bluuebunny/crossref_metadata_2025 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

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

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

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

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

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

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 >2 log10 and a >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

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

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
1305. Comparison of Pharmacokinetics of DSTA4637S, a novel THIOMABTM Antibody-Antibiotic Conjugate, in Patients with Staphylococcus aureus Bacteremia Receiving Standard-of-Care Antibiotics with Pharmacokinetics in Healthy Volunteers
Authors: Rymut Sharon M , Deng Rong , Owen Ryan , Saad Ola , Berhanu Aklile , Lim Jeremy , Carrasco-Triguero Montserrat , Couch Jessica A , Peck Melicent C
Published: January 2021

Background

DSTA4637S, a THIOMABTM antibody-antibiotic conjugate against Staphylococcus aureus, is a potential therapy for complicated S. aureus bacteremia. Single doses showed favorable safety and pharmacokinetics (PK) in healthy volunteers (HVs). This study compares HV PK results to PK from a Phase 1b study evaluating multiple doses in patients with bacteremia.

Methods

In a Phase 1a study, HVs received single intravenous (IV) doses (5, 15, 50, 100, or 150 mg/kg) of DSTA4637S. The Phase 1b, randomized, double-blind, placebo-controlled, multiple ascending-dose study enrolled patients with MRSA or MSSA bacteremia receiving ≥ 4 weeks of standard-of-care (SOC) antibiotics in combination with IV DSTA4637S (15, 45, or 100 mg/kg) weekly (4-6 doses). Intensive PK serum and plasma sampling was performed after first and last doses of DSTA4637S. Total antibody (TAb) was measured in serum by ELISA. DSTA4637S conjugate (ac-dmDNA31) and unconjugated dmDNA31 were measured in plasma with IA-LC-MS/MS and LC-MS/MS, respectively. DSTA4637S PK was analyzed using a non-compartmental approach using WinNonlin.

Results

DSTA4637S PK data were evaluated in 20 HVs in the Phase 1a study and 19 patients with S. aureus bacteremia in the Phase 1b study. In both HVs and patients, systemic exposures of TAb and ac-dmDNA were generally dose proportional over the dose ranges tested. In patients compared to HVs, Cmax, cycle 1 for ac-dmDNA31 and TAb were reduced 26.7-51.3% and 32.4-44.1%, respectively, contributing to lower patient AUC0-7. Unconjugated dmDNA31 concentrations were low (< 11 ng/mL), peaking 1-2 days after dosing, in both studies. There was no clear association between DSTA4637S exposure (ac-dmDNA31) and demographic factors (age, weight, sex), clinical status (bacteremia at dosing, infection site), adverse events (infusion-related reactions), or exploratory biomarkers (CRP, procalcitonin, inflammatory cytokines).

Conclusion

DSTA4637S PK analysis demonstrated lower exposures in patients with S. aureus bacteremia compared to HVs. Potential explanations for reduced exposures include factors related to disease status, non-specific organ uptake, and target-mediated clearance.

Disclosures

Sharon M. Rymut, PhD, Genentech (Employee, Shareholder) Rong Deng, PhD, Roche (Consultant, Employee, Shareholder) Ryan Owen, PhD, Genentech (Employee, Shareholder) Ola Saad, PhD, Genentech - Roche (Employee) Aklile Berhanu, PhD, Genentech, Inc. (Employee, Equity interest (Stock/Stock Options)) Jeremy Lim, PharmD, Roche (Employee, Shareholder) Montserrat Carrasco-Triguero, PhD, Genentech (Employee) Jessica A. Couch, PhD, Genentech (Employee, Shareholder) Melicent C. Peck, MD, PhD, Genentech (Employee)
104. Evaluation of a 2-Step Testing Algorithm for Clostridioides difficile Infection
Authors: Bettger Caitlin C , Giancola Stephanie , Cybulski Robert , Okulicz Jason , Barsoumian Alice
Published: January 2021

Background

A 2-step testing strategy for diagnosis of Clostridioides difficile infection (CDI) is recommended to limit over-diagnosis when clinical criteria requirements for stool sample submission cannot be enforced. Real-world evaluations of this strategy are limited.

