Beta-lactam Therapy Research Articles

Comparing the activity of broad-spectrum beta-lactams in combination with aminoglycosides against VIM-producing Enterobacteriaceae.

Metallo-beta-lactamase (MBL)-producing carbapenem-resistant Enterobacteriaceae (CRE) infections continue to pose a serious threat to healthcare. Due to their unique active site, MBLs evade the activity of many novel beta-lactam/beta-lactamase inhibitor combinations, which have been specifically targeted toward those carbapenemases with serine active sites. Furthermore, resistance to most, if not all, other clinically relevant antimicrobial classes leaves few reliable therapeutic options. Combination therapy has thus played a vital role in the treatment of MBL-producing CRE infections. In this study, we utilized the static time-kill assay to investigate clinically relevant concentrations of cefepime, piperacillin-tazobactam, and meropenem alone and in combination with either amikacin or the novel plazomicin to determine if combinations of routinely used beta-lactam therapy with an aminoglycoside would achieve bactericidal activity against eight clinically isolated Verona integron-encoded MBL (VIM)-producing CRE. Furthermore, we compared this activity to the combination of aztreonam/avibactam, which has shown potent activity against MBL-producing CRE. Both aztreonam/avibactam and meropenem with either aminoglycoside were rapidly bactericidal within 4 hours and remained bactericidal through 24 hours against all isolates with few exceptions. Combinations including cefepime and piperacillin-tazobactam were also rapidly bactericidal, but activity after 24 hours was inconsistent depending upon the partner aminoglycoside and isolate. Further investigation is warranted to elucidate optimal antibiotic exposures against MBL-producing CRE, including novel agents in the pipeline.IMPORTANCECarbapenem-resistant Enterobacterales (CRE) are one of the most pressing antimicrobial-resistant threats at present. In addition to exhibiting resistance to many, if not all, commonly used antimicrobial agents, CRE achieves these resistant phenotypes through a variety of mechanisms, each of which can uniquely affect available treatment options. The present study is an in vitro investigation of several Verona integron-encoded metallo-beta-lactamase (VIM)-producing CRE isolated from patients at our academic medical center. Because metallo-beta-lactamases (MBLs) are inherently resistant to many of the novel treatments designed to treat CRE due to their different active site composition, we tested several antimicrobial combinations containing routinely utilized broad-spectrum beta-lactams and aminoglycosides. Our results further our understanding of combination therapy options against VIM-producing CRE, including with non-carbapenem-beta-lactams cefepime and piperacillin. By optimizing combinations of existing antimicrobial agents, we hope to expand the available armamentarium against these resistant pathogens.

Empiric Antibiotic Therapy in 1402 Children With Parapneumonic Effusion/Pleural Empyema in Germany: A Long-term Surveillance Study.

This study investigated empiric antibiotic treatment (EAT), guideline adherence, antibiotic streamlining and clinical outcomes in 1402 hospitalized children with pediatric parapneumonic effusion/pleural empyema (PPE/PE). A nationwide surveillance study collected data on EAT, clinical course/outcome, pathogens, susceptibility testing and antibiotic streamlining of children with PPE/PE in Germany between 2010 and 2018. Subgroups were compared using χ2 test/Fisher exact test, Mann-Whitney U test and linear regression analysis adjusting for patient age where appropriate. Complete data on EAT were available for 1402 children. In children with monotherapy (n = 567) and in children with combination therapy of 2 antibiotics (n = 589), the most commonly used antibiotics were aminopenicillin/beta-lactamase inhibitor [138/567 (24.3%) and 102/589 (17.3%)] and cefuroxime [291/567 (51.3%) and 294/589 (49.9%)]. The most common combinations with these beta-lactams were macrolides, aminoglycosides and clindamycin. We observed no difference in clinical severity/outcome between EAT with aminopenicillin/beta-lactamase inhibitor and cefuroxime, neither when used in monotherapy nor when used in combination therapy of 2 antibiotics. Species diagnosis of Streptococcus pneumoniae (n = 192), Streptococcus pyogenes (n = 111) or Staphylococcus aureus (n = 38) in polymerase chain reaction or culture from pleural fluid or blood resulted in a switch to an appropriate narrow-spectrum beta-lactam therapy in 9.4%, 18.9 % and 5.2% of children. In a subset of children with reported bacterial susceptibility testing, penicillin resistance was reported in 3/63 (4.8%) of S. pneumoniae and methicillin resistance in S. aureus was reported in 10/32 (31.3%) of children. This study points to antibiotic overtreatment in children with PPE/PE, particularly the frequent use of combinations of antibiotics. Children receiving combinations of antibiotics did not show differences in clinical outcomes. The low rate of children with streamlined antibiotic therapy even upon pathogen detection indicates a necessity for antibiotic stewardship measures in PPE/PE and the need of investigating other potential therapeutic strategies as anti-inflammatory therapy.

Serum Concentration at 24 h With Intensive Beta-Lactam Therapy in Sepsis and Septic Shock: A Prospective Study: Beta-Lactam Blood Levels in Sepsis.

