bluuebunny/crossref_metadata_2025_split huggingface dataset:
1285. Outcomes in Patients with Gram-Negative Bacteremia from Phase 2 and Phase 3 Clinical Trials of Cefiderocol, a Novel Siderophore Cephalosporin
Authors: Kinoshita David PatersonDavid PatersonMasahiro , Toyoizumi Kiichiro , Matsunaga Yuko , Echols Roger 
Published: January 2021

Abstract

Background
Cefiderocol (CFDC) is the first siderophore cephalosporin approved (US and EU) for a broad range of infections caused by Gram-negative (GN) bacteria, including carbapenem-resistant Enterobacterales (ENT) and non-fermenters (NFs). Bacteremia is a serious manifestation of GN infection and understanding how well an antibiotic works to clear the bacteremia is an important part of drug evaluation.

Methods
All completed clinical studies for CFDC development were used to identify patients with GN bacteremia. Information collected included the primary infection site, species identification and antibiotic susceptibility, post randomization blood cultures and clinical and bacteremia outcome. In patients with missing data (blood cultures) clinical response of cure was used to impute microbiological eradication. Indeterminate responses resulted from a combination of missing data and clinical failure, including death prior to test of cure (TOC).

Results
Three clinical studies randomized 900 patients (CFDC 552; comparators 348) of whom 84 (CFDC 52; comparators 32) had GN bacteremia at baseline (Table). Bacteremia rate by study was CREDIBLE-CR 25.3%, APEKS-cUTI 6.2%, APEKS-NP 6.0%. Escherichia coli (29), Klebsiella pneumoniae (23) and Acinetobacter spp (21) were most frequent species. Sources included urinary tract (31), lung (22), unknown (10), IV line (8), intraabdominal (6), or other (7). Persistence of bacteremia at TOC was seen in 2/52 (3.8%) CFDC and 2/32 (6.2%) control patients (Table), usually due to lack of source control. Clinical outcomes varied by study and infection source and were often confounded (indeterminate response). Eradication in patients with ENT at TOC was determined for 27/39 (69%) for CFDC and 16/23 (70%) for controls, and for 9/16 (56%) for CFDC and 10/11 (91%) for controls in patients with NFs, respectively.
Table. Clinical and bacteremia microbiological outcomes per patient at TOC.

Conclusion
Post-treatment negative blood cultures were inconsistently collected, especially in APEKS-NP and -cUTI, however, negative blood cultures on therapy without recurrence was seen in 96% of CFDC patients with sufficient information. A dedicated clinical trial in GN bacteremia (GAME CHANGER; NCT03869437) is ongoing and will better delineate microbiological outcomes.

Disclosures
David Paterson, Accelerate (Speaker’s Bureau)BioMerieux (Speaker’s Bureau)BioMerieux (Advisor or Review Panel member)Entasis (Advisor or Review Panel member)Merck (Advisor or Review Panel member)Merck (Grant/Research Support)Merck (Speaker’s Bureau)Pfizer (Speaker’s Bureau)Shionogi & Co., Ltd. (Grant/Research Support)VenatoRx (Advisor or Review Panel member) Masahiro Kinoshita, MPharm, Shionogi & Co., Ltd. (Employee) Kiichiro Toyoizumi, PhD, Shionogi & Co., Ltd. (Employee) Yuko Matsunaga, MD, Shionogi Inc. (Employee) Roger Echols, MD, Shionogi Inc. (Consultant)
1286. Pharmacokinetics, Excretion, and Mass Balance of [14C]-Rezafungin Following Intravenous (IV) Administration in Healthy Adults
Authors: Ong Voon , Flanagan Shawn , Sandison Taylor , Wills Sarah 
Published: January 2021

Abstract

Background
Rezafungin is a once-weekly novel echinocandin antifungal currently in Phase 3 development for treatment of candidemia and invasive candidiasis (ReSTORE) and for prevention of invasive fungal disease caused by Candida, Aspergillus, and Pneumocystis in blood and marrow transplant recipients (ReSPECT). Nonclinical ADME studies in rats and monkeys show rezafungin is primarily excreted unchanged in feces, with urine as a minor route. This study was conducted to characterize the routes of elimination of [14C]-rezafungin and the pharmacokinetics of total radioactivity and plasma rezafungin in humans.