Methods

The Antimicrobial Stewardship Program at Brooke Army Medical Center, San Antonio, TX, implemented a 2-step CDI algorithm: polymerase chain reaction (PCR) testing followed by toxin enzyme immunoassay (EIA). The goal was to improve diagnosis of CDI and reduce unnecessary antibiotic use. Patients with PCR+ tests from August 2018 to September 2019 were included. Charts were reviewed for demographics, laboratory data, treatment, and outcomes. Cases were grouped based on concordant (PCR+/EIA+) or discordant (PCR+/EIA-) results. To determine factors contributing to treatment decisions, an analysis of discordant cases were compared by treatment status. Groups were compared by Chi-squared, Fisher’s exact, or Mann-Whitney U tests.

Results

A total of 216 PCR+ tests from 215 patients were recorded. Of these, 155 (71.8%) were discordant. Demographics, laboratory data, and risk factors for CDI were similar between groups (Table 1; p >0.05 for all). Compared to discordant cases, concordant cases were more frequently hospitalized (59% vs 43.9%; p=0.05), had a higher median daily stool count (5 [4–7] vs 4 [2–6], p=0.03), met criteria for severe CDI (33.3% vs 18.7%; p=0.05), received treatment (95.1% vs 66.5%; p< 0.01) and were readmitted in 30 days with CDI (8.3% vs 1.3%; p=0.02). Among discordant cases, median daily stool count was higher in treated vs untreated cases (4 [3–7] vs 3 [1–5], p=0.02). Otherwise, there was no difference in variables according to treatment status (Table 2; p >0.05 for all). Discordant cases with infectious disease (ID) or gastroenterology (GI) consultation had a high rate of treatment (73.9% and 61.1%, respectively).

Table 1. Characteristics and outcomes of patients with concordant and discordant tests.

Table 2. Characteristics and outcomes of treated and untreated patients with discordant tests.

Conclusion

Implementation of 2-step strategy reduced antibiotic treatment by nearly 30%. However, the majority of discordant cases were deemed clinically significant and received treatment by providers, including ID or GI specialists. Further studies are needed to determine the unmeasured factors that guide treatment decisions in discordant cases.

Disclosures

All Authors: No reported disclosures
1309. Imipenem/Cilastatin/Relebactam (I/R) Alone and in Combination against Pseudomonas aeruginosa (PSA) in the In Vitro Pharmacodynamic Model
Authors: Chen Iris H , Nicolau David P , Kuti Joseph L
Published: January 2021

Background

I/R, a carbapenem-beta-lactamase inhibitor antibiotic, is active against most imipenem-resistant PSA, including MDR isolates. Combination therapy may enhance activity against MDR pathogens and suppress resistance. This study’s objective was to assess the efficacy of I/R compared with combinations including colistin (CST) or amikacin (AMK) against PSA in an IVPD model.

Methods

Human-simulated concentrations of I/R 500/250 mg every six hours, a total daily dose of CST 360 mg, and AMK 25 mg/kg daily were reproduced alone and in combination against 6 imipenem-non-susceptible PSA with I/R MICs of 1/4 to 8/4 mg/L in an IVPD over 24h. The primary endpoint was the difference in 24h colony forming units (CFU) between each combination regimen and its components alone. The log ratio differences of the area under the CFU curve were also calculated to compare the overall bacterial burden resulting from exposure to I/R alone with those treated by combination regimens. Emergence of resistance was tested at 24h using drug-containing plates at 3xMIC.

Results

I/R, CST, and AMK alone produced 24hCFU changes consistent with isolate MICs. One isolate (already I/R non-susceptible) developed I/R resistance, and 4 and 3 developed CST and AMK resistance, respectively. I/R plus CST suppressed all resistance and resulted in synergistic or additive interactions against three of six isolates with 24h CFU reductions ranging from -2.62 to -4.67 log10CFU/mL. This combination further reduced overall bacterial burden by 79-81% compared with I/R alone against two I/R-non-susceptible strains. I/R plus AMK also prevented resistance emergence but exhibited indifferent interactions against all isolates at 24h with the combined drugs achieving -0.51 to -3.33 log10CFU/mL reductions. Minor overall reductions in bacterial burden were observed relative to I/R alone.

Conclusion

I/R plus CST resulted in additivity or synergy against three of six PSA and prevented I/R and CST resistance, whereas the addition of AMK only suppressed resistance. The greatest overall reductions in bacterial burden, however, were observed with I/R plus CST against I/R-non-susceptible isolates, supporting targeted use of this combination against this phenotype when alternatives are unavailable.

