Our study shows that a high proportion of patients hospitalized with a positive Serratia culture are IV drug users and have HCV co-infection. There is significant ceftriaxone resistance and ESBL activity noted in our population. Based on this, we suggest empiric treatment with cefepime or consider carbapenem therapy for Serratia bloodstream isolates pending full susceptibility data. Focus should be on proper antibiotic treatment as the readmission rate and LOS are high.

A Retrospective Case Series of Concomitant Carbapenem and Valproic Acid Use: Are Best Practice Advisories Working?

Background: A Best Practice Advisory (BPA) warns clinicians of an interaction between carbapenems and valproic acid (VPA) that can cause significant declines in VPA levels leading to serious consequences for patients treated for seizure disorder and unknown implications for alternative indications. Objective: The goal of this study was to assess BPA efficacy in avoiding concomitant VPA/carbapenems, and to characterize use of these agents, clinical implications, and potential alternative therapeutic options. Methods: Retrospective chart review was performed on all patients over the course of 1 year who were concomitantly prescribed a carbapenem and VPA at Hartford Hospital, Hartford, CT. Data collected included: level of care, duration of concomitant therapy, indications, VPA levels during or surrounding overlap, documentation of the interaction, and therapeutic implications. Results: Carbapenems and VPA were administered to 591 and 625 patients, respectively; the BPA fired 126 times in 24 patients, and 15 patients were initiated on these agents concomitantly. Eight (53%) patients received VPA for seizures. The remaining seven (47%) received VPA for alternative indications. Eight of nine VPA levels were sub-therapeutic during carbapenem therapy and polypharmacy was administered in all patients receiving VPA for non-convulsive indications. Conclusion: Co-prescribing of these drugs was rare; however, the BPA was ineffective in 63% of instances. Reductions in VPA efficacy for any indication should be expected with concomitant carbapenem administration. Antibiotics other than carbapenems should be considered when coverage of multidrug resistant Gram-negative pathogens is required in patients whose VPA treatment cannot be interrupted or switched to a therapeutic alternative.

Do Weekly Surveillance Cultures Contribute to Antibiotic Stewardship and Correlate with Outcome of HSCT in Children? A Multicenter Real-World Experience of 5 Years from the Indian Subcontinent

The utility of weekly rectal swab surveillance cultures (RSSCs) as a resource to identify gut colonization with extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli or Klebsiella pneumoniaecarbapenemase (KPC)-producing organisms and guide empirical antibiotic therapy in hematopoietic stem cell transplantation (HSCT) recipients continues to be a subject of interest. There is an urgent need to assess and justify modifications to empirical antibiotics based on regional epidemiology and patient groups. This study aimed to study the utility of weekly rectal swab surveillance cultures (RSSCs) to guide empirical antibiotic therapy and to examine the impact of gut colonization on transplantation outcomes. This retrospective analysis of 317 successive first HSCTs performed mainly for hemoglobinopathies was conducted in 3 pediatric bone marrow transplantation centers in the Indian subcontinent between April 2016 and April 2021. Transplantation, infection control, and febrile neutropenia management protocols were identical in the 3 centers. First-line antibiotics were chosen based on RCCS reports, with meropenem used for ESBL and high-dose meropenem with colistin used for carbapenemase-resistant colonization for first half of the study, with no adjustment made in the second half. Clinical response to antibiotics, long-term outcomes, antibiotic-resistant bacteremia, and acute graft-versus-host disease (GVHD) were analyzed. The log-rank test, chi-square, and Wilcoxon rank-sum tests were used to compare data using R Statistical software. Of the 871 weekly RSSCs done, 162 were positive for ESBL- or KPC-resistant organism. RCCSs were ESBL-positive in 106 patients (33%) and KPC-positive in 10 patients (3%). Among the 97 ESBL-positive patients for whom a antimicrobial susceptibility testing report was available, only 22 (25%) demonstrated clinical resistance to piperacillin-tazobactam (Pip-Taz). Among the 10 KPC-positive patients, only 4 (40%) demonstrated clinical resistance to Pip-Taz and 3 (30%) had clinical resistance to meropenem. Two-thirds of patients with ESBL-positive RSSC in whom first-line empirical antibiotics were used responded clinically. Even among the 15 patients who were resistant to first-line empirical antibiotics (Pip-Taz) on RSSC reports, 67% responded clinically to Pip-Taz. Twenty-seven of these patients (56%) never needed carbapenem therapy. Empirical Pip-Taz therapy in ESBL-positive patients did not prolong meropenem use within 100 days of transplantation (P=.18). All patients with a KPC-positive RSSC who received first-line empirical antibiotics responded clinically, including 4 who were resistant to Pip-Taz and 3 who were meropenem-resistant on RCCS. Comparing patients who were ESBL-positive, KPC-positive, and not positive for either showed no statistically significant differences in overall survival (OS) (P=.95), disease-free survival (DFS) (P=.45), transplantation-related mortality (TRM) (P=.97), graft rejection (P=.68), or rate of acute GVHD grade II-IV (P=.78). No statistically significant differences were seen between the ESBL-positive patients who received and those who did not receive higher-level empirical antibiotics in OS (P=.32), DFS (P=.64), TRM (P=.65), graft rejection (P=.46), acute GVHD grade II-IV (P=.26), or antibiotic-resistant bacteremia (P=.3). In the context of HSCT for nonmalignant hematologic disorders, choosing empiric antibiotic therapy based on RSSCs is not justified, even in regions with a high prevalence of antimicrobial resistance. Antimicrobial susceptibility testing reports in surveillance cultures did not correlate with in vivo clinical response. Colonization reported on weekly RSSCs showed no correlation with clinical outcomes. © 2021 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.

