bluuebunny/crossref_metadata_2025 huggingface dataset:
1043. Activity of Mecillinam Against Enterobacterales Isolates Collected From Patients With Urinary Tract Infections (UTIs) in the USA During 2019
Authors: Hawser Stephen , Morrissey Ian , Henriksen Anne Santerre
Published: December 2021

Background

Mecillinam is a β-lactam antibiotic that exerts its antibacterial activity by binding to penicillin-binding protein 2. In the USA, intravenous (IV) mecillinam is in development for the treatment of complicated UTIs in the hospital setting and as step-down therapy transitioning from IV mecillinam to oral pivmecillinam so that patients can continue treatment at home. To support the clinical development of mecillinam in the USA for the treatment of both complicated and uncomplicated UTI, this observational study investigated the activity of mecillinam against Enterobacterales isolates from patients with UTI in the USA, collected during 2019.

Methods

This study evaluated the activity of mecillinam and other antimicrobial agents against 1075 selected Enterobacterales clinical isolates collected from patients with UTI in the USA during 2019. Antibiotic activity (minimum inhibitory concentration [MIC]) was determined by Clinical & Laboratory Standards Institute (CLSI) agar dilution methodology, and susceptibility was interpreted according to CLSI guidelines.

Results

Among the selected 1075 isolates, producers of extended-spectrum beta-lactamase (ESBL) represented 9.6% of Escherichia coli and 50% of Klebsiella pneumoniae. Ninety-five percent of the isolates tested were susceptible to mecillinam (Table 1). The MIC50 and MIC90 values for mecillinam were 0.25 and 2 µg/mL, respectively. Fosfomycin MIC50 and MIC90 were 1 and 32 µg/mL, respectively (97.6% of isolates were susceptible). Mecillinam showed the lowest MIC90 value of all single antibiotics tested. The highest MIC90 was 128 µg/mL for both nitrofurantoin and cefotaxime. The lowest percentage of resistance was obtained with fosfomycin (1.7%), followed by mecillinam (4%).

Table 1: Summary MIC and susceptibility data for all isolates tested (n=1075)

Conclusion

Overall, mecillinam showed excellent activity and a comparable resistance profile to fosfomycin. Resistance rates to ceftazidime, cefotaxime, ciprofloxacin and trimethoprim/sulfamethoxazole of greater than 20% are concerning due to the frequent use of these antibiotics in clinical practice to treat UTIs. Taken together, these data demonstrate that mecillinam has promising activity, with low resistance observed in Enterobacterales species causing UTIs in the USA. Clinical development of mecillinam in the USA is ongoing.

Disclosures

Stephen Hawser, PhD, Utility Therapeutics (Grant/Research Support) Ian Morrissey, Utility Therapeutics (Grant/Research Support) Anne Santerre Henriksen, MS, Advanz (Consultant)Shionogi BV (Consultant)UTILITY Therapeutics (Consultant)
1045. Safety of the Synthetic Saponin Adjuvant TQL1055: Preliminary Results from a First-in-humans Trial
Authors: Bennett Sean R , Martin Tyler
Published: December 2021

Background

Saponin adjuvants reliably enhance immune response to a variety of antigens, but their use is hindered by dose-limiting toxicities and supply constraints. TQL1055 is a semi-synthetic analog of the natural saponin adjuvant QS-21, rationally modified to improve tolerability and enable large-scale manufacturing. We previously showed that the combination of acellular pertussis vaccine (aP) and TQL1055 was well-tolerated and increased anti-pertussis toxin (PT) antibody responses in mice and rabbits, with a no observed adverse effect level (NOAEL) > 2000 mcg/dose.

Methods

Here we report interim results from a Phase 1 first-in-humans dose-escalation study of TQL1055. Healthy adults 18 to 50 years of age were sequentially enrolled into 6 groups (n=12/group) and randomized 10:2 to receive one intramuscular dose of aP + TQL1055 or aP alone on Day 1. TQL1055 dose increased by group from 25 to 800 mcg (Figure 1). Local adverse events (AEs) (injection site pain, redness, swelling) and systemic AEs (fever, chills, headache, fatigue, myalgia, arthralgia, nausea, vomiting, diarrhea) were solicited through Day 8. Clinical laboratory panels (chemistry, hematology, coagulation) were performed on Days 1 (pre-dose), 8, and 29. Serious AEs were collected through Day 365. Antibodies to PT were assessed at all visits.

Figure 1. Study Design

Results

Blinded safety data from the first four groups (n=48) through Day 8 were analyzed, including 2 subjects/group receiving aP alone. All solicited AEs were mild or moderate (Figure 2). Local AEs, mainly injection site pain, occurred in 75% of subjects (mild 65%, moderate 10%). The incidence of total local AEs increased with TQL1055 dose, from 50% at 25 mcg to 92% at 200 mcg. The mean duration of local AEs was 1.8 days and also increased with TQL1055 dose, from 1.3 days at 25 mcg to 2.1 days at 200 mcg. Systemic AEs, mostly fatigue, headache, and nausea, occurred in 63% of subjects (mild 40%, moderate 23%), with no fevers. The mean duration of systemic AEs was 1.4 days, with no association with TQL1055 dose. No severe or serious adverse events were reported.