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) Joseph L. Kuti, PharmD, Allergan (Speaker’s Bureau)bioMérieux (Research Grant or Support, Other Financial or Material Support, Speaker Honorarium)Melinta (Research Grant or Support)Merck & Co., Inc. (Research Grant or Support)Paratek (Speaker’s Bureau)Summit (Other Financial or Material Support, Research funding (clinical trials))
1312. Metallo-β-lactamase-Producing Enterobacterales (MBL-EB): Is it Time to Rethink Our Assessment Tools?
Authors: Abdelraouf Kamilia , Nicolau David P
Published: January 2021

Background

We previously reported the potent in vivo activity of ceftazidime/avibactam human-simulated regimen (HSR) against MBL-EB despite the observed resistance in vitro and the lack of avibactam MBL-inhibitory activity (AAC 2014 Nov;58(11):7007-9). Similar to avibactam, relebactam (REL) is a diazabicyclooctane that inhibits serine β-lactamases belonging to Classes A - C but not MBLs. In the current study, we examined the in vivo activity of cefepime (FEP)/REL combination HSR against MBL-EB in a murine thigh infection model.

Methods

Six clinical MBL-EB isolates expressing VIM, IMP or NDM and co-expressing at least one β-lactamase of Classes A - C (KPC, CTX-M, TEM, SHV, ACT, CMY) were utilized. MICs of FEP and FEP/REL combination (at fixed REL concentration of 4 mg/L) were determined using broth microdilution. FEP HSR (2 g q12h as 0.5 h infusion) alone and in combination with REL HSR (250 mg q6h as 0.5 h infusion) were established in the infection model. Thighs of neutropenic ICR mice were inoculated with bacterial suspensions of 107 CFU/ml. Two hours later, mice were administered the FEP HSR or the FEP/REL HSR. Efficacy was measured as the change in log10CFU/thigh at 24 h compared with 0 h controls.

Results

All isolates were FEP resistant (MIC ≥ 32 mg/L). Addition of REL had no impact on the MIC of the isolates. In in vivo studies, the average bacterial burden at 0 h was 5.84 ± 0.41 log10CFU/thigh. In accordance with the in vitro susceptibility, administration of FEP HSR was associated with net bacterial growth among all isolates ranging from 0.46 ± 0.60 to 2.97 ± 0.53 log10CFU/thigh. In contrast, FEP/REL combination HSR resulted in substantial bacterial reductions among all isolates ranging from -0.73 ± 0.13 to -1.72 ± 0.14 log10CFU/thigh, indicating that REL enhanced the FEP activity in vivo.

Conclusion

Despite the powerful β-lactam hydrolytic capability of MBLs in vitro, FEP inactivation in the murine model was attributed predominantly to the expression of the serine β-lactamases. The in vitro/in vivo discordance in β-lactam/β-lactamase activity against MBL-EB reveals a potential flaw in the currently utilized in vitro susceptibility testing methodologies and highlights a challenge encountered during the development of new agents against these isolates.

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)
1317. Pharmacokinetics (PK) of Ampicillin-Sulbactam (SAM) during Orthotopic Liver Transplantation (OLT)
Authors: Lasko Maxwell J , Serrano Oscar , Nicolau David P , Kuti Joseph L
Published: January 2021

Background

SAM is used as surgical prophylaxis during OLT due to its broad spectrum activity against Gram-positive,-negative and anaerobic pathogens. SAM resistance among Gram-negatives is rising, making dosage selection paramount to preventing surgical site infections. Current guidelines recommend a 3g dose, consisting of 2g ampicillin (AMP) and 1g sulbactam (SUL), every 2h. There are no data; however, describing SAM PK during OLT to support an optimized dosing regimen.

Methods

This was a single-center PK study of OLT patients receiving SAM for surgical prophylaxis at a dose selected by the anesthesiologist. Patients were excluded if they were undergoing simultaneous liver and kidney transplantation and had a CrCL < 30 mL/min at start of surgery. Up to 24 blood samples, along with times of pertinent events, were collected throughout the OLT. AMP and SUL plasma concentrations were determined. Population PK analyses were conducted in Pmetrics using R. Akaike information criterion (AIC) and visual inspection determined best model fit. Individual PK parameters were simulated to describe free AMP time above the MIC90 (fT >MIC90) of 32 mg/L.