137. Risk Factors of B-lactams Associated Cytopenias during Outpatient Parenteral Antimicrobial Therapy: Results from a Large National Sample

BackgroundCytopenias are rare complications of prolonged beta-lactam use; however, incidence and associated risk factors are not well described. MethodsPatients aged 18-64 years in the 2010-2016 IBM MarketScan Commercial Database discharged from the hospital on cephalosporin, penicillin, or carbapenem outpatient Parenteral Antimicrobial Therapy (OPAT) were included. The primary endpoint was hospital admission coded for neutropenia, leukopenia, or thrombocytopenia within the first 6 weeks post index discharge and within 7 days of beta-lactam discontinuation. Patients with history of malignancy and those who are on chemotherapy were excluded. Significant factors in univariate analysis were incorporated into a multivariable logistic regression model with sequential exclusion of variables with p > 0.1.ResultsA total of 35,102 patients received beta-lactam OPAT; median age was 52 years and 53.6% were male. The primary outcome occurred in 150 (0.43%) patients at a median of 19 days (IQR 10-28 days after index discharge), which included 63 (0.18%) neutropenia, 85 (0.24%) thrombocytopenia, and 23 (0.07%) leukopenia admissions. Factors independently associated with readmission cytopenias included chronic liver disease (OR 4.61 [CI 2.93-7.25]), valvular heart disease (2.69 [1.71-4.24]), receipt of vancomycin (2.10 [1.42-3.12]), or antifungal therapy (4.42 [2.01-9.68]); lower risk was associated with carbapenem therapy (0.49 [0.32-0.75]) and diabetes (0.48 [0.31-0.74]) (Table 1).ConclusionReadmissions with cytopenias during beta-lactam OPAT were rare and carbapenem use was associated with lower risk compared to other classes of beta-lactams. Combination of beta-lactam with vancomycin was associated with an increased risk of cytopenias, and those patients might benefit from closer monitoring.Table 1. Factors Associated with Cytopenias during Beta-Lactams Outpatient Parenteral Antimicrobial Therapy (OPAT) Disclosures Margaret A. Olsen, PhD, MPH, Pfizer (Consultant, Research Grant or Support)

1259. Carbapenems Versus Non-carbapenem Beta-Lactams for the Treatment of Ceftriaxone-Susceptible and Piperacillin-Tazobactam-Nonsusceptible Enterobacterales Isolates

