Microbiological Failure Research Articles

239. Comparing Alternative Treatment Options for Stenotrophomonas maltophilia bacteremia

Abstract Background Stenotrophomonas maltophilia can cause nosocomial infections in immunocompromised hosts and patients with indwelling devices or broad-spectrum antibiotic exposure. Treatment of S maltophilia infections poses a challenge due to intrinsic resistance mechanisms, including inducible L1 metallo and L2 cephalosporinase beta-lactamases. Trimethoprim-sulfamethoxazole (SXT) is recognized as the agent of choice for S maltophilia infections. Outcomes with alternative antimicrobials are not well described. Methods We conducted a retrospective study of adults with positive blood cultures with S maltophilia who received ≥48h of directed antimicrobials at our institution between 3/2013 and 6/2022. Patients were stratified by their antimicrobial treatment, including levofloxacin, SXT, minocycline, ceftazidime, or combination therapy. The primary outcome was 30d all-cause mortality. Secondary outcomes were microbiological and clinical cure. Microbiological failure was defined as blood cultures growing S maltophilia during or within 7d of discontinuing therapy. Clinical failure was defined as a lack of resolution of signs or symptoms of infection requiring therapy adjustment. Results Of 67 patients with positive S maltophilia blood cultures, 53 patients treated with levofloxacin (n = 27), SXT (n = 10), minocycline (n = 8), combination (n = 5) or ceftazidime (n = 3) were included. The remaining 14 patients were excluded for receiving < 48h of therapy. The median Charlson comorbidity index was 4 [IQR 3-6]. The most common source of bacteremia was catheter-related (n = 27). Overall, 30d mortality was 26.4%. There was no significant difference in 30d mortality among patients treated with levofloxacin, SXT, minocycline, combination or ceftazidime (p = 0.23). Interestingly, patients with monomicrobial S maltophilia bacteremia had statistically higher 30d mortality (35.3% versus 11.8%, p < 0.05). Microbiological and clinical cure rates were similar between treatment groups (p = 0.06 and p = 0.16, respectively). Conclusion Treatment options for S maltophilia bacteremia resulted in similar 30d mortality; however, findings were limited by the small sample size. Larger, prospective studies are warranted to detect differences in treatment alternatives. Disclosures All Authors: No reported disclosures

1222. Impact of Microbiology Reporting Changes in Treatment of AmpC Bloodstream Infections

Abstract Background Recent literature suggests that AmpC production may be overcalled in Enterobacterales, leading to unnecessary broad-spectrum antimicrobial utilization. The Infectious Diseases Society of America (IDSA) has since reassessed classification of high and low risk organisms with inducible AmpC expression. With this updated guidance, our health system approved changes to our microbiology reporting of AmpC producers in an effort to guide prescribing of appropriate antibiotics. The primary objective of this project was to compare antibiotic prescribing patterns for high and low risk AmpC producers in patients with bloodstream infections (BSI) based on the addition of appended comments to antimicrobial susceptibility results. Methods This multicenter, retrospective, cohort study included patients with BSI from October 2022 to March 2023who received at least 48 hours of antimicrobial therapy for the following high and low risk AmpC producers: Citrobacter spp., Enterobacter spp., Klebsiella aerogenes, Serratia spp., Morganella spp., Providencia spp. The primary endpoint was the number of patients placed on optimal therapy based on adherence to the appended microbiology comment and IDSA guidance. Secondary endpoints included time to effective treatment, time to optimal treatment, duration of therapy, 30 day mortality, microbiological failure, microbiological relapse, 30 day readmission, length of stay, and hospital acquired Clostridioides difficile infection. Results A total of 191 positive blood cultures were identified with 93 patients (pre-appended comment = 57; post-appended comment = 36) meeting inclusion criteria. Patients were more likely to receive optimal therapy post-appended comment based on IDSA guidance for BSI (38.6% vs 72.2%, OR 4.14; 1.68-10.21). When stratified by high risk and low risk organism, the number of patients on optimal therapy increased in the post-appended comment group but was not statistically significant (high risk: 70.3% vs 88%, OR 3.08; 0.72-13.32; low risk: 10% vs 36.3%, 5.14; 0.92-28.50). No difference in secondary outcomes were detected. Conclusion Implementation of an appended microbiology note has the potential to have a positive impact on antimicrobial prescribing patterns in treatment of AmpC bloodstream infections. Disclosures All Authors: No reported disclosures

Could an optimized joint pharmacokinetic/pharmacodynamic target attainment of continuous infusion ceftazidime-avibactam be a way to avoid the need for combo therapy in the targeted treatment of deep-seated DTR Gram-negative infections?