Introduction: Early administration of appropriate antibiotics has been shown to be among the most effective interventions to reduce mortality in septic patients. We evaluated the attainment of efficacy and safety targets at 24 h associated with the use of intensive beta-lactam therapy in patients admitted to the intensive care unit for sepsis. Methods: This was a prospective study with patients who received beta-lactams for sepsis or septic shock between February 2023 and September 2023. The antibiotic dose was unadjusted for renal function and administered by a loading dose followed by extended infusions, according to local practices. Blood samples were taken at the trough 24 h after the start of the beta-lactam to obtain serum levels. These levels were compared to efficacy and innocuity thresholds found in the literature. Results: Among 36 included patients, all of them achieved serum concentrations above the minimum inhibitory concentration (MIC) for 100% of the therapeutic interval and 75% of them achieved serum concentrations above four times the MIC for 100% of the therapeutic interval. The predefined toxicity thresholds were reached by 8.3% of patients. Renal impairment was the factor most associated with the achievement of higher serum levels. Conclusion: Nonrenally adjusted doses of beta-lactams administered by extended infusion showed good attainment of effective concentrations and few toxic concentrations in critically ill patients with sepsis or septic shock. Further studies are needed to better define the association between toxic concentrations and toxicity manifestations.

2789. Cefepime Versus Non-Cefepime/Non-Carbapenem Therapy for Blood Stream Infections Caused by Non-ESBL-Producing Serratia Marcescens: A Subgroup Analysis of The Carbapenem-Serratia Multicenter Retrospective Cohort Study

Abstract Background Serratia Marcescens causes serious infections. Carbapenems were prescribed due to the bacterium’s ability to develop inducible AmpC-mediated resistance. Recent IDSA guidance recommends ceftriaxone and in high-burden cases, cefepime. Evidence on the role of cefepime in the treatment of Serratia bacteremia is scarce. We aim to evaluate the outcomes of patients who received cefepime-containing empiric and/or definitive therapy (CFCT) to those receiving non-cefepime therapy (NCFCT). Methods This is a sub-analysis of a retrospective study of 7 Massachusetts acute care hospitals from January 1, 2015, to October 31, 2022. We included hospitalized adults (≥18 years) with Serratia Marcescens bacteremia. IRB approval was obtained. Demographics, clinical course characteristics, and choice of antibiotic therapy were collected. Primary outcome was 30-day mortality, and secondary outcome was composite antimicrobial failure (see Definitions in Table 1). Chi Square and Mann-Whitney U tests were computed using SPSS statistical package. Results The original Carbapenem-Serratia study had 73 out of 128 patients who met the inclusion criteria (Figure 1). The non-carbapenem group (n=56) was further studied for the purpose of this subanalysis and was divided into CFCT (n=15) and NCFCT (n=41). The two subgroups were similar in baseline comorbidities, severity measures, and sources of bacteremia (Table 1). Neither 30-day mortality nor the composite outcome of antimicrobial failure were significantly different with relative risks of 0.94 (95% CI 0.16 to 5.3, P=0.948) and 1.21 (95% CI 0.27 to 5.4, P=0.800), respectively. Study exclusion flow-chart with subanlaysis. ESBL phenotypically defined by ceftriaxone resistance (MIC <1). Characteristics and outcomes of patient with Serratia bacteremia treated with a cefepime versus non-cefepime nor carbapenem therapy regimen. * Immunocompromised patients are those receiving immunosuppressants, chemotherapy, or transplants, having HIV with CD4+ T cell count <200 cells/mm3, neutropenia with ANC < 500 cells/mm3, or corticosteroid use with prednisone or equivalent >10 mg for ≥ 14 days. † Hospital-acquired bacteremia is diagnosed when a positive blood culture obtained from patients hospitalized for 48 hours or longer. Healthcare-associated bacteremia was defined as a positive blood culture is obtained within 48 hours of hospital admission and the patient fulfills specific pre-defined criteria utilized in prior studies. Community-acquired bacteremia refers to positive a blood culture obtained within 48 hours after hospital admission in patients who do not fit the criteria for healthcare-associated infections. ‡ Deep seated complicated infection included Infective endocarditis, septic arthritis, osteomyelitis, or epidural abscess § Empiric antibiotic therapy: Antibiotics administered before antimicrobial susceptibility testing (AST) results, with a minimum 48-hour of uninterrupted duration and appropriate dosing. || Definitive antibiotic therapy (i.e., antibiotics administered after the AST results, also with a minimum of 48-hour duration). ¶ Duration of total definitive antibiotic therapy was counted from day of AST results until last day of definitive antimicrobial therapy. # Microbiological failure, microbiological relapse, in- hospital mortality, 30-day mortality, infection-related hospital readmission, or recurrent Serratia bateremia within 30 days. Microbiological failure refers to the growth of Serratia after 48 hours of definitive antibiotic therapy, while microbiological relapse is the regrowth of Serratia after a negative blood culture (Kunz Coyne et al., 2023). Note: Two patients had recurrence of Serratia bacteremia within 30 days, neither were resistant to third generation cephalosporins. Δ Infection-related re-admission was defined when a patient is readmitted not solely for a procedure or surgery, and they experience fever, worsening leukocytosis, or required escalation of antimicrobial therapy from the definitive therapy of the index admission. Conclusion Averting cefepime in the antimicrobial therapy of Serratia bacteremia is not associated with a significant increase in 30-day mortality or the composite outcome of antimicrobial failure. When applicable, a narrower beta-lactam therapy such as ceftriaxone may be appropriate. Limitations include a small sample size, with higher risk for type II error, and overlap in definitive antibiotic therapy. Further prospective studies are needed to confirm these findings, especially in patients with deep-seated infections. Disclosures All Authors: No reported disclosures