Abstract Background Ceftriaxone-susceptible (CRO-S) and piperacillin-tazobactam-non susceptible (TZP-NS) Enterobacterales isolates have become a frequently isolated phenotype emerging in practice. The genotypic profile is still not clearly elucidated, although prior genotypic sequencing data of these isolates with this phenotypic profile suggests that they are not extended-spectrum beta-lactamase (ESBL) producers. Due to the unfamiliarity with this phenotype and the potential for overuse of broad-spectrum antibiotics, we investigated the clinical outcomes of CRO-S/TZP-NS isolates with carbapenem versus non-carbapenem beta-lactam (NCBL) therapy. Methods This was a retrospective chart review of patients with a diagnosed infection caused by a CRO-S/TZP-NS Enterobacterales isolate admitted to any of the three NYU hospitals: Long Island, Tisch, or Brooklyn campuses, treated with a beta-lactam (BL) antibiotic from October 2015 to October 2020. The primary outcome was treatment failure defined as an escalation of antibiotics due to clinical worsening, 30-day all-cause mortality, or relapse of infection with the same genus and species. Patients who received ≥ 72 consecutive hours of BL antibiotics were considered to be on definitive therapy. Results A total of 111 patients were included in this study, 9 in the carbapenem group and 102 in the NCBL group. There was no statistically significant difference in the clinical failure rate between the two groups (0% vs 10.8% respectively, P=0.56). A univariate analysis assessed the association of clinical failure with TZP, CRO, cefpodoxime, cefepime, and 1st-3rd generation cephalosporins grouped. There were no statistically significant increases in 30-day treatment failure in any of the individual categories. Conclusion There were no statistically significant differences in 30-day failure with the use of carbapenem vs NCBL antibiotics. No individual BLs or classes were associated with an increased risk of clinical failure. This study suggests that there is a role for NCBL antibiotics for Enterobacterales isolates with this phenotypic presentation and supports prior data that they are less likely to be ESBL producers. Prospective studies are warranted to confirm these findings. Disclosures All Authors: No reported disclosures

207. Ineffective Initial Antibiotics for Enteric Bacteremia: Does Every Hour Count with Rapid Diagnostics and Stewardship Intervention?

Abstract Background It has been a long-standing practice to administer broad-spectrum antibiotics early for sepsis as each hour delay is associated with increase in mortality. With increasing rates of antibiotic resistance fueled by unnecessary use of antibiotics, it is delicate to balance the benefits vs consequences of empiric carbapenem therapy. With rapid molecular blood culture diagnostics available, identification of extended-spectrum beta-lactamase (ESBL) producing bacteremia can occur within hours and therapy optimized with active stewardship intervention. With rapid diagnostics, does each hour of ineffective antibiotic therapy really count? Methods This multicenter, retrospective, cohort study compared adult inpatients with E. coli bacteremia from a urinary source who received initial effective (EA) vs ineffective antibiotics (IA). The primary outcome was clinical treatment success at day 4. Secondary endpoints included length of stay (LOS), infection-related mortality, incidence of C. difficile infection (CDI), and subgroup analysis of outcomes by ESBL (CTX-M type) vs non-ESBL. Associations with endpoints were assessed using Fisher’s Exact tests using R v. 4.0.3. Results Clinical treatment success at day 4 was higher in the EA (n = 488) vs IA (n = 119) groups (93.7% vs 86.6%, p = 0.01) and median LOS was shorter (5 [IQR 4-6] vs 5 [IQR 5-7] days, p &amp;lt; 0.01). There were no differences in infection-related mortality (3.1% vs 3.4%, p = 0.8), 30-day mortality (2.5% vs 2.5%, p &amp;gt; 0.9), or incidence of CDI (1.8% vs 0%, p = 0.3) in the EA vs IA groups, respectively. For patients on IA &amp;lt; 24 h vs &amp;gt; 24 h, there was no difference in clinical improvement at day 4 (86.7% vs 90.5%, p &amp;gt; 0.9) nor 30-day mortality (2.4% vs 4.8%, p = 0.4). Clinical treatment success at day 4 was higher among non-CTX-M (n = 476) vs CTX-M (n = 131) patients (93.9% vs 86.3%, p = 0.01) even among those that received initial EA (94.5% vs 83.3%, p = 0.02). Median LOS was also shorter in CTX-M vs non CTX-M (5 [IQR 4-6] vs 5 [IQR 4-8] days, p &amp;lt; 0.01). Conclusion There was no mortality difference among patients receiving initial EA vs IA for E. coli bacteremia with rapid molecular blood culture diagnostics with active stewardship. Therapy for patients on IE is rapidly corrected and stewardship programs can use this intervention to promote judicious use of carbapenems. Disclosures All Authors: No reported disclosures

Comparison of therapy with \u03b2-lactam/\u03b2-lactamase inhibitor combinations or carbapenems for bacteraemia of nonurinary source caused by ESBL-producing Escherichia coli or Klebsiella pneumoniae