The objective of this study was to assess the relationship between joint pharmacokinetic/pharmacodynamic (PK/PD) target attainment of continuous infusion (CI) ceftazidime-avibactam and the microbiological outcome of documented difficult-to-treat resistant (DTR) Gram-negative infections. A 2-year retrospective cohort study was performed in patients receiving CI ceftazidime-avibactam mono- or combo therapy for documented DTR Gram-negative infections and undergoing therapeutic drug monitoring of both ceftazidime and avibactam. The free fractions of steady-state concentrations (fCss) of ceftazidime and avibactam were calculated. The joint PK/PD target was considered optimal when both the fCss/MIC ratio for ceftazidime ≥4 (equivalent to 100% fT>4xMIC) and the fCss/CT ratio for avibactam >1 (equivalent to 100% fT >CT of 4.0 mg/L) were simultaneously achieved (quasi-optimal if only one of the two and suboptimal if neither of the two was achieved). Multivariate logistic regression analysis was applied for testing potential variables associated with microbiological failure. Fifty-eight patients were treated with CI ceftazidime-avibactam mono- (36) or combo therapy (22) for documented DTR Gram-negative infections [74.2% for primary or secondary bloodstream infections (BSIs)]. Combo therapy was administered more frequently to intensive care unit (ICU) patients (P = 0.023) or for pneumonia (P = 0.001) and less frequently for intra-abdominal infections and BSIs (P = 0.04). Microbiological failure occurred in five cases (8.6%, three in mono- and two in combo therapy). In the multivariate analysis, the suboptimal/quasi-optimal joint PK/PD target emerged as the only independent predictor of microbiological failure (odds ratio [OR] 11.11; 95% confidence interval [CI] 1.31-93.98; P = 0.023), whereas monotherapy was not (P = 0.99). Optimized joint PK/PD target attainment of CI ceftazidime-avibactam monotherapy could represent a way forward for allowing microbiological eradication of DTR Gram-negative infections and could render unnecessary combo therapy.

Development of VRE meningitis due to haematogenous spread while on high-dose daptomycin therapy.

Vancomycin-resistant Enterococcus faecium (VRE) meningitis accounts for only 0.3%-4.0% of bacterial meningitis cases and typically occurs following neurosurgical intervention. We describe a rare case of a patient without neurological devices in situ or a recent neurological procedure who developed VRE meningitis via haematogenous spread. Optimal treatment for VRE meningitis is unknown. A 67-year-old male with end-stage liver failure underwent liver transplantation complicated by VRE bacteraemia and subsequently developed VRE meningitis while on high-dose daptomycin therapy (12 mg/kg/day). Due to clinical and microbiological failure with daptomycin, he was switched to linezolid and symptoms resolved rapidly. He completed 2 weeks of linezolid, fully recovered, and continued to do well without complications at the 5 month follow-up. This case highlights the severity of VRE infections in solid organ transplant recipients and raises concerns about daptomycin penetration into the CNS. Linezolid could be considered the preferred treatment for VRE CNS infections rather than high-dose daptomycin.

Ertapenem Versus Meropenem for the Treatment of Extended Spectrum Beta-Lactamase-Producing Enterobacterales Bacteremia in Critically Ill Patients.

The preferred carbapenem for treatment of infections caused by extended spectrum beta-lactamase-producing Enterobacterales (ESBL-E) in critically ill patients is debated. The purpose of this study was to evaluate the difference in clinical failure between ertapenem and meropenem for treatment of ESBL-E bacteremia in critically ill patients. Of concern is ertapenem use in hypoalbuminemia given the potential for higher drug clearance. This retrospective, matched cohort study compared critically ill patients treated with ertapenem or meropenem for ESBL-E bacteremia between October 2016 and August 2022. Patients were matched on age, sex, lowest albumin, and in a 1:2 ratio of ertapenem to meropenem. The primary outcome, clinical failure, was a composite of 30-day mortality, antibiotic escalation, and microbiological failure. Secondary outcomes included all-cause readmission and development of superinfection. Of 54 patients, 18 received ertapenem and 36 meropenem. Most had a urinary infection source (55.6% vs 41.7%, P = 0.393). There was no difference in clinical failure (50.0% vs 38.9%, P = 0.436). Ertapenem patients had antibiotic escalation more often (33.3% vs 2.8%, P = 0.002). There was no difference in 30-day mortality (11.1% vs 27.8%, P = 0.298), microbiological failure (27.8% vs 11.1%, P = 0.142), all-cause readmission (22.2% vs 13.9%, P = 0.461), or development of superinfection (11.1% vs 13.9%, P = 1.000). There was no difference in clinical failure in a small, retrospective cohort of critically ill patients receiving ertapenem or meropenem for ESBL-E bacteremia. Ertapenem may be appropriate in some critically ill and hypoalbuminemic patients, though additional data are needed.