203. Evaluating the Impact of Extended-Infusion Beta-Lactam Therapy on Clinical Outcomes and the Subsequent Emergence of Resistance in Adults with Gram-Negative Bloodstream Infections

Abstract Background Data are conflicting regarding the impact of extended-infusion beta-lactam (EI-BL) therapy on patient outcomes. We investigated the impact of EI-BL therapy on clinical outcomes and subsequent emergence of resistance in adults with Gram-negative bloodstream infections (GN-BSI) admitted to 24 US hospitals in 2019. Methods Patients who received ≥ 3 days of EI-BL (i.e., ≥ 3-hour infusion) were compared to patients who received the same agents as ≤ 1-hour standard infusions (SI-BL). The EI-BL group underwent 3:1 nearest neighbor propensity score matching without replacement with the SI-BL group based on: Pitt bacteremia score ≥ 4, Charlson comorbidity index ≥ 5, severe immunocompromise, ICU status, source control, active empiric therapy, urinary source, and the 3 most common species. Multivariable regression was applied to the matched cohort to investigate mortality, recurrent infection with the same species, subsequent emergence of resistance (i.e., ≥ 4-fold increase in MIC of the β-lactam used to treat the index BSI), and treatment-related adverse events (AEs), all censored at day 90. Results There were 352 and 4,509 patients in the EI-BL and SI-BL groups, respectively. Excellent balance was achieved across all variables in the 3:1 matched cohort. The odds of mortality at day 90 were lower in the EI-BL vs SI-BL group (aOR=0.71, 95% CI 0.52-0.97, p=0.033). When stratified to evaluate the mortality benefit in those with and without severe illness or elevated MICs, a significant mortality benefit was only identified in patients with severe illness and/or elevated MICs. No differences were observed in recurrent infection. There was an increased odds of catheter complications (aOR=3.14, 95% 1.66-5.96, p< 0.001) and early antibiotic discontinuation because of AEs (aOR=3.66, 95% CI 1.68-7.95, p=0.001) in the EI-BL group. Emergence of resistance was similar in the EI-BL and SI-BL groups at 2.9% vs 7.2%, respectively (p=0.351). Conclusion The benefits of EI-BL therapy need to be balanced with associated AEs. EI-BL therapy should be prioritized in the severely ill or those infected with non-susceptible organisms. The subsequent emergence of resistance warrants investigation in a larger cohort. Disclosures Sara M. Karaba, MD, PhD, MHS, Entasis: Advisor/Consultant Sara E. Cosgrove, MD, MS, Debiopharm: Advisor/Consultant|Duke Clinical Research Institute: Advisor/Consultant

1186. Beta is Better: Impact of a Multifaceted Stewardship Initiative on the Sequential Timing of Beta-Lactam Administration

Abstract Background Appropriate antibiotic sequence (i.e. beta-lactam before vancomycin) may reduce early mortality in patients with bloodstream infections (BSIs). Herein, we describe the impact of a multifaceted stewardship initiative on the sequence of antibiotic administration across three hospitals. Methods We performed a pre-post analysis describing the impact of a multifaceted stewardship initiative from March 1, 2021 – May 22, 2022 (pre) and May 31, 2022 – Feb 12, 2023 (post) on the sequence of antibiotic administrations in adults > 18 years old with at least one positive blood culture who received vancomycin and a beta-lactam (i.e. cefepime, meropenem, or piperacillin-tazobactam) across three hospitals: a major university hospital and two community hospitals. Our initiative consisted of 1) a health-system wide adult beta-lactam order panel combining load and maintenance doses for select beta-lactams (Figure 1) 2) nursing administration instructions facilitating the appropriate sequential order of antibiotic administration (i.e. beta-lactam before vancomycin) (Figure 2) and 3) system-wide education to physicians, pharmacists, and nurses. The rate of beta-lactam first administration was compared between groups. Beta-lactam first rates were further stratified by hospital and antibiotic administration locations. Chi-square tests were used to compare rates between groups. Beta-Lactam Order Panel, Piperacillin-tazobactam Beta-Lactam First: Nursing Administration Instructions, Cefepime Results 361 patients were included for analysis: 224 pre- and 137 post-intervention. Piperacillin-tazobactam was the most common beta-lactam among studied patients (71.5%, Table 1). Beta-lactam first rates were already high at baseline, then higher post-intervention compared to pre-intervention (96.4% vs 93.8%, p = 0.283) (Table 2).Table 1.Receipt of Beta-Lactam Therapy in Adult Patients with Positive Blood CulturesTable 2.Sequence of Antibiotic Administration Conclusion A multifaceted initiative to promote beta-lactam before vancomycin administration increased adherence to this preferred practice in our health system, though baseline rates were high. Clinical decision support paired with system-wide education involving key stakeholders can help standardize appropriate antibiotic sequence. Future study could evaluate impact on a larger scale, on patient outcomes, and evaluate sustainability of beta-lactam first practice. Disclosures Rebekah W. Moehring, MD, MPH, FIDSA, FSHEA, UpToDate, Inc.: Author Royalties