Methods
Nine healthy male subjects received a single IV 400-mg rezafungin infusion containing 200 µCi of [14C]-rezafungin. Serial blood samples, urine, and feces were collected at specified times over 60 days; subjects were initially confined in the clinical research unit (CRU) for 17 days postdose and returned for two follow-up visits (days 29 and 60). During the period of time subjects were away from the CRU, recovery of radioactivity was estimated by linear interpolation.

Results
Rezafungin exhibited a long plasma half-life and was mainly excreted in feces unchanged. Cumulative recovery of radioactivity from excreta collected through the first 17 days was 52% (38% in feces, 14% in urine), reinforcing the slow overall elimination of rezafungin. Overall recovery of the administered dose by day 60 was estimated to be 88.3% (65.6% in feces, 22.7% in urine) (Figure 1). Mean blood/plasma concentration ratios ranged from 0.860 to 1.02 through the last collection time point (day 60), which indicated low association of radioactivity with blood cells. Rezafungin was the predominant compound measured in plasma and feces across all collected time points. In the urine, as observed in rat and monkey metabolite profiling studies, low level, inactive, oxidative metabolites were identified as 2-, 3-, 4-hydroxylpentyl rezafungin, and despentyl-rezafungin
Figure 1

Conclusion
Results from this human excretion balance, metabolism and PK study are consistent with nonclinical results, which showed fecal excretion as the major route of elimination of rezafungin. Rezafungin was the predominant compound in plasma and feces.

Disclosures
Voon Ong, PhD, Cidara Therapeutics, Inc. (Employee, Shareholder) Shawn Flanagan, PhD, Cidara Therapeutics, Inc. (Employee, Shareholder) Taylor Sandison, MD, MPH, Cidara Therapeutics, Inc. (Employee, Shareholder)
102. Effects of an Antimicrobial Stewardship-guided MRSA Nasal Screening Review on Vancomycin Utilization for Respiratory Infections: A Quasi-Experimental Study
Authors: Pineda Ross , Kanatani Meganne , Deville Jaime 
Published: January 2021

Abstract

Background
Methicillin-resistant Staphylococcus aureus (MRSA) remains a significant pathogen in patients with respiratory infections. Guidelines recommend empiric MRSA coverage in patients at increased risk, resulting in substantial vancomycin use. Recent literature highlights the use of MRSA nasal assays as a rapid screening tool for MRSA pneumonia, demonstrating high negative predictive values and allowing for shorter empiric coverage. We aimed to evaluate the impact of MRSA nasal screening review by the antimicrobial stewardship program (ASP) on vancomycin utilization for respiratory infections.

Methods
This was a retrospective, quasi-experimental, pre-post intervention study. The intervention saw the addition of an MRSA screening review tool into the ASP electronic record, highlighting patients on vancomycin (actively or recently administered) with a negative MRSA screening. Vancomycin days of therapy (DOT) was collected for all orders indicated for a respiratory infection in the two weeks following a negative screening. Additional outcomes include vancomycin total dose and DOT per 1,000 patient days. Outcomes were compared via independent samples t-tests.

Results
1,110 MRSA screenings resulted across 2 months, of which the majority were excluded for either not having vancomycin ordered, or for having vancomycin ordered for a non-respiratory indication, leaving 37 and 35 evaluable screenings in the pre- and post-intervention groups, respectively. Regarding vancomycin DOT, we did not identify a significant difference between pre- and post-intervention groups with respective means of 2.45 (SD=1.52) and 2.14 (SD=1.12) (p=0.35). We identified a total 8.78 vancomycin DOT per 1,000 patient days in the pre-intervention group versus 6.69 in the post-intervention group.

Conclusion
ASP-guided review of MRSA screenings was associated with a nonsignificant decrease in mean vancomycin DOT and lower total DOT per 1,000 patient days for respiratory infections following a negative screen. Given the recent implementation of our intervention, our analysis covered a small sample size, highlighting the need for continued data collection. MRSA screenings are not always fully or immediately utilized in our institution, demonstrating room to de-escalate MRSA-targeted antibiotics.

Disclosures
All Authors: No reported disclosures
1290. Real-World Experience with Omadacycline for Nontuberculous Mycobacterial and Gram-Negative Infections: A Multicenter Evaluation
Authors: Morrisette Taylor , Philley Julie V , Sigler Carly , Frens Jeremy J , Webb Andrew J , Stevens Ryan W , Howard Catessa , Bouchard Jeannette , Bookstaver P B , Barger Melissa , Lagnf Abdalhamid M , Alosaimy Sara , Rybak Michael J 
Published: January 2021

Abstract

Background
Omadacycline (OMC) is an aminomethylcycline antibiotic in the tetracycline class that has been Food and Drug Administration-approved for acute bacterial skin and skin structure infections and community-acquired bacterial pneumonia. OMC has been shown to have potent in vitro activity against a broad-spectrum of Gram-positive and Gram-negative organisms, as well as Nontuberculous Mycobacteria (NTM). Due to it’s unique activity and availability as an oral agent, off-label use of OMC has been increasing. We evaluated the real-world effectiveness and safety of OMC for a variety of infections.