Clinical outcomes of ceftolozane-tazobactam dosing in patients with sepsis undergoing renal replacement therapies.

A retrospective descriptive study conducted at our institution between May 1, 2017, and March 15, 2022. The primary endpoint was to determine the clinical cure for patients who received C/T for documented infection while on RRT. The secondary endpoints were the microbiologic cure, 30-day infection recurrence, and 30-day crude mortality. Of the 27 patients who met the inclusion criteria, 17 (63%) were males, median age was 69 (62 - 82) years, and weight 67 (57 - 79) kg. The majority of patients had pneumonia 19 (70.4%) followed by bacteremia 5 (18.5%). Multidrug resistant Pseudomonas spp. was the causative organism of infection in 22 subjects (81.5%). Clinical cure was achieved in 17 subjects (63%). Of the 14 subjects who had their culture repeated, 10 (71.4%) patients had microbiologic cure vs. 4 (28.5%) patients who had a microbiologic failure (p = 0.327). 30-day infection recurrence occurred in 6 (35.3%) patients of the clinical cure group and 2 (20%) patients in the clinical failure group (p = 0.362), while mortality occurred in 5 (29.4%) subjects vs. 7 (70%) in both groups, respectively (p = 0.049). The most frequently used doses of C/T were 1.5 g IV q8h while undergoing continuous venovenous hemodiafiltration and 0.75 g IV q8h while undergoing hemodialysis (p = 0.209). The median duration of therapy was 9 (4.5 - 13) days in the clinically cured group vs. 5 (3.75 - 5.5) days in those who had clinical failure (p = 0.038). There was no adverse event reported using these doses during the study period. The used doses of C/T in this study were higher than those approved by the U.S. FDA, while clinical success is uncertain. Larger outcomes and pharmacokinetics studies are needed to establish effective dosing and therapy duration.

Pharmacokinetic/Pharmacodynamic Target Attainment of Continuous Infusion Piperacillin-Tazobactam or Meropenem and Microbiological Outcome among Urologic Patients with Documented Gram-Negative Infections.

(1) Objectives: To describe the relationship between pharmacokinetic/pharmacodynamic (PK/PD) target attainment of continuous infusion (CI) piperacillin-tazobactam or meropenem monotherapy and microbiological outcome in a case series of urological patients with documented Gram-negative infections. (2) Methods: Patients admitted to the urology ward who were treated with CI piperacillin-tazobactam or meropenem monotherapy for documented Gram-negative infections and underwent real-time therapeutic drug monitoring (TDM)-guided expert clinical pharmacological advice (ECPA) program from June 2021 to May 2023 were retrospectively retrieved. Average steady-state (Css) piperacillin-tazobactam and meropenem concentrations were determined, and the free fractions (fCss) were calculated. Optimal PK/PD target attainments were defined as an fCss/MIC ratio >4 for CI meropenem and an fCss/MIC ratio of piperacillin >4 coupled with an fCss/CT ratio for tazobactam >1 for piperacillin-tazobactam (joint PK/PD target). The relationship between beta-lactam PK/PD targets and microbiological outcome was explored. (3) Results: Sixteen urologic patients with documented Gram-negative infections (62.5% complicated urinary tract infections (cUTI)) had 30 TDM-guided ECPAs. At first TDM assessment, beta-lactam dosing adjustments were recommended in 11 out of 16 cases (68.75%, of which 62.5% decreases and 6.25% increases). Overall, beta-lactam dosing adjustments were recommended in 14 out of 30 ECPAs (46.6%). Beta-lactam PK/PD target attainments were optimal in 100.0% of cases. Microbiological failure occurred in two patients, both developing beta-lactam resistance. (4) Conclusion: A TDM-guided ECPA program may allow for optimizing beta-lactam treatment in urologic patients with documented Gram-negative infections, ensuring microbiological eradication in most cases.