189. Outcomes of High-dose Oral Beta-lactam Step-down Therapy Compared to Alternative Oral Therapy for Bacteremic Urinary Tract Infections

Abstract Background Pyelonephritis and associated bacteremia are often treated with intravenous antibiotics followed by oral step-down therapy to a fluoroquinolone (FQ) or trimethoprim/sulfamethoxazole (TMP/SMX). Oral beta-lactams were historically utilized less often due to concern for treatment failure. Literature suggests oral beta-lactams are effective, but there are no preferred oral beta-lactam agents or dosing recommendations. This study evaluates outcomes of high-dose oral beta-lactam therapy for Enterobacterales bacteremia due to a urinary tract infection (UTI) compared to alternative therapy. Methods A retrospective, multicenter, observational cohort study was conducted evaluating patients admitted from February 1, 2020, to October 1, 2022, with gram-negative bacteremia from a urinary source. Adult patients were included if they received empiric intravenous antibiotic active against the bacteria isolated and transitioned to appropriately dosed oral cephalexin, amoxicillin, TMP/SMX, or FQ (Table 1). Excluded were patients who received less than 72 hours of oral therapy, had a diagnosis of renal abscess or lobar nephronia, and those who expired during admission. The primary outcome compared the composite of recurrent bacteremia or mortality within 30 days of completing oral therapy. Secondary outcomes included recurrent UTI, emergency department (ED) or hospital readmission, and Clostridioides difficile infections within 30 days of treatment completion. Results There were 194 patients who met inclusion criteria. The primary outcome occurred in 1/75 (1.3%) patients in the oral beta-lactam group and 2/119 (1.7%) patients in the FQ or TMP/SMX group (p=1.0). Two patients in the FQ or TMP/SMX expired within 30 days and 1 patient in the beta-lactam group had a recurrent bacteremia. There were 16 (21.3%) and 14 (11.8%) patients in the beta-lactam and FQ or TMP/SMX group, respectively, treated for recurrent UTI (p=0.073). Twenty (27%) patients in the beta-lactam group required ED re-evaluation or hospital readmission compared to 30 (25%) patients who received a FQ or TMP/SMX (p=0.74). Zero patients had a Clostridioides difficile infection. Conclusion Oral beta-lactams are as effective as oral FQ and TMP/SMX for the treatment of bacteremia from a urinary source. Disclosures All Authors: No reported disclosures

Role of a Real-Time TDM-Based Expert Clinical Pharmacological Advice Program in Optimizing the Early Pharmacokinetic/Pharmacodynamic Target Attainment of Continuous Infusion Beta-Lactams among Orthotopic Liver Transplant Recipients with Documented or Suspected Gram-Negative Infections.

(1) Objectives: To describe the attainment of optimal pharmacokinetic/pharmacodynamic (PK/PD) targets in orthotopic liver transplant (OLT) recipients treated with continuous infusion (CI) beta-lactams optimized using a real-time therapeutic drug monitoring (TDM)-guided expert clinical pharmacological advice (ECPA) program during the early post-surgical period. (2) Methods: OLT recipients admitted to the post-transplant intensive care unit over the period of July 2021-September 2023, receiving empirical or targeted therapy with CI meropenem, piperacillin-tazobactam, meropenem-vaborbactam, or ceftazidime-avibactam optimized using a real-time TDM-guided ECPA program, were retrospectively retrieved. Steady-state beta-lactam (BL) and/or beta-lactamase inhibitor (BLI) plasma concentrations (Css) were measured, and the Css/MIC ratio was selected as the best PK/PD target for beta-lactam efficacy. The PK/PD target of meropenem was defined as being optimal when attaining a fCss/MIC ratio > 4. The joint PK/PD target of the BL/BLI combinations (namely piperacillin-tazobactam, ceftazidime-avibactam, and meropenem-vaborbactam) was defined as being optimal when the fCss/MIC ratio > 4 of the BL and the fCss/target concentration (CT) ratio > 1 of tazobactam or avibactam, or the fAUC/CT ratio > 24 of vaborbactam were simultaneously attained. Multivariate logistic regression analysis was performed for testing potential variables that were associated with a failure in attaining early (i.e., at first TDM assessment) optimal PK/PD targets. (3) Results: Overall, 77 critically ill OLT recipients (median age, 57 years; male, 63.6%; median MELD score at transplantation, 17 points) receiving a total of 100 beta-lactam treatment courses, were included. Beta-lactam therapy was targeted in 43% of cases. Beta-lactam dosing adjustments were provided in 76 out of 100 first TDM assessments (76.0%; 69.0% decreases and 7.0% increases), and overall, in 134 out of 245 total ECPAs (54.7%). Optimal PK/PD target was attained early in 88% of treatment courses, and throughout beta-lactam therapy in 89% of cases. Augmented renal clearance (ARC; OR 7.64; 95%CI 1.32-44.13) and MIC values above the EUCAST clinical breakpoint (OR 91.55; 95%CI 7.12-1177.12) emerged as independent predictors of failure in attaining early optimal beta-lactam PK/PD targets. (4) Conclusion: A real-time TDM-guided ECPA program allowed for the attainment of optimal beta-lactam PK/PD targets in approximately 90% of critically ill OLT recipients treated with CI beta-lactams during the early post-transplant period. OLT recipients having ARC or being affected by pathogens with MIC values above the EUCAST clinical breakpoint were at high risk for failure in attaining early optimal beta-lactam PK/PD targets. Larger prospective studies are warranted for confirming our findings.