Methods
This was a multicenter, retrospective, observational study that was conducted from January 2020 to June 2020. We included all patients ≥ 18 years of age that received OMC for ≥ 72 hours for any indication and/or pathogen. The primary outcome was clinical success, defined as a lack of 30-day (non-NTM) or 90-day (NTM) mortality or microbiologic recurrence and absence of therapy escalation or alteration. Reasons for OMC utilization and incidence of potential adverse effects attributable to OMC were also analyzed.

Results
A total of 18 patients were included from six geographically distinct academic health systems (median age: 56 (IQR, 49-60.5) years; 61% male; 72% Caucasian). The majority of OMC use was in NTM (61%; 100% Mycobacterium abscessus) and in Acinetobacter baumannii (22%) for bone/joint (39%) and respiratory tract (33%) infections. OMC was used primarily in the outpatient setting alone (83%) and most isolates did not have OMC susceptibility conducted (89%). Clinical success was reported in 83% of the total population (71% non-NTM and 91% NTM). The majority of patients were prescribed OMC due to antimicrobial resistance to previous antibiotic(s) (61%) and/or due to OMC’s availability as an oral agent (44%). Three patients experienced side effects while on therapy (serum creatinine elevation, AST/ALT increase, and gastrointestinal distress).

Conclusion
OMC appears to be effective and well-tolerated for a variety of infections caused by various pathogens, including M. abscessus and A. baumannii.

Disclosures
Michael J. Rybak, PharmD, MPH, PhD, Paratek (Grant/Research Support)
1292. Safety Profile of the Novel Siderophore Cephalosporin Cefiderocol in Randomized Phase 2 and Phase 3 Clinical Studies of Serious Gram-Negative Infections
Authors: Matsunaga Yuko , Sonoyama Takuhiro , Casanova Luis , Nagata Tsutae Den , Echols Roger , De Gregorio Fabio , Ogura Eriko , Portsmouth Simon 
Published: January 2021

Abstract

Background
Cefiderocol (CFDC), the first siderophore cephalosporin, is approved in the United States (complicated urinary tract infections [cUTI]) and Europe for the treatment of patients with Gram-negative (GN) infections with limited treatment options.

Methods
This analysis investigated the safety profile of CFDC across three prospective, multicenter, randomized clinical studies: APEKS-cUTI (double-blind, non-inferiority Phase 2 study in patients with cUTI) vs imipenem-cilastatin (1 g/1 g, three-times daily); APEKS-NP (double-blind, non-inferiority Phase 3 study in patients with nosocomial pneumonia [NP]) vs meropenem (2 g, q8h); CREDIBLE-CR (open-label, descriptive Phase 3 study in patients with cUTI, NP, bloodstream infections/sepsis [BSI/sepsis]) caused by carbapenem-resistant GN bacteria; patients in the control arm received best available therapy (BAT; up to 3 agents, dosing based on local label). CFDC was given at 2 g, q8h, infused over 1 (APEKS-cUTI) or 3 (APEKS-NP, CREDIBLE-CR) hours. One adjunctive agent with CFDC was only allowed in CREDIBLE-CR.

Results
549 patients were treated with CFDC, 347 control treated (Table 1). More than 50% of patients were aged ≥65 years, except BAT arm in CREDIBLE-CR. The majority of patients were admitted to the ICU in APEKS-NP and CREDIBLE-CR. The median treatment duration with CFDC was similar (9–11 days) across studies. The rates of TEAEs and serious AEs (SAEs) between CDFC and comparators were similar in each study (Table 2). The rates of adverse drug reactions were lower with CFDC than with comparators in each study, with a greater difference in CREDIBLE-CR than in APEKS-cUTI and APEKS-NP. TEAEs leading to death rates are shown in Table 2. Eight CFDC-related Clostridioides difficile infections occurred across studies (APEKS-cUTI: n=1; APEKS-NP: n=4; CREDIBLE-CR: n=3 [ie, C. difficile colitis; pseudomembranous colitis]). In total, eight experienced seizures (APEKS-cUTI: CFDC n=1; APEKS-NP: CFDC n=3, meropenem n=2; CREDIBLE-CR: CFDC n=1, BAT n=1), none of which were related to study drugs. Parameters of iron homeostasis showed no differences between CFDC and comparators.
Table 1. Baseline characteristics and treatment duration (safety populations)

Table 2. Overall safety parameters (safety populations)

Conclusion
CFDC demonstrated a comparable safety profile to carbapenems or other cephalosporins and was generally well tolerated in critically ill patients.