Outcome of patients with carbapenem-resistant Acinetobacter baumannii infections treated with cefiderocol: A multicenter observational study

BackgroundNo clear evidence supports the use of cefiderocol as first line treatment in A. baumannii infections. MethodsWe conducted an observational retrospective/prospective multicenter study including all patients> 18 years with carbapenem-resistant A. baumannii (CRAB) infections treated with cefiderocol, from June 12021 to October 30 2022. Primary endpoint was 30-day mortality, secondary end-points the clinical and microbiological response at 7 days and at the end of treatment. Furthermore, we compared the clinical and microbiological outcomes among patients who received cefiderocol in monotherapy or in combination. ResultsThirty-eight patients with forty episodes of infection were included [mean age 65 years (SD+16.3), 75% males, 90% with hospital-acquired infections and 70% showing sepsis or septic shock]. The most common infections included unknown source or catheter-related bacteremia (45%) and pneumonia (40%). We observed at 7 days and at the end of therapy a rate of microbiological failure of 20% and 10%, respectively, and of clinical failure of 47.5% and 32.5%, respectively; the 30-day mortality rate was 47.5%. At multivariate analysis clinical failure at 7 days of treatment was the only independent predictor of 30-day mortality. Comparing monotherapy (used in 72.5%) vs. combination therapy (used in 27.5%), no differences were observed in mortality (51.7 vs 45.5%) and clinical (41.4 vs 63.7%) or microbiological failure (24.1 vs 9.1%). ConclusionsThe findings of this study reinforce the effectiveness of cefiderocol in CRAB infections, also as monotherapy. However, prospective multicenter studies with larger sample sizes and a control group treated with standard of care are needed to identify the best treatment for CRAB infections.

Real-world clinical outcomes of cefiderocol therapy in the Veterans Health Administration, 2019–2022

Background: Cefiderocol is a novel siderophore cephalosporin with broad-spectrum activity. In the CREDIBLE-CR phase 3 clinical trial examining treatment of carbapenem-resistant gram-negative infections, cefiderocol had similar clinical and microbiological efficacy compared to the best available therapy, but the mortality rate was unexpectedly higher in the cefiderocol group. We investigated the postapproval, real-world clinical outcomes of cefiderocol therapy. Methods: We conducted a prospective, observational study of patients who received cefiderocol for at least 2 days within the Veterans’ Health Administration (VHA) between the date of approval by the US Food and Drug Administration (FDA), November 14, 2019, and August 31, 2022. Types of infections were defined by NHSN criteria. Clinical failure was a composite outcome based on type of infection including survival (30- and 90-day mortality) and resolution of signs and symptoms of infection. Microbiologic failure was defined as culturing the same organism, as defined by the CDC NHSN, at least 7 days after the start of cefiderocol. Structured data were sourced from the VHA Corporate Data Warehouse, and each eligible episode underwent manual chart review. Results: During the study period, 8,763,652 patients across 132 VA medical centers received 1,142,940,842 prescriptions (not limited to antibiotics). Overall, 48 unique individuals had received cefiderocol, with 48 cefiderocol courses prescribed. Patients had a median age of 70.5 years (range, 61–75), and a median Charlson comorbidity score of 6 (range, 2–9). The most common infectious syndromes were lower respiratory tract infection in 23 (47.9%) of these 48 patients and urinary tract infection in 14 (29.2%) of these patients. The most common pathogens cultured were P. aeruginosa in 30 patients (62.5%), Enterobacterales in 17 patients (35.4%), and A. baumannii in 10 patients (20.8%). The clinical failure rate was 35.4% (17 of 48), and 15 (88.2%) of these 17 patients died within 3 days of clinical failure. The 30-day and 90-day microbiologic failure rates were 33.3% (16 of 48) and 45.8% (22 of 48), respectively. The 30-day and 90-day all-cause mortality rates were 27.1% (13 of 48) and 45.8% (22 of 48), respectively (Table 1). Conclusions: Our study cohort included older individuals with multiple comorbidities who were treated with cefiderocol mainly for lower respiratory tract and urinary tract infections, with Pseudomonas aeruginosa as the main causative pathogen. Clinical and microbiologic failure were seen in>30% of patients, and >40% of these patients died within 90 days. These data contribute to the growing body of literature on the real-world use of cefiderocol and provide outcome data on clinical failure, microbiologic failure, and mortality.Financial support: This study was supported by the Department of Veterans Affairs Clinical Science Research and Development (VA CSRD grant no. IK2 CX001981).Disclosures: None

Cefepime Versus Piperacillin-Tazobactam for the Treatment of Intra-Abdominal Infections Secondary to Potential AmpC Beta-Lactamase-Producing Organisms.