Oral antimicrobial therapy for cellulitis versus outpatient parenteral antimicrobial therapy: a single-centre audit of cellulitis outcomes.

Cellulitis is a common acute skin and soft tissue infection that causes substantial morbidity and healthcare costs. To audit the impact on cellulitis management, regimen tolerability and outcomes of switching from outpatient parenteral antimicrobial therapy (OPAT) using intravenous (i.v.) cefazolin once daily plus probenecid to oral beta-lactam therapy (OBLT) using oral flucloxacillin plus probenecid. We undertook a retrospective audit on cellulitis management, regimen tolerability and outcomes at the Dunedin Public Hospital Emergency Department (ED) before and after a change of the local outpatient cellulitis treatment pathway from OPAT using i.v. cefazolin once daily plus probenecid to OBLT using oral flucloxacillin plus probenecid. OPAT was used in 97/123 (78.9%) patients with cellulitis before compared to 1/70 (1.4%) after the pathway change (odds ratio (OR), 0.04, P < 0.01). OBLT was used in 26/123 (21.1%) patients with cellulitis before and 69/70 (98.6%) after (OR, 218.8, P < 0.01). Antimicrobial change due to intolerance occurred in 4/123 (3.2%) patients with cellulitis before and 4/70 (5.7%) after (OR, 1.8, P, not significant (NS)) the pathway change. Inpatient admission within 28 days occurred in 15/123 (12.2%) cellulitis patients before and 9/70 (12.9%) after (OR, 1.1, P, NS) the pathway change. Implementation of a change in outpatient cellulitis treatment pathway resulted in a significant change in prescribing practice. Our findings suggest that OBLT was both tolerable and had similar outcomes to OPAT.

Efficacy of a Pharmacy Resident-Driven Beta-Lactam Allergy Assessment at a Community Hospital

Abstract Background Beta-lactams are the most commonly used antibiotics, although they are also associated with hypersensitivity reactions. Although approximately 10% of the population report an allergy to a beta-lactam, identifying erroneous beta-lactam allergies can lead to improved patient outcomes and lower rates of antimicrobial resistance. Methods This study was a single-center, retrospective review of a pharmacy resident driven beta-lactam allergy assessment. The allergy assessment consisted of a chart review and a 3-question interview. The primary outcome of this study was a composite of the following interventions: beta-lactam allergy delabeling, reaction specification, and/or identification of previously tolerated beta-lactams. Secondary outcomes included patients who were relabeled if delabeling occurred, patients who received beta-lactam therapy after changes occurred to their charted allergy, and impact on hospital utilization of beta-lactam alternative antibiotics. Results A total of 42 patients were interviewed between September 13, 2021, and December 17, 2021, with follow-up occurring 90 days after the initial interview. The most common beta-lactam allergy reported was penicillin (90.5%). Of the patients who were assessed, 95.2% met at least one of the components of the primary endpoint. Specifying the previous toleration of beta-lactam agents was the most common intervention, occurring after 78.6% of assessments. Complete delabeling of the patient's beta-lactam allergy occurred after 38.1% of the interviews conducted. Conclusions A pharmacy-resident driven beta-lactam allergy assessment was effective at clarifying beta-lactam allergies, including the complete delabeling of erroneous beta-lactam allergies.

Treatment of Enterococcus faecalis Infective Endocarditis: A Continuing Challenge.

Today, Enterococcus faecalis is one of the main causes of infective endocarditis in the world, generally affecting an elderly and fragile population, with a high mortality rate. Enterococci are partially resistant to many commonly used antimicrobial agents such as penicillin and ampicillin, as well as high-level resistance to most cephalosporins and sometimes carbapenems, because of low-affinity penicillin-binding proteins, that lead to an unacceptable number of therapeutic failures with monotherapy. For many years, the synergistic combination of penicillins and aminoglycosides has been the cornerstone of treatment, but the emergence of strains with high resistance to aminoglycosides led to the search for new alternatives, like dual beta-lactam therapy. The development of multi-drug resistant strains of Enterococcus faecium is a matter of considerable concern due to its probable spread to E. faecalis and have necessitated the search of new guidelines with the combination of daptomycin, fosfomycin or tigecycline. Some of them have scarce clinical experience and others are still under investigation and will be analyzed in this review. In addition, the need for prolonged treatment (6-8 weeks) to avoid relapses has forced to the consideration of other viable options as outpatient parenteral strategies, long-acting administrations with the new lipoglycopeptides (dalbavancin or oritavancin), and sequential oral treatments, which will also be discussed.