Figure 2. Solicited Adverse Events by Severity and TQL1055 Dose

Conclusion

In this early analysis, the safety profile of aP + TQL1055 appears similar to that of licensed aP vaccines, without severe or prolonged injection site pain. These data support further dose escalation and assessment of immunogenicity.

Disclosures

Sean R. Bennett, MD PhD, Adjuvance Technologies (Employee) Tyler Martin, MD, Adjuvance Technologies (Employee, Shareholder)
124. Establishment of a Post-Influenza Aspergillosis Model in Corticosteroid-Immunosuppressed Mice
Authors: Wurster Sebastian , García Jezreel Pantaleón , Albert Nathaniel D , Evans Scott , Kontoyiannis Dimitrios P
Published: December 2021

Background

Post-influenza aspergillosis (PIA) is a feared complication in patients with severe influenza, especially those receiving corticosteroids. However, validated murine models of PIA in a background of corticosteroid immunosuppression are lacking, compounding efforts to better characterize the immunopathology and treatment of this emerging entity.

Methods

8-week-old female BALB/c mice were infected with ~5% of the lethal dose of a mouse-adapted influenza A/Hong Kong/1968 (H3N2) strain (flu), delivered by aerosolization, versus control (aerosolized saline). Mice then received two intraperitoneal injections of 10 mg cortisone acetate (CA) or mock injections on days 5 and 8 after flu infection. On day 9, mice were intranasally challenged with 50,000 A. fumigatus AF-293 conidia or mock-infected with saline. Survival was monitored until day 16 and infection severity was scored using the modified murine sepsis score (MSS, 0 = healthy to 3 = moribund). Pulmonary fungal burden was determined by an 18S quantitative PCR assay on day 16 or upon death. 15-16 mice per group were assessed across 3 independent experiments.

Results

Flu infection alone caused modest early morbidity, followed by full recovery of the mice until day 16. Treatment with CA after flu infection led to 12% mortality and increased morbidity that persisted until day 16 (median MSS = 0.8). Similarly, mice infected with AF after CA treatment had 12% mortality and a median MSS of 0.7. Combination of all 3 challenges (flu, CA, and AF) led to 40% mortality and severe morbidity in surviving mice (median MSS = 2.7). Likewise, prior flu infection of CA-treated, AF-infected mice increased the pulmonary fungal burden from 27k to 80k median conidial equivalents. In contrast, mice not receiving CA treatment showed consistently low morbidity (median day-16 MSS = 0.5) and minimal fungal burden after AF challenge, regardless of prior flu infection.

Conclusion

We have established a model of PIA in CA-immunosuppressed mice that underscores the detrimental effect of corticosteroid therapy on the outcomes of PIA. In the future, we will employ this model to study the impact of various pharmacological interventions on the natural history of PIA in the background of corticosteroid immunosuppression.

Disclosures

Dimitrios P. Kontoyiannis, MD, Astellas (Consultant)Cidara Therapeutics (Advisor or Review Panel member)Gilead Sciences (Consultant, Grant/Research Support, Other Financial or Material Support, Honoraria)
1046. Immunogenicity and Safety of a Quadrivalent Meningococcal Conjugate Vaccine (MenACYW-TT) Administered as a Booster to Adults ≥ 59 Years of Age
Authors: Robertson Corwin A , Jacqmein Jeffry , Selmani Alexandre , Galarza Katherine , Oster Philipp
Published: December 2021

Background

MenACYW-TT (MenQuadfi®, Sanofi) is a quadrivalent (serogroups A, C, W, and Y) meningococcal tetanus toxoid conjugate vaccine. It was recently approved for use in persons aged ≥ 2 years in the US and persons aged ≥ 1 year in Europe and certain other countries; trials in infants as young as 6 weeks are ongoing. This study evaluated seroresponse after a MenACYW-TT booster given to adults who received either quadrivalent meningococcal polysaccharide vaccine (MSPV4) or MenACYW-TT three years earlier at age ≥ 56 years. Immune persistence up to 7 years after primary vaccination was also evaluated.

Methods

This was a Phase 3 randomized, open-label study (NCT04142242) of adults aged ≥ 59 years who participated in previous studies of MenACYW-TT vs MPSV4 (NCT01732627 and NCT02842866). The study was conducted in the US and Puerto Rico. Immune response and persistence were assessed with a serum bactericidal assay using human complement (hSBA). Sufficiency of the vaccine seroresponse was considered demonstrated if the lower limit of the 1-sided 97.5% CI for the percentage of subjects with an hSBA vaccine seroresponse against serogroups A, C, W and Y was > 40%. Safety data were collected up to 30 days after booster vaccination.