Results

Five patients were enrolled. Participants had a mean ± SD age of 64 ± 7 years, body weight 82 ± 8 kg, CrCL of 75 ± 35 mL/min, and received various SAM doses (1.5-3g q2-3h). A 2 compartment model fitted the data better than a 1 compartment model for both AMP (AIC: 396 vs. 423) and SUL (AIC: 334 vs. 347). Final models included fractional clearance (CLf) terms on typical total body clearance (CLθ) to account for the placement of the portal vein clamp. AMP PK parameters (AIC: 372) were: CLθ, 9.7 ± 2.6 L/h; CLf, 0.73 ± 0.49; volume of central compartment (Vc), 7.2 ± 1.4 L; intercompartment constants (k12 and k21), 4.08 ± 3.28 and 2.63 ± 2.9 h-1, respectively. Final SUL PK parameters (AIC: 314) were: CLθ, 8.3 ± 2.5 L/h; CLf, 0.92 ± 0.55; Vc, 7.3 ± 1.6 L; k12, 4.60 ± 4.41 h-1, and k21, 4.07 ± 3.31 h-1. Exposures ranged from 58-96% with only 3g q2h providing nearly 100% fT >MIC90.

Conclusion

This is the first study to describe intra-operative SAM PK in OLT recipients and the effect of portal vein clamp on AMP and SUL clearance. These data will help guide optimized SAM dosing regimens for OLT surgery based on local MIC distributions for targeted pathogens.

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) Joseph L. Kuti, PharmD, Allergan (Speaker’s Bureau)bioMérieux (Research Grant or Support, Other Financial or Material Support, Speaker Honorarium)Melinta (Research Grant or Support)Merck & Co., Inc. (Research Grant or Support)Paratek (Speaker’s Bureau)Summit (Other Financial or Material Support, Research funding (clinical trials))
105. Evaluation of a Multiplex PCR Panel for the Microbiologic Diagnosis of Pneumonia in Hospitalized Patients: A Retrospective Analysis from an Academic Medical Center
Authors: Zacharioudakis Ioannis , Zervou Fainareti , Inglima Kenneth , See Benjamin , Aguero-Rosenfeld Maria E
Published: January 2021

Background

Pneumonia is a leading cause of hospitalization and mortality. Due to the low yield of available diagnostic tests, ATS/IDSA pneumonia guidelines recommend a microbiologic work-up only for hospitalized patients with severe pneumonia.

Methods

From 5/2019 to 1/2020, we selected adult patients with clinical and radiographic findings highly suggestive of pneumonia. The BioFire® FilmArray® pneumonia panel was performed on sputum specimens that met quality microbiologic criteria and the results were compared to those of sputum cultures and other tests sent per standard of care. A limit of 105 copies/mL was used for positivity in semi-quantitative bacterial targets. The empiric antimicrobial regimen was reviewed to quantify the potential for antimicrobial optimization.

Results

Seventy patients were included in the analysis. Median age was 70 (IQR 53.5–81.75), and the majority (43 patients, 61.4%) were classified as Class IV and V using the pneumonia severity index, indicating severe cases of pneumonia. Sixty-nine patients completed at least a 5-day course for pneumonia and 14.3% died during their hospitalization. The fifteen patients (21.4%) that submitted a sputum culture before the initiation of antimicrobial therapy, had a trend towards a positive sputum culture (60% (9/15) vs 36.4% (20/55)) (p=0.09). The BioFire® FilmArray® pneumonia Panel increased the number of patients who received a microbiologic diagnosis from 29 (41%) to 59 (84.3%) (p< 0.001). The per isolate analysis revealed significantly more targets detected for Haemophilus influenzae (p=0.002) and Streptococcus pneumoniae (p=0.05). On review of empiric antimicrobial treatment, there was possibility for antimicrobial optimization in 80% of patients, including 9 cases of pathogens (4 MRSA, 3 Legionella pneumophila, 2 CTX-M gram-negative rods) where the pathogens were not covered and another 70 antimicrobials in 49 patients that could be stopped.

Flow chart

Bacterial Pathogens Detected in Standard of Care Alone Testing and with the Addition of Pneumonia Panel.

Potential for Antimicrobial Optimization Using the Pneumonia Panel

Conclusion

Incorporation of the pneumonia panel in the diagnostic work-up of patients hospitalized with pneumonia substantially increased the rate of microbiologic diagnosis and had the potential to guide appropriate antimicrobial therapy. Future studies to quantify the effects on clinical outcomes and cost-effectiveness from tailored therapy are needed.