Acute bacterial lymphadenitis in children: a retrospective, cross-sectional study

Acute bacterial lymphadenitis is a common childhood condition, yet there remains considerable variability in antibiotic treatment choice, particularly in settings with low prevalence of methicillin-resistant Staphylococcus aureus such as Europe and Australasia. This retrospective cross-sectional study reviewed children presenting with acute bacterial lymphadenitis to a tertiary paediatric hospital in Australia between 1 October 2018 and 30 September 2020. Treatment approaches were analysed with respect to children with complicated versus uncomplicated disease. A total of 148 children were included in the study, encompassing 25 patients with complicated disease and 123 with uncomplicated lymphadenitis, as defined by the presence or absence of an associated abscess or collection. In culture-positive cases, methicillin-susceptible S. aureus (49%) and Group A Streptococcus (43%) predominated, while methicillin-resistant S. aureus was seen in a minority of cases (6%). Children with complicated disease generally presented later and had a prolonged length of stay, longer durations of antibiotics, and higher frequency of surgical intervention. Beta-lactam therapy (predominantly flucloxacillin or first-generation cephalosporins) formed the mainstay of therapy for uncomplicated disease, while treatment of complicated disease was more variable with higher rates of clindamycin use. Conclusion: Uncomplicated lymphadenitis can be managed with narrow-spectrum beta-lactam therapy (such as flucloxacillin) with low rates of relapse or complications. In complicated disease, early imaging, prompt surgical intervention, and infectious diseases consultation are recommended to guide antibiotic therapy. Prospective randomised trials are needed to guide optimal antibiotic choice and duration in children presenting with acute bacterial lymphadenitis, particularly in association with abscess formation, and to promote uniformity in treatment approaches.What is Known:• Acute bacterial lymphadenitis is a common childhood infection.• Antibiotic prescribing practices are highly variable in bacterial lymphadenitis.What is New:• Uncomplicated bacterial lymphadenitis in children can be managed with single agent narrow-spectrum beta-lactam therapy in low-MRSA prevalence settings.• Further trials are needed to ascertain optimal treatment duration and the role of clindamycin in complicated disease.

Analysis of a beta-lactam allergy assessment protocol challenging diverse reported allergies managed by an antimicrobial stewardship program.

To assess the safety and efficacy of a novel beta-lactam allergy assessment algorithm managed by an antimicrobial stewardship program (ASP) team. Retrospective analysis. One quaternary referral teaching hospital and one tertiary care teaching hospital in a large western Pennsylvania health network. Patients who received a beta-lactam challenge dose under the beta-lactam allergy assessment algorithm. A beta-lactam allergy assessment protocol was designed and implemented by an ASP team. The protocol risk stratified patients' reported allergies to identify patients appropriate for a challenge with a beta-lactam antibiotic. This retrospective analysis assessed the safety and efficacy of this protocol among patients receiving a challenge dose from November 2017 to July 2021. Over a 45-month period, 119 total patients with either penicillin or cephalosporin allergies entered the protocol. Following a challenge dose, 106 (89.1%) patients were treated with a beta-lactam. Eleven patients had adverse reactions to a challenge dose, one of which required escalation of care to the intensive care unit. Of the patients with an unknown or low-risk reported allergy, 7/66 (10.6%) had an observed adverse reaction compared to 3/42 (7.1%) who had an observed reaction with a reported high-risk or anaphylactic allergy. Our implemented protocol was safe and effective, with over 90% of patients tolerating the challenge without incident and many going on to receive indicated beta-lactam therapy. This protocol may serve as a framework for other inpatient ASP teams to implement a low-barrier allergy assessment led by ASP teams.

Outcomes of high-dose oral beta-lactam definitive therapy compared to fluoroquinolone or trimethoprim-sulfamethoxazole oral therapy for bacteremia secondary to a urinary tract infection.

Compare outcomes of patients receiving high-dose oral beta-lactam versus standard oral therapy for Enterobacterales bacteremia from a urinary tract infection (UTI). Retrospective, multicenter, observational cohort. Three Michigan community teaching hospitals. Adult patients admitted between February 1, 2020, and October 1, 2022, with gram-negative bacteremia from a urinary source were evaluated. Patients receiving active empiric intravenous (IV) antibiotics and transitioned to appropriately dosed oral cephalexin, amoxicillin, fluoroquinolone (FQ), or trimethoprim/sulfamethoxazole (TMP/SMX) were included. Patients receiving less than 72 hours of oral therapy, diagnosed with renal abscess, lobar nephronia, or expired during admission were excluded. Standard oral therapy was defined as FQ or TMP/SMX. The primary outcome compared the composite of recurrent bacteremia or mortality within 30 days of therapy between groups. Secondary outcomes compared recurrent UTI, emergency department or hospital readmission, and Clostridioides difficile within 30 days. 194 patients were included (beta-lactam, n = 75 vs standard therapy, n =119). Patients in both groups were treated for a median of 11 days, with 4 days IV and 7 days oral therapy. There was no difference in the primary outcome between groups (beta-lactam 1.3% vs standard therapy 1.7%, OR 1.27 [95% CI 0.11-14.2]). No patients experienced C. difficile in either group (p = 1.0). Infectious disease consultation was independently associated with standard therapy prescribing (OR 4.4 [95% CI 2.24-8.26]). High-dose oral beta-lactams were as safe and effective as oral FQ or TMP/SMX for the treatment of bacteremia from a urinary source. Most patients received 8-10 days of therapy in both groups.

Beta-lactam comprehensive allergy management program in a community medical center.