Disclosures
Yuko Matsunaga, MD, Shionogi Inc. (Employee) Takuhiro Sonoyama, MD, Shionogi & Co., Ltd. (Employee) Luis Casanova, PharmD, Shionogi B.V. (Employee) Tsutae Den Nagata, MD, Shionogi & Co., Ltd. (Employee) Roger Echols, MD, Shionogi Inc. (Consultant) Fabio De Gregorio, MD, Shionogi B.V. (Employee) Eriko Ogura, MD, Shionogi & Co., Ltd. (Employee) Simon Portsmouth, MD, Shionogi Inc. (Employee)
1295. Activity of SPR206, a Polymyxin B Derivative, Compared to Colistin Alone and in Combination Against Multidrug-Resistant Pseudomonas aeruginosa Strains
Authors: Abdul-Mutakabbir Jacinda C , Nguyen Logan , Stamper Kyle , Maassen Philip , Lev Katherine , Morrisette Taylor , Kebriaei Razieh , Rybak Michael J 
Published: January 2021

Abstract

Background
The emergence of multidrug-resistant (MDR) Pseudomonas aeruginosa strains, has resulted in the use of previously discarded antibiotics, such as the polymyxins (polymyxin B and colistin (COL)). Consequently, the polymyxins are continually characterized by the cytotoxicity associated with their use. SPR206 is a polymyxin analogue, however the N-terminal lipophilic side chain has been extensively modified, decreasing the potential for adverse events. SPR206 has reduced minimum inhibitory concentrations (MIC) MIC50 and MIC90 in P. aeruginosa strains when compared to COL. The objective of this study was to compare the in-vitro activity of SPR206 to COL both alone and in combination with other antimicrobials against MDR P. aeruginosa.

Methods
MIC susceptibility testing was performed against 15 carbapenem-resistant P. aeruginosa strains via broth microdilution. SPR206, COL, aztreonam (AZT) and ceftazidime/ avibactam (CAZ/AVI) were evaluated against the P. aeruginosa strains. Dual therapy and triple therapy combinations, either COL or SPR206-based, were tested against four representative strains in 24h time-kill experiments (TKE). Each antibiotic was tested at both 0.5 and 1x the MIC. A &gt;2 log10 and a &gt;3log10 reduction in CFU/ml were defined as synergistic and bactericidal activity, respectively.

Results
The MIC testing revealed a lower range of MIC values for SPR206 compared to all agents tested, including COL, for the 15 MDR P. aeruginosa strains. A mean 2-fold reduction in MIC values was observed when comparing the activity of SPR206 to COL. Neither the SPR206 nor COL+CAZ/AVI combinations presented with synergistic activity in the TKEs. SPR206 or COL + CAZ/AVI +AZT, showed synergistic activity against each strain, irrespective of COL or SPR206 base and the tested concentration. At 0.5x MIC bactericidal activity was observed in two of the strains with either COL or SPR206 + AZT. However, at 1xMIC the SPR206+AZT combination exhibited bactericidal activity, equal to that of the triple therapy regimens, against each strain.

Conclusion
The combination of SPR206 with other antibiotic agents showed promise in eradicating MDR P. aeruginosa. Further research is warranted to solidify the role of SPR206 in the current antibiotic armamentarium.

Disclosures
Michael J. Rybak, PharmD, MPH, PhD, Paratek (Grant/Research Support)
1299. In Vitro-In Vivo Discordance with β-lactams against Metallo-β-lactamase-Producing Enterobacterales: Implications for Susceptibility Testing
Authors: Abdelraouf Kamilia , Reyes Sergio , Nicolau David P 
Published: January 2021

Abstract

Background
Using murine models of thigh and lung infection, we previously reported the potent in vivo activity of carbapenem human-simulated regimens against metallo-β-lactamase-producing Enterobacterales despite the observed resistance in vitro (JAC 2020 Apr 1;75(4):997-1005, AAC 2014;58(3):1671-7). In the current study, we examined the in vivo activity of cefepime human-simulated regimen against metallo-β-lactamase-producing Enterobacterales in a murine thigh infection model.