Background: Recent studies have established cefepime as an effective treatment option for AmpC beta-lactamase (AmpC) Enterobacterales; however, the efficacy of beta-lactam/beta-lactamase inhibitors is unclear. Objective: The objective of this study was to determine if piperacillintazobactamis an appropriate alternative to cefepime for the treatment of intra-abdominal infections (IAIs) secondary to AmpC-producing organisms. Methods: This multicenter, retrospective cohort study was conducted in hospitalized adults with an IAI caused by an AmpC-producing organism and received either cefepime or piperacillin-tazobactam for definitive treatment after a source control procedure. The primary outcome was a composite of surgical site infections, recurrent IAIs, or in-hospital mortality. Secondary outcomes included the individual components of the composite outcome, hospital length of stay (LOS), microbiologic failure, study antibiotic duration, time to clinical resolution, and incidence of Clostridioides difficile infection (CDI). Results: This study included 119 patients. There was no difference in the primary outcome between the cefepime and piperacillin-tazobactam groups (35% vs 27%, P = 0.14). Microbiological failure was the only secondary outcome with an observed difference between groups (17% vs 0%, P = 0.01): hospital LOS (15 vs 13 days, P = 0.09), days of therapy (7 vs 7 days, P = 0.87), time to clinical resolution (7 vs 4 days, P = 0.30), and CDI (1% vs 2%, P = 0.58) were all similar.

In Vitro Activities and Inoculum Effects of Cefiderocol and Aztreonam-Avibactam against Metallo-β-Lactamase-Producing Enterobacteriaceae.

Cefiderocol and aztreonam-avibactam (ATM-AVI) both had activity against carbapenem-resistant Gram-negative bacilli, including those that produce metallo-β-lactamases (MBLs). We compared the in vitro activities and inoculum effects of these antibiotics against carbapenemase-producing Enterobacteriaceae (CPE), especially MBL-producing isolates. The MICs of cefiderocol and ATM-AVI were determined using broth microdilution method for a 2016 to 2021 collection of Enterobacteriaceae isolates which produced MBL, KPC, or OXA-48-like carbapenemases. MICs with high bacteria inoculum were also evaluated for susceptible isolates. A total of 195 CPE were tested, including 143 MBL- (74 NDM, 42 IMP, and 27 VIM), 38 KPC-, and 14 OXA-48-like-producing isolates. The susceptible rates of MBL-, KPC-, and OXA-48-like producers to cefiderocol were 86.0%, 92.1%, and 92.9%, respectively, and that to ATM-AVI were 95.8%, 100%, and 100%, respectively. NDM producers displayed lower susceptibility and higher MIC50s/MIC90s of cefiderocol (78.4%, 2/16 mg/L) than IMP (92.9%, 0.375/4 mg/L) and VIM (96.3%, 1/4 mg/L) producers. NDM- and VIM-producing Escherichia coli showed lower susceptibility to ATM-AVI (77.3% and 75.0%, respectively) compared to MBL-CPE of other species (100% susceptible). Inoculum effects for cefiderocol and ATM-AVI were observed among 95.9% and 95.2% of susceptible CPE, respectively. A switch from susceptible to resistant category was observed in 83.6% (143/171) of isolates for cefiderocol and 94.7% (179/189) for ATM-AVI. Our results revealed that NDM-producing Enterobacteriaceae had lower susceptibility to cefiderocol and ATM-AVI. Prominent inoculum effects on both antibiotics were observed for CPE, which suggested a risk of microbiological failure when they were used for CPE infections with high bacteria burden. IMPORTANCE The prevalence of infections caused by carbapenem-resistant Enterobacteriaceae is increasing worldwide. Currently, therapeutic options for metallo-β-lactamase (MBL)-producing Enterobacteriaceae remain limited. We demonstrated that clinical metallo-β-lactamase (MBL)-producing Enterobacteriaceae isolates were highly susceptible to cefiderocol (86.0%) and aztreonam-avibactam (ATM-AVI) (95.8%). However, inoculum effects on cefiderocol and ATM-AVI were observed for over 90% of susceptible carbapenemase-producing Enterobacteriaceae (CPE) isolates. Our findings highlight a potential risk of microbiological failure when using monotherapy with cefiderocol or ATM-AVI to treat severe CPE infection.

Short course antibiotic treatment of Gram-negative bacteraemia (GNB5): a study protocol for a randomised controlled trial

IntroductionProlonged use of antibiotics is closely related to antibiotic-associated infections, antimicrobial resistance and adverse drug events. The optimal duration of antibiotic treatment for Gram-negative bacteremia (GNB) with a urinary tract...

A novel method to evaluate ceftazidime/avibactam therapy in patients with carbapenemase-producing Enterobactericeae (CPE)bloodstream infections.