The Beta-lactam Comprehensive Allergy Management Program (CAMP) was implemented to facilitate complete beta-lactam allergy history documentation in the electronic medical record (EMR) and increase beta-lactam utilization. The study objective was to assess the rate of complete allergy histories and days of antimicrobial therapy (DOT) before versus after CAMP implementation. Quasi-experimental study with interrupted time-series analysis. Non-teaching, urban, and community medical center within a multi-hospital health system. Adult inpatients with a beta-lactam allergy receiving antimicrobial therapy. The multidisciplinary CAMP team screened, interviewed, and collected allergy history details of adult inpatients with a beta-lactam allergy receiving antimicrobial therapy starting January 4, 2021. Patients were stratified as high, moderate, or low risk of IgE-mediated allergy and referred to an allergist for skin testing or drug challenge. The EMR was updated with interview details and drug challenge or skin test results. The primary endpoint was rate of complete allergy history documentation before (12/1/18-4/1/19) compared to after (1/4/21-5/1/21) program implementation. The secondary endpoint was days of inpatient beta-lactam therapy. Implementation logistics, de-labeling rate, and antimicrobial therapy changes were evaluated. The program evaluated 392 individuals, with 184 and 208 patients comprising the pre- and post-intervention groups, respectively. The post-intervention period was associated with an increase of 19.8% in complete allergy histories (0.359 PPc; R 2 0.26; p = 0.002) and 9.34 beta-lactam DOT per 1,000-days-present (1.106 PPc; R 2 0.194; p = 0.009). Implementation of a comprehensive beta-lactam allergy management program was associated with higher rates of complete beta-lactam allergy history and beta-lactam use.

1805. Safety Outcomes Following Beta-Lactam use in Patients with a Documented Beta-Lactam Allergy

Abstract Background Management of bacterial infections typically consist of beta-lactam antibiotics. Individuals with histories of beta-lactam allergy are more likely to receive alternative broad-spectrum antibiotics which may be less efficacious or lead to increased adverse events. Patients can be prescribed full doses of structurally non-related beta-lactam antibiotics due to the low similarity of side chains between these medications and penicillin, and the low incidence of penicillin allergies being true allergies. Nevertheless, there is a lack of data regarding safety outcomes in patients who are treated with a beta lactam with a documented allergy. Methods This was a single-center retrospective observational study of patients with a documented beta-lactam allergy who received at least one dose of any beta-lactam antimicrobial excluding aztreonam from SUNY Downstate Health Sciences University between January 2015 – October 2021. Electronic medical records were reviewed for relevant study data. The primary outcome was the incidence of allergic reaction on full dose beta lactam with a documented allergy in the medical record. Results Baseline characteristics are summarized in Table 1. Two patients experienced a suspected allergic reaction while on beta-lactam therapy. Anaphylaxis was not reported and pharmacologic rescue agents were not required for each case. The antimicrobial agent was changed after the reaction was noted in both cases. Conclusion Patients who were administered beta-lactam antimicrobials with beta-lactam allergy had low rates of allergic reaction. The rate of allergic reactions observed is similar to the incidence of allergy in patients without documented allergies reported in the literature. Administration of beta-lactams with dissimilar side chains such as beta-lactam beta-lactamase inhibitors and third and fourth generation cephalosporins were safely administered to patients with a documented allergy. Disclosures All Authors: No reported disclosures.

1822. Clinical Outcomes Associated with Oral Beta-Lactam Therapy versus Oral Fluoroquinolones/TMP-SMX for Uncomplicated Gram-Negative Bacteremia

Abstract Background Agents commonly used as oral step-down therapy in Enterobacterales bacteremia include fluoroquinolones and TMP-SMX. The use of these oral agents have been associated with adverse events. Oral β-lactams are not recommended to treat Enterobacterales bacteremia because of concerns for sub-therapeutic serum concentrations. Given the limited data on clinical effectiveness of oral β-lactams and increased limitations with fluoroquinolones and TMP-SMX, oral β-lactams may be an alternative option. The purpose of this study is to evaluate the clinical effectiveness in patients transitioned to oral β-lactams versus fluoroquinolones or TMP-SMX for the step-down treatment of uncomplicated Enterobacterales bacteremia. Methods A multi-center, retrospective, propensity-score matched, observational cohort study was conducted from July 1, 2017 to December 31, 2020, at 11 Memorial Hermann Health System hospitals among 690 patients with uncomplicated Enterobacterales bacteremia. Patients were included if they received &amp;gt; 1 day of intravenous antibiotic therapy followed by definitive oral step-down therapy with a β-lactam, fluoroquinolone, or TMP-SMX. The primary outcome was treatment failure within 30 days of starting oral antibiotics, defined as at least one of the following: recurrent bacteremia, transition to IV antibiotics, new-onset sepsis, 30-day readmission, or 30-day all-cause mortality. Results After the patients were propensity score matched 1:1, a total of 199 patients with uncomplicated Enterobacterales bacteremia were included in each group. Treatment failure occurred in 8 patients (4%) who received β-lactams and 10 patients (5%) who received fluoroquinolones or TMP-SMX (OR, 0.79 [95% CI, 0.306-2.04] p-value 0.629). Median length of hospital stay was 5 days for both groups (p-value 0.911), and median duration of oral antibiotics was 10 days in the fluoroquinolone or TMP-SMX group and 11 days in the β-lactam group (p-value 0.377). Conclusion Based on the results of this study, no significant difference in treatment failure was seen in patients who were transitioned to β-lactams versus fluoroquinolones or TMP-SMX as oral step-down therapy for uncomplicated Enterobacterales bacteremia. Oral β-lactams appear to be a safe and effective option. Disclosures All Authors: No reported disclosures.