Disclosures

All Authors: No reported disclosures
1319. Pharmacokinetics of Ceftolozane/Tazobactam in Patients with Burns
Authors: Hall Ronald G , Pasipanodya Jotam , Putnam William C , Griswold John , Dissanaike Sharmila , Kallem Raja Reddy , Edpuganti Vindhya , Subramaniyan Indhumathy
Published: January 2021

Background

Antimicrobial dosing in moderate/severe burns patients is complicated due to the potential unpredictable hyperdynamic pathophysiologic states including 1) hypoproteinemia, 2) acute kidney injury and 3) onset of septicemia. Therefore, distribution assumptions about the population pharmacokinetic (PopPK) profiles of either endogenous or xenobiotic pharmacophores in this patient population can lead to biased parameter estimates. In order to prevent potential bias an agnostic nonparametric adaptive grid approach to describe ceftolozane/tazobactam (C/T) PopPK profiles in patients with partial- and full-thickness burns was employed.

Methods

A human clinical PK study in burn patients was conducted using the standard approved dose of C/T (2 grams/1 gram). A single intravenous dose was administered over 60 minutes. Whole blood was obtained pre-dose and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, and 24 hours following the start of infusion. LC-MS/MS bioanalytical methods were developed, validated and employed to determine C/T concentrations in human plasma. PopPK were modeled using Pmetrics package for R. One-, two- and three-compartment models were examined and compared. The influence of several parameters, including %body surface area burns, creatinine clearance (CrCL), weight, albumin and age were tested.

Results

The bioanalytical method for determination of C/T in human plasma met all recommended criteria of the LC-MS/MS. Five males and one female (ages 24 to 66 years), contributed 148 plasma PK samples. The female had 35% partial-thickness burns. The males had full-thickness burns ranging from 27 to 66%. The median CrCL was 104 mL/min (range 73-148 mL/min). Two-compartment model with absorption (Ka) from compartment 1 to 2 and elimination from compartment 2 (Ke), with nonlinear interactions between C/T elimination and CrCL best described the data. Figure A show that bias was minimal. Importantly, both drugs exhibited marked variability for both volume and elimination (Table), since volume was bimodally distributed (Figure B).

A) Observation-versus-Prediction; B) Estimated Ke, V and Ka population parameter densities

Summary of pharmacokinetic parameters

Conclusion

C/T exhibited high variability surpassing that observed with severe infections, suggesting that dose adjustment and/or may be therapeutic drug monitoring may be needed to balance target attainment from dose-related toxicities.

Disclosures

Ronald G. Hall, II, PharmD, MSCS, Medical Titan Group (Grant/Research Support)Merck (Research Grant or Support)
1323. Substantial Doses of Daptomycin and Rifampin Eradicate S. epidermidis Biofilm in an In Vitro Pharmacodynamic (IVPD) Model
Authors: Piehl Emily C , Daffinee Kathryn E , LaPlante Kerry
Published: January 2021

Background

The concentration of antibiotics at the site of action needed to eradicate biofilm is currently unknown. Studies have previously suggested that bacteria in biofilms are 1000-fold more resistant to antibiotics than free-floating planktonic bacteria. We sought to describe concentrations of daptomycin alone and in combination with rifampin in relation to the pharmacodynamic exposures for biofilm eradication.

Methods

We utilized a methicillin-resistant high biofilm-forming S. epidermidis strain RP62a (ATCC® 35984) over a 48-hour in vitro PD biofilm model. The Centers for Disease Control (CDC) Biofilm Reactor model was used with chromium cobalt materials to simulate an orthopedic device infection. The reactor was inoculated and underwent a 24-hr growth phase and 16-hr conditioning phase to form biofilm on the chromium cobalt coupons, and then a 48-hr PK-PD phase was run. The daptomycin MIC for RP62a was 0.5 mg/L and the rifampin MIC was 0.015 mg/L. We modeled a growth control of the isolate alone, a 12 mg/kg regimen of daptomycin (fCmax: 14.7 mg/L, Ke 0.09), a daptomycin concentration of 1000 mg/L (2000x MIC), and a combination model of daptomycin 1000 mg/L with rifampin 15 mg/L (1000x MIC). Coupons with bacteria embedded in biofilm were sonicated, vortexed, and plated on Tryptic Soy Agar for colony counts read at 24 hrs. Bactericidal activity was defined as ≥ 3-log10 CFU/mL reduction from the initial inoculum.