This study reports experience managing eight patients with bloodstream infections treated with a continuous infusion of ceftazidime-avibactam. Patients who were treated for documented CPE BSIs susceptible to CAZ-AVI and who underwent real-time therapeutic drug monitoring were retrospectively assessed. Ceftazidime MICs were assessed in presence of increasing concentrations of avibactam by the broth microdilution method. An inhibitory sigmoid Emax model was used to characterize ceftazidime MIC reduction as a function of avibactam concentration, and the MICi was derived by conditioning the best-fit model using steady-state avibactam concentrations (Css). Ceftazidime fCss/MICi ratio was calculated for each patient and correlated to microbiological outcome. By adopting the innovative concept of effective MIC with an inhibitor (MICi), a trend towards higher microbiological failure and resistance development was found in patients with a lower ceftazidime fCss/MICi ratio (2/3 vs. 0/5). Assessment of changes in the ceftazidime MIC in relation to increasing avibactam concentration could represent a more robust pharmacokinetic/pharmacodynamic method for predicting microbiological failure given beta-lactam/beta-lactamase inhibitor combinations.

Piperacillin/tazobactam versus cefepime or carbapenems for cefoxitin-non-susceptible Enterobacter cloacae, Klebsiella aerogenes, Citrobacter freundii, Serratia marcescens and Morganella morganii bacteraemia in immunocompromised patients.

The role of piperacillin/tazobactam for treatment of serious infections due to AmpC-producing organisms remains debatable, particularly in immunocompromised patients. This was a retrospective cohort study in immunocompromised patients that investigated the effect of definitive treatment with either piperacillin/tazobactam versus cefepime or carbapenems for bacteraemia caused by cefoxitin-non-susceptible Enterobacterales. The primary endpoint was a composite of clinical and microbiological failure. A logistic regression model was constructed to assess the impact of definitive treatment choice on the primary endpoint. A total of 81 immunocompromised patients with blood cultures positive for cefoxitin-non-susceptible Enterobacterales were included for analysis. There was more microbiological failure in the piperacillin/tazobactam arm compared with the cefepime/carbapenem arm (11.4% versus 0.0%, P = 0.019). Definitive treatment with cefepime or a carbapenem was associated with a decreased odds of clinical or microbiological failure (OR 0.303, 95% CI 0.093-0.991, P = 0.048) when controlling for baseline characteristics. In immunocompromised patients with bacteraemia due to cefoxitin-non-susceptible Enterobacterales, definitive treatment with piperacillin/tazobactam was associated with an increased risk of microbiological failure and higher odds of clinical or microbiological failure compared with cefepime or carbapenems.

Treatment Failure Due to Adaptive Resistance Mechanisms in a Severe and Complicated Bloodstream Infection Due to Elizabethkingia meningoseptica.

Elizabethkingia meningoseptica is an uncommonly encountered multidrug-resistant gram-negative bacterium that causes infections primarily among vulnerable hosts. A true opportunistic pathogen, its ability to cause severe sepsis and complicated infection in selected patients has been noted. Very limited preclinical and clinical data exist with regard to suitable therapeutic options. In this study, we present the case of prolonged bloodstream and central nervous system infection due to E. meningoseptica treated with dose-optimized combination antibiotic therapy, with evidence of microbiological (including development of adaptive resistance mechanisms) and clinical failure.

Sequential oral antibiotic in uncomplicated Staphylococcus aureus bacteraemia: a propensity-matched cohort analysis

ObjectivesWe aimed to analyse the efficacy and safety of oral sequential therapy (OST) in uncomplicated Staphylococcus aureus bacteraemia (SAB). MethodsSingle-centre observational cohort at a tertiary hospital in Spain, including all patients with the first SAB episode from January 2015 to December 2020. We excluded patients with complicated SAB and those who died during the first week. Patients were classified into the OST group (patients who received oral therapy after initial intravenous antibiotic therapy [IVT]), and IVT group (patients who received exclusively IVT). We performed a propensity-score matching to balance baseline differences. The primary composite endpoint was 90-day mortality or microbiological failure. Secondary endpoints included 90-day SAB relapse. ResultsOut of 407 SAB first episodes, 230 (56.5%) were included. Of these, 112 (n = 48.7%) received OST and 118 (51.3%) IVT exclusively. Transition to oral therapy was performed after 7 days (interquartile range, 4–11).The primary endpoint occurred in 10.7% (11/112) in OST vs. 30.5% (36/118) in IVT (p < 0.001). SAB relapses occurred in 3.6% (4/112) vs. 1.7% (2/118) (p 0.436). None of the deaths in OST were related to SAB or its complications.After propensity-score matching, the primary endpoint was not more frequent in the OST group (relative risk, 0.42; 95% CI, 0.22–0.79). Ninety-day relapses occurred similarly in both groups (relative risk, 1.35; 95% CI, 0.75–2.39). DiscussionAfter an initial intravenous antibiotic, patients with uncomplicated SAB can safely be switched to oral antibiotics without apparent adverse outcomes. This strategy could save costs and complications of prolonged hospital stays. Prospective randomized studies are needed.