184. Impact of the BioFire® FilmArray® Blood Culture Identification 2 Panel on Antimicrobial Treatment of Enterobacterales Blood Stream Infections

Abstract Background The BioFire® FilmArray® Blood Culture Identification 2 (BCID2) panel is a rapid diagnostic tool that uses multiplex polymerase chain reaction technology to identify 43 different genetic targets. BCID2 detects 13 additional targets, including 7 resistance markers, not detected by the original BCID panel. For this reason, our institution changed panels from BCID to BCID2 in August 2020. The purpose of this study was to assess the time to antibiotic change for Enterobacterales bloodstream infections before and after switch to BCID2. Methods This was a retrospective, observational, before-and-after study conducted at an 885-bed academic medical center. Adult patients with blood cultures positive for E. coli or K. pneumoniae (EC/KP) who received broad spectrum beta-lactam therapy were included. Patients with a polymicrobial or concurrent infection, hemodynamic instability, lack of source control by day 5, or death within 72 hours (hrs) of cultures being collected were excluded. The primary outcome was time to antibiotic change in the BCID group compared to the BCID2 group. Secondary outcomes included time to de-escalation or escalation and the number of opportunities for de-escalation or escalation. Results 88 patients were included, 55 in the BCID-group and 33 in the BCID2-group. Baseline characteristics are reported in Table 1. Median time to first antibiotic change was 65.3 hrs in the BCID-group vs 69.6 hrs in the BCID2-group (p=0.53). Times to first de-escalation and escalation and number of opportunities for de-escalation and escalation are presented in Table 2. Proportion of missed de-escalation opportunities based on panel results was greater in the BCID2 group (63.6% vs 0%, p&amp;lt; 0.05). Conclusion Opportunities to make timely antibiotic modifications with the use of the BCID2 panel exist for EC/KP blood stream infections. While no difference in time to first antibiotic change was present between groups, this highlights the importance of having an active stewardship team member available to respond to rapid diagnostic test results. Disclosures All Authors: No reported disclosures.

UTILIZATION OF A HOSPITALIST DRIVEN PENICILLIN SKIN TESTING PROTOCOL TO PROMOTE ANTIBIOTIC STEWARDSHIP

<h3>Introduction</h3> Antibiotic resistance is an increasing problem throughout the world. Inappropriate labeling of penicillin allergies results in suboptimal antibiotic selection for patients. Penicillin skin testing is a valuable tool for facilitating a switch to beta-lactam antibiotics. <h3>Methods</h3> A retrospective analysis of all patients with a documented history of penicillin allergy were included in the study from March 2017 to May 2019; a total of 128 patients were included. Analysis involved nature of penicillin allergy and results of penicillin skin test. Benzylpenicilloyl polylysine (PRE-PEN®) tested major determinant, and diluted penicillin G tested minor determinant. The primary outcome of the study is the rate of antibiotic deescalation, and secondary outcome is a comparison of the duration of non beta-lactam therapy in appropriately re-labeled versus non re-labeled subjects (student t-test). <h3>Results</h3> 12 of 128 patients (9.4%) had a negative histamine test and were labeled indeterminate. Of the remaining 116 patients, 111 had a negative test (95.7%) and 5 (4.3%) had a positive test to PRE-PEN ® or dilute penicillin G. 78 of the 111 negative (70.3%) were switched to a narrower spectrum-based antibiotic, and subsequently did not experience allergic reaction. There was a significantly decreased use of vancomycin, aztreonam, carbapenem, fluoroquinolone and clindamycin. There was no significant difference in duration of non beta-lactam therapy in appropriately re-labeled versus non re-labeled subjects (3.6 days vs. 4.25 days; p=0.35). <h3>Conclusion</h3> Our protocol has demonstrated that a penicillin skin testing protocol can substantially reduce broad spectrum antibiotic use and increase antibiotic stewardship.

Dual beta-lactam treatment: Pros and cons.

The battle against microscopic pathogens has always baffled the scientific community. Nowadays, multidrug-resistant microorganisms lead to high in-hospital mortality, increased hospital stays, and high health-related costs. Treating infections due to these high-resistance pathogens with a low number of antibiotic molecules creates the need for new strategies. Although some already think of a "postantibiotic era" with bacteriophages as the main futuristic weapon in antibacterial armament, others rethink the usage of the already existent drugs. Dual beta-lactam therapy has been used for quite some time as an empirical therapy for some severe infections such as endocarditis or meningitis. However, studies regarding the use of a beta-lactam combination stopped being made a long time ago, and it seems the scientific community has no interest in evaluating this as a treatment option. Could this strategy be applied to treat infections due to multidrug-resistant bacteria? Could this be the answer while waiting for the "postantibiotic era"? What kind of pathogens could we fight using dual beta-lactams? What are the downsides of this strategy? These are some of the questions the authors try to answer in this review. In addition, we try to convince our peers to turn once more into researching beta-lactam combinations and exploring its potential benefits.