BackgroundExtended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae has become a public health concern. This study aimed to compare the clinical outcomes of patients with nonurinary source bacteraemia caused by ESBL-producing Escherichia coli (E. coli) or Klebsiella pneumoniae (ESBL-producing EK) receiving β-lactam/β-lactamase inhibitor combinations (BLICs) versus carbapenem treatment and assess the risk factors of mortality with these two drugs.MethodsWe conducted a retrospective single-centre study of adult hospitalised patients with ESBL-producing EK bloodstream infection (BSI) from nonurinary source at our centre over a 4-year period. One hundred and eighty patients who received BLICs or carbapenems were included in the analysis. The outcome variables were 14-day treatment failure and 30-day mortality. For more reliable results, propensity score analysis was performed to compare the efficacy of the two drugs and analyse their risk factors for 30-day mortality.ResultsOut of 180 patients, 114 received BLICs, and 66 received carbapenem therapy. Compared to carbapenem-treated patients, those treated with BLICs were older and had higher age-adjusted Charlson comorbidity index, but they had shorter stay in the hospital. Additionally, their Pitt bacteraemia score, SOFA score, rate of leukaemia, and immune compromise were lower. After propensity score matching (PSM), the baseline characteristics of patients in the two treatment groups were balanced. BLICs were associated with a higher 14-day treatment failure rate (20.6%, 13/63) than carbapenems (16.3%, 7/43), although the difference was not significant in either univariate analysis (P = 0.429) or multivariate analysis (P = 0.122). And the 30-day mortality rate in BTG (11.1%, 7/63) and CTG (11.6%, 5/43) did not significantly differ (univariate analysis, P = 0.926; multivariate analysis, P = 0.420). In the multivariate analysis, after PSM, leukaemia was the only independent predictor of mortality in both BTG and CTG.ConclusionsOur study showed that BLICs had higher 14-day treatment failure rate compared with carbapenems, although there were no statistically significant differences because of the small number of patients, therefore, further evaluation of the efficacy of BLICs is needed.

Role of early foldscopy (microscopy) of endotracheal tube aspirates in deciding restricted empirical therapy in ventilated patients

PurposePrevention of healthcare-associated infections (HAI) like ventilator associated pneumonia (VAP) is particularly challenging especially in resource limited settings. Complex microbial interactions between patients and health care workers (HCWs) further complicate the situation, requiring a holistic approach for successful management. To bridge the gap between laboratory and intensive care unit (ICU) this study was conducted to find the role of hand-held microscope ‘Foldscope’ in restricting empirical therapy in intubated patients. MethodsA total of 75 endotracheal aspirates (ETA) were collected from intubated patients in the ICU with (group 1) and without (group 2) VAP. For group 2, those with less than 48 ​h ventilation and with endotracheal tube (ETT) in situ were considered. Presence of biomass was detected through foldscope and ETA samples were processed for quantitative gram staining (QGS), semi-quantitative and quantitative culture. Phenotypic and genotypic characterization of Acinetobacter baumannii, the commonest isolate, was done and findings were statistically analysed. ResultsBiomass was present as seen through a foldscope in 45 cases (90%) in group 1 and 17 cases (68%) in group 2. In both the groups, A. baumannii was the most common isolate. Biomass production, significant QGS and culture was significantly more in group 1 (p ​< ​0.05). However, carbapenem resistant A. baumannii (CRAB) was comparably present in both the groups thus showing limited role of empirical carbapenem therapy. ConclusionsEarly assessment of biomass in mechanically ventilated patients could provide guidance for empirical antibiotic therapy. Foldscope proved to be an excellent tool for restricting empirical therapy and driving antimicrobial stewardship in low resource settings.

Novel Specific Metallo-β-Lactamase Inhibitor ANT2681 Restores Meropenem Activity to Clinically Effective Levels against NDM-Positive Enterobacterales