Epidemiology and Clinical Outcomes of Non-HACEK Gram-Negative Infective Endocarditis.

The objectives of this study were to describe the changing epidemiology of gram-negative infective endocarditis (GNIE) and to identify factors associated with treatment failure and death. Adult patients with GNIE were included if they met modified Duke criteria for definitive infective endocarditis (IE) between April 2010 and December 2021. Patients were identified using Boolean search terms. Clinical failure was a defined as a composite of all-cause 42-day mortality or microbiologic failure. All analyses were performed using Stata, version 15.1. One-hundred twenty-three patients were included. The most common pathogens were Serratia spp. (43%), Pseudomonas aeruginosa (21%), and Klebsiella spp. (14%). Fifty-two percent of cases were among persons who injection drugs (PWID; n = 64), for whom Serratia spp. (70%) was the most common cause of GNIE. Overall, patients infected with P. aeruginosa had higher microbiologic failure rates than other patients (23% vs 6%; P = .004). Patients who received combination therapy (n = 53) had comparable median lengths of stay (23 vs 19.5 days; P = .412), microbiologic failure rates (11.3% vs 7.1%; P = .528), clinical failure rates (18.9% vs 22.9%; P = .592), and 90-day mortality rates (13.2% vs 25.7%; P = .088) as those treated with monotherapy. After applying stepwise logistic regression, male gender, Pitt Bacteremia Score, and not receiving surgical intervention despite a surgical indication were associated with clinical failure. This is the first study to identify Serratia spp. as the most common etiology of GNIE, which was particularly true among PWID. Microbiologic failures occurred most commonly among P. aeruginosa, and use of combination antimicrobial therapy did not improve clinical outcomes.

Real-world experience with cefiderocol therapy for Pseudomonas aeruginosa and other multidrug resistant gram-negative infections within the Veterans Health Administration, 2019-2022.

Single-center and regional studies have reported outcomes after treatment with cefiderocol, a novel siderophore cephalosporin. We report on real-world use, clinical outcomes, and microbiological outcomes with cefiderocol therapy within the Veterans' Health Administration (VHA). Prospective, observational descriptive study. Veterans' Health Administration, 132 sites across the United States, during 2019-2022. This study included patients admitted to any VHA medical center who received cefiderocol for ≥2 days. Data were obtained from the VHA Corporate Data Warehouse and through manual chart review. We extracted clinical and microbiologic characteristics and outcomes. In total, 8,763,652 patients received 1,142,940,842 prescriptions during the study period. Of these, 48 unique individuals received cefiderocol. The median age of this cohort was 70.5 years (IQR, 60.5-74), and the median Charlson comorbidity score was 6 (IQR, 3-9). The most common infectious syndromes were lower respiratory tract infection in 23 patients (47.9%) and urinary tract infection in 14 patients (29.2%). The most common pathogen cultured was P. aeruginosa in 30 patients (62.5%). The clinical failure rate was 35.4% (17 of 48), and 15 (88.2%) of these 17 patients died within 3 days of clinical failure. The 30-day and 90-day all-cause mortality rates were 27.1% (13 of 48) and 45.8% (22 of 48), respectively. The 30-day and 90-day microbiologic failure rates were 29.2% (14 of 48) and 41.7% (20 of 48), respectively. In this nationwide VHA cohort clinical and microbiologic failure occurred in >30% of patients treated with cefiderocol, and >40% of these died within 90 days. Cefiderocol is not widely used, and many of the patients who received it had substantial comorbidities.

1863. Treatment and Outcomes of Cefoxitin-Non-Susceptible Serratia marcescens, Klebsiella aerogenes, Citrobacter freundii, Enterobacter cloacae, and Morganella morganii Bacteremia with Piperacillin/Tazobactam Versus Cefepime or Carbapenem in Immunocompromised Patients