Methods
A population of clinical (n=21) and isogenic engineered (n=5) metallo-β-lactamase-producing Enterobacterales isolates expressing VIM, IMP or NDM but not co-expressing ESBLs or serine carbapenemases were utilized. KPC-producing strains (n=3) were included as positive controls. MICs of cefepime, piperacillin-tazobactam and meropenem were determined using broth microdilution in conventional cation-adjusted Muller Hinton and EDTA-supplemented broth at EDTA concentration of 300 mg/L (zinc-limited). The in vivo efficacy of a cefepime human-simulated regimen (2 g q8h as 2 h infusion) was determined in the neutropenic murine thigh infection model against the test isolates. Efficacy was measured as the change in log10cfu/thigh at 24 h compared with 0 h controls.

Results
Metallo-β-lactamase-producing Enterobacterales were found to be cefepime, piperacillin-tazobactam and meropenem non-susceptible in conventional broth. Supplementation with EDTA resulted in multi-fold reduction in the MICs and restoration of susceptibility. In accordance with the MICs generated in the zinc-limited broth, the administration of cefepime human-simulated regimen was associated with substantial bacterial reductions among mice infected with the clinical as well as the isogenic engineered metallo-β-lactamase-producing isolates. As anticipated with serine-based resistance, absence of MIC reduction in zinc-limited broth and lack of in vivo activity against KPC-producers were observed.

Conclusion
For metallo-β-lactamase-producing Enterobacterales, in vitro susceptibility testing to β-lactams with conventional media such as cation-adjusted Muller Hinton broth, a zinc-rich testing medium, is flawed since it does not recapitulate the host environment in which zinc concentrations are low.

Disclosures
David P. Nicolau, PharmD, Cepheid (Other Financial or Material Support, Consultant, speaker bureau member or has received research support.)Merck & Co., Inc. (Consultant, Grant/Research Support, Speaker’s Bureau)Wockhardt (Grant/Research Support)
1303. Characterization of Isavuconazole Serum Concentrations with Various Administration Routes in a Hospitalized Cohort
Authors: Spivey Justin , Wrenn Rebekah , Liu Beiyu , Maziarz Eileen K , Maziarz Eileen K , Kram Bridgette 
Published: January 2021

Abstract

Background
Patients with invasive fungal infections are often critically ill and immunosuppressed with multiple comorbidities that may impact drug absorption and exposure. This study sought to characterize isavuconazole serum concentrations (ISCs) in a cohort of real-world hospitalized patients when administered by intravenous solution (IV), enteral as intact capsules, or tube as opened capsule contents.

Methods
This retrospective cohort analysis included all hospitalized patients who received isavuconazole as prophylaxis or treatment between September 2017 and September 2018 and had therapeutic drug monitoring performed. For patients receiving isavuconazole by tube, the capsules were opened and contents were diluted with 10-30 mL of sterile water. Administration was per package insert for intact capsules and IV solution. ISCs were obtained as part of routine care and were quantified by high-performance liquid chromatography. An appropriate trough was defined as within 4 hours of the next scheduled dose. Currently, there is a lack of correlation between isavuconazole exposure and efficacy or toxicity; thus, ISCs were compared between administration routes.

Results
93 ISCs were obtained during 65 encounters from 55 unique patients. The majority of patients were post-transplant (69.1%) and death occurred during 12 (18.5%) encounters. ISCs based on different characteristics of the cohort are shown in Table 1. All ISC assessments were detectable, median 2.3 mg/dL (Q1: 1.5 mg/dL, Q3: 3.3 mg/dL). Administration via tube achieved similar ISCs compared with IV therapy (1.6 mg/dL vs. 1.9 mg/dL, respectively). However, administration of intact capsules resulted in higher median ISCs, 3 mg/dL (Q1: 1.9 mg/dL, Q3: 4.1 mg/dL). All 14 patients with administration via tube were post-transplant, which was not shown to have a significant impact on ISCs (median, transplant 2.2 mg/dL vs. non-transplant 2.7 mg/dL).
Table 1. Characterization of Isavuconazole Concentrations

Conclusion
ISCs were detectable in all patients regardless of transplant status or location at the time of assessment. Administration of isavuconazole via an enteral feeding tube achieved comparable serum concentrations compared with FDA-approved routes of administration and may represent an important alternative for select patients.

Disclosures
All Authors: No reported disclosures