ABSTRACTThe global dissemination of metallo-β-lactamase (MBL)-producing carbapenem-resistant Enterobacterales (CRE) is a serious public health concern. Specifically, NDM (New Delhi MBL) has been a major cause of carbapenem therapy failures in recent years, particularly as effective treatments for serine-β-lactamase (SBL)-producing Enterobacterales are now commercially available. Since the NDM gene is carried on promiscuous plasmids encoding multiple additional resistance determinants, a large proportion of NDM-CREs are also resistant to many commonly used antibiotics, resulting in limited and suboptimal treatment options. ANT2681 is a specific, competitive inhibitor of MBLs with potent activity against NDM enzymes, progressing to clinical development in combination with meropenem (MEM). Susceptibility studies have been performed with MEM-ANT2681 against 1,687 MBL-positive Enterobacterales, including 1,108 NDM-CRE. The addition of ANT2681 at 8 μg/ml reduced the MEM MIC50/MIC90 from >32/>32 μg/ml to 0.25/8 μg/ml. Moreover, the combination of 8 μg/ml of both MEM and ANT2681 inhibited 74.9% of the Verona integron-encoded MBL (VIM)-positive and 85.7% of the imipenem hydrolyzing β-lactamase (IMP)-positive Enterobacterales tested. The antibacterial activity of MEM-ANT2681 against NDM-CRE compared very favorably to that of cefiderocol (FDC) and cefepime (FEP)-taniborbactam, which displayed MIC90 values of 8 μg/ml and 32 μg/ml, respectively, whereas aztreonam-avibactam (ATM-AVI) had a MIC90 of 0.5 μg/ml. Particularly striking was the activity of MEM-ANT2681 against NDM-positive Escherichia coli (MIC90 1 μg/ml), in contrast to ATM-AVI (MIC90 4 μg/ml), FDC (MIC90 >32 μg/ml), and FEP-taniborbactam (MIC90 >32 μg/ml), which were less effective due to the high incidence of resistant PBP3-insertion mutants. MEM-ANT2681 offers a potential new therapeutic option to treat serious infections caused by NDM-CRE.

Risk Factors for Intra-Abdominal Infections Caused by Carbapenemase-Producing Enterobacteriaceae in a Surgical Setting.

Background: The aim of this study was to identify risk factors for acquisition of intra-abdominal infections (IAI) caused by carbapenemase-producing Enterobacteriaceae (CPE) in surgical patients. Methods: A matched case-control study was performed. We included all cases with CPE-related IAI acquired during admission to a general surgery department from January 2013 to December 2018, and they were matched with control subjects with IAI caused by non-resistant bacteria (ratio 1:3). Independent risk factors were obtained by logistic regression. Results: Forty patients with IAI-CPE were matched with 120 control subjects. Independent risk factors for acquisition of IAI-CPE were previous hospitalization (odds ratio [OR] 2.56; 95% confidence interval [CI] l 1.01-6.49; p = 0.047), digestive endoscopy (OR 4.11; 95% CI 1.40-12.07; p = 0.010), carbapenem therapy (OR 9.54; 95% CI 3.33-27.30; p < 0.001), and aminoglycoside use (OR 45.41; 95% CI 7.90-261.06; p < 0.001). Conclusions: Four clinical factors can identify patients at high-risk of IAI-CPE.

The effect of double-carbapenem therapy on mortality rates and microbiological cure rates in patients diagnosed with carbapenem-resistant Klebsiella pneumoniae infections in comparison to monotherapy and currently used combinations of antibiotics

Introduction: Infection with the bacteria carpamenease-producing Klebsiella pneumoniae represents a significant cause of mortality in hospitalised patients. These multidrug resistant bacteria are resistant to currently used antibiotics as a result of carbapenemase production. Dual carbapenem therapy has been proposed as a valid therapeutic option, this therapy combines two carbapenem antibiotics, with one acting as a suicide inhibitor allowing the subsequent carbapenem to exert a bactericidal effect. &#x0D; Aim: The aim of this meta-analysis was to determine if dual carbapenem therapy had a significant effect on mortality rate and microbiological cure rate in patients diagnosed with carbapenemase-producing Klebsiella pneumoniae infections in comparison to standard antibiotic therapies. &#x0D; Methods: The search terms “(dual OR double) carbapenem (therapy OR treatment) AND klebsiella pneumoniae” were used to search databases and inclusion and exclusion criteria were applied to retrieved papers, a total of seven studies were identified for inclusion in the meta-analysis. The quality of included studies was assessed using the cochrane tool for risk of bias assessment and funnel plots were produced to determine the influence of publication bias. A random effects model was used to assess the outcomes; mortality rate and microbiological cure rate. &#x0D; Results and Conclusion: Dual carbapenem therapy had a time dependent effect on patient mortality rates. Dual carbapenem therapy significantly lowered mortality rates in patients in comparison to standard antibiotic therapy, especially in comparison to monotherapy treatment regimens. Additionally, dual carbapenem therapy significantly improved microbiological cure rate in patients when compared to standard antibiotic treatment regimens demonstrating the possible clinical applications of a dual carbapenem antibiotic regimen in the treatment of carbapenemase-producing Klebsiella pneumoniae infections.