Abstract Background A recent guidance suggested “caution if prescribing piperacillin-tazobactam for serious infections caused by organisms at high risk of significant AmpC production” and that the preferred antibiotic choice should be either cefepime or a carbapenem, despite an admitted lack of definitive evidence. Examination of this question in immunocompromised patients may provide such evidence. Methods This was a retrospective, single-center study conducted from January 2016 to December 2021. We included immunocompromised patients aged 18 years or older who had a laboratory confirmed blood culture positive for Enterobacterales showing non-susceptibility to cefoxitin and were definitively treated with piperacillin-tazobactam, cefepime, or a carbapenem. The primary endpoint was a composite of clinical or microbiological failure, which was comprised of in-hospital 30-day mortality, white blood count &amp;gt;12 x 109/L or temperature &amp;gt;38°C on days 5-7, microbiological failure on days 3-5, or microbiological recurrence/relapse on days 5-30. Results We identified 81 patients who were included for analysis. Baseline characteristics between arms were similar between groups except for more frequent severe neutropenia (p=0.010) and higher Pitt bacteremia scores (p=0.042) in the cefepime/carbapenem group. Within the piperacillin/tazobactam arm, 17 of 35 (48.6%) had clinical or microbiological failure, compared to 17 of 46 (37.0%) patients in the carbapenem/cefepime arm (p=0.294). Microbiological failure occurred in 4 of 35 (11.4%) patients treated with piperacillin/tazobactam compared to 0 of 46 (0%) patients treated with a carbapenem/cefepime (p=0.019). In multivariate analysis, patients treated with a carbapenem/cefepime had a 69% lower odds of clinical or microbiological failure compared to those treated with piperacillin/tazobactam (OR = 0.31; 95% confidence interval, 0.10-0.98). Conclusion In immunocompromised patients with bacteremia due to cefoxitin-non-susceptible Serratia marcescens, Klebsiella aerogenes, Citrobacter freundii, Enterobacter cloacae, or Morganella morganii, definitive treatment with piperacillin/tazobactam was associated with a higher likelihood of microbiological failure compared with treatment with a carbapenem or cefepime. Disclosures All Authors: No reported disclosures.

1982. Epidemiology and Clinical Outcomes of non-HACEK Gram-negative Infective Endocarditis

Abstract Background Infective endocarditis (IE) due to non-HACEK Gram-negative (GN) pathogens is rare, but optimal treatment has not yet been defined. The objective of this study was to report the epidemiology, clinical characteristics, and outcomes of GNIE across our health system. Methods Adult patients with GNIE were identified between April 2010 through December 2021 and included if they met DUKE criteria for definitive IE. Patients with persistently positive blood cultures for Gram-positive pathogens or yeast were excluded if valve cultures did not grow GN bacteria. Clinical failure was defined as a composite of all-cause mortality or microbiologic failure at day 42. Microbiologic failure was defined as an escalation of antimicrobial therapy after emergence of resistance, increased vegetation size, or failure to clear blood cultures by day 14. Results Overall, 123 patients were included. GN pathogens included Serratia spp. (43%), P. aeruginosa (21%), Klebsiella spp. (14%), and other GN bacteria (22%) (Figure). 64 (52%) cases were among persons who inject drugs (PWID) (Table 1). GNIE secondary to Serratia spp. was more common in PWID compared to other pathogens (85% vs 27%; P&amp;lt; 0.001). Microbiologic failure was more common for P. aeruginosa than other pathogens (23% vs 5%; P=0.004). A stepwise multivariate logistic regression model identified age, PITT bacteremia score, and duration of positive blood cultures as independent predictors of clinical failure (Table 2). Patients who received &amp;gt; 72 hours of combination therapy (n=53) had a comparable length of stay (23 days vs 19.5; P=0.412), microbiologic failure rate (11.3% vs 7.1%, P=0.528), clinical failure rate (18.9% vs 22.9%, P=0.592), and 90-day mortality rate (13.2% vs 25.7%, P=0.088) to those who did not receive combination therapy. 80% (4/5) of patients who experienced 30-day readmission secondary to an antimicrobial adverse event received combination therapy. Table 1: Epidemiology and Overview CCI: Charleson Comorbidity Index; MDR: Multiple drug resistance; VGS: Viridans Group Streptococcus spp. #S. marcescens (n=50); S. liquefasciens (n=2); undifferentiated species (n=1) *K. pneumoniae (n=11); K. oxytoca (n=5); K. variicola (n=1); E. coli (n=12); P. mirabilis (n=3); P. vulgaris (n=1); E. cloacae complex (n=2); E. aerogenes (n=1) ^B. cepacia (n=2); S. maltophillia (n=2); A. lwoffi (n=2); P. stutzeri (n=1); A. baumanni (n=1) Table 2: Multivariate Logistic regression for factors associated with 42-day failure Conclusion To our knowledge this is the largest cohort of patients with non-HACEK GNIE, and the first to identify Serratia spp. to be the most common etiology of GNIE, particularly among PWID. Microbiologic failures occurred commonly among P. aeruginosa. Overall, we did not identify a clinical benefit to combination therapy; additional studies are needed to validate these findings. Disclosures Ryan K. Shields, PharmD, MS, Infectious Disease Connect: Advisor/Consultant|Merck: Advisor/Consultant|Merck: Grant/Research Support|Roche: Grant/Research Support.