Results

The simulated humanized dosing regimen of daptomycin 12 mg/kg (fAUC0-24/MIC: 204) was similar to the growth control model. Bactericidal kill was demonstrated at 24hr and 48hr in the daptomycin 1000 mg/L model (fAUC0-24/MIC: 20,248) but did not fall beneath the limit of detection. The daptomycin and rifampin combination model demonstrated bactericidal kill at 24hr and 48hr and went below the limit of detection.

Conclusion

This study demonstrated that significantly higher concentrations of antibiotics are needed at the site of action to eradicate biofilm than what maximum systemic dosing can provide. Identifying these concentrations provides a foundation for localized antibiotic therapy and further studies are needed to elucidate these concentrations for a variety of antibiotics and biofilm-forming organisms.

Disclosures

Kerry LaPlante, PharmD, Merck (Advisor or Review Panel member, Research Grant or Support)Ocean Spray Cranberries, Inc. (Research Grant or Support)Pfizer Pharmaceuticals (Research Grant or Support)Shionogi, Inc. (Research Grant or Support)
1324. Target Attainment of Exebacase, a First-In-Class Antibacterial Lysin, to Determine Optimal Doses for Adult Patients with Staphylococcus aureus (S. aureus) Bloodstream Infections (Bacteremia) Including Endocarditis
Authors: Ghahramani Parviz , Khariton Tatiana , Chiu Joannellyn , Cassino Cara
Published: January 2021

Background

Exebacase, a novel, antibacterial direct lytic agent for the treatment of S. aureus bacterimia and endocarditis, studied in Phase 1 and 2 trials, demonstrated potential to improve clinical outcomes when used in addition to conventional antibiotics. Objectives were to develop population PK (PPK) model and perform target attainment (TA) simulations to determine optimal clinical doses.

Methods

PPK model was developed with data from 72 patients receiving Exebacase, in addition to the standard of care, as single 2-hr infusion of 0.25 mg/kg (0.12 mg/kg for patients with creatinine clearance (CrCL) < 60 mL/min). PPK model was used for TA simulations of various IV regimens.

Results

3-compartment model best fit the data, parameters were well estimated (CL=4.2 L/hr (RSE=5.5%), Vc=4.5 L (RSE=8.2%)). Total volume of distribution (Vd) was 20.2 L. Values were lower than estimated previously in healthy subjects, CL=7.1 L/hr and Vd=27.7 L. CrCL was the only clinically meaningful covariate. Patients with moderate and severe renal impairment are expected to have 1.3 to 2-fold higher AUC0-24 or Cmax than patients with normal renal function. Age was statistically significant on peripheral clearance but was not clinically meaningful (≤4% effect on exposure).

TA simulations were stratified by renal function across a range of fixed as well as weight-based doses (all simulated as 2-hr infusion). In patients with normal renal function or mild impairment, 18 mg dose result in Cmax and AUC0-24 of 1254 ng/mL and 3026 ng*hr/mL, respectively. In patients with moderate or severe renal impairment, 12 mg dose result in Cmax and AUC0-24 of 1107 ng/mL and 3099 ng*hr/mL, respectively. In ESRD patients including hemodialysis, 8 mg dose result in Cmax and AUC0-24 of 910 ng/mL and 3109 ng*hr/mL, respectively. These exposures place >99% subjects above efficacious thresholds of AUC/MIC >0.2 established in animals.

Conclusion

PPK model described exebacase PK in patients adequately. CL and Vd were estimated to be 40% and 17% lower, respectively, than healthy subjects. CrCL was the only clinically meaningful covariate requiring dose adjustment. TA assessments identified doses that achieve minimum efficacy target (AUC/MIC≥0.2) in >99% of patients with S. aureus. Based on these simulations, fixed dosing schedule was recommended.

Disclosures

Parviz Ghahramani, PhD, PharmD, MSc, MBA, Consultant to ConatFect (Consultant) Tatiana Khariton, PhD, Consultant to ConatFect (Consultant) Joannellyn Chiu, PhD, Consultant to ConatFect (Consultant) Cara Cassino, MD, ContraFect Corporation (Employee)ContraFect Corporation (Employee)