Results

A total of 471 persons were enrolled. Sufficiency of a MenACYW-TT booster was demonstrated for MPSV4- and for MenACYW-TT-primed subjects. hSBA seroresponse rates were higher among MenACYW-TT- vs MPSV4-primed subjects (79.3%–93.1% vs 49.2%–60.8%, respectively). Three to 7 years after primary vaccination, hSBA geometric mean titers (GMTs) and seroprotection rates (SPRs) declined in both MenACYW-TT- and MPSV4-primed subjects, with hSBA GMTs and SPRs for serogroups C, W, and Y generally remaining higher for MenACYW-TT- vs MPSV4-primed subjects; those for serogroup A were similar regardless of priming vaccine. Rates of adverse events following a MenACYW-TT booster were similar between MenACYW-TT- and MPSV4-primed subjects. No safety concerns were identified.

Conclusion

A MenACYW-TT booster was well tolerated and immunogenic when administered to either MPSV4- or MenACYW-primed adults aged ≥ 59 years. Up to 7 years after primary vaccination, immune persistence for serogroups C, W, and Y tended to be greater for MenACYW-TT vs MPSV4.

Disclosures

Corwin A. Robertson, MD, MPH, FACP, Sanofi Pasteur (Employee, Other Financial or Material Support, Stockholder) Alexandre Selmani, PhD, Sanofi Pasteur (Employee) Katherine Galarza, MD, Sanofi Pasteur (Employee) Philipp Oster, MD, Sanofi Pasteur (Employee, Stockholder)
1052. Characterisation of the DNA binding properties of ridinilazole, a selective antibiotic currently in phase III trials for the treatment of Clostridioides difficile
Authors: Mason Clive , Avis Tim , Coward Chris , Powell David , Duperchy Esther , Hu Chenlin , Jahangir Alam M , Begum Khurshida , Garey Kevin W , Reich Stefanie , Moss Stephen
Published: December 2021

Background

Clostridioides difficile infection (CDI) is recognised by the CDC as an “urgent threat” in the USA, responsible for nearly 13,000 deaths, and carries an economic burden ranging from &5.4 to &6.3 billion per year. In a phase II study, ridinilazole was shown to be effective at treating CDI and decreasing subsequent recurrence compared to vancomycin. However, the precise mechanism of action of ridinilazole has yet to be fully elucidated. We now present data that reveals ridinilazole clearly co-localises with DNA in C. difficile and binds with high affinity to the minor groove of DNA. These interactions are predicted to have consequences on cellular functions within C. difficile.

Methods

High resolution confocal microscopy was used to track the intracellular localisation of ridinilazole in C. difficile. Fluorescence intensity was used to characterise the DNA binding properties of ridinilazole; sequence specificity was demonstrated with AT- or GC-rich DNA polymers, and tight binding was shown using short double-stranded oligonucleotides. Hanging drop vapour diffusion enabled co-crystallisation and subsequent structural determination of DNA-bound ridinilazole.

Results

Confocal microscopy revealed clear co-localisation of ridinilazole to the DNA within C. difficile. Ridinilazole demonstrated a dose-dependent increase in fluorescence in response to increasing concentration of target DNA. Fluorescence binding studies revealed that ridinilazole shows a preference towards AT-rich DNA sequences. Tight binding characteristics were demonstrated by ridinilazole in complex with short double-stranded oligonucleotides, returning dissociation constants (Kd) of 20 – 50 nM. Crystallisation enabled co-structures of ridinilazole bound to the minor groove of double-stranded DNA oligonucleotides to be solved.

Conclusion

Ridinilazole demonstrates tight binding with sequence specificity within the minor groove of DNA and co-localises with DNA in C. difficle. Further analysis is ongoing to fully understand this novel mechanism of action, the downstream consequences of these interactions and how they contribute to the bactericidal activity of ridinilazole.

Disclosures

Clive Mason, PhD, Summit Therapeutics (Employee, Shareholder) Tim Avis, n/a, Summit therapeutics (Shareholder) Chris Coward, PhD, Summit Therapeutics (Employee, Scientific Research Study Investigator, Shareholder) David Powell, PhD, Summit Therapeutics (Employee) Kevin W. Garey, Pharm.D., M.S., FASHP, Summit Therapeutics (Research Grant or Support)
1058. In Vitro and In Vivo Antibacterial Activity of Cefiderocol against Burkholderia spp
Authors: Oota Merime , Hama Hitomi , Yoshitomi Toriko , Nakamura Rio , Takemura Miki , Yamano Yoshinori , Hackel Meredith , Sahm Daniel F
Published: December 2021

Background

Burkholderia spp. is an opportunistic pathogen associated with respiratory infections. Cefiderocol (CFDC), a siderophore cephalosporin approved in US and EU, is active in vitro against carbapenem-resistant Gram-negative bacteria including Burkholderia spp. This study examined in vitro and in vivo activity of CFDC against Burkholderia spp.

Methods

MICs of CFDC and 13 marketed antibacterial drugs against 462 clinical isolates of Burkholderia spp. collected in 2014 - 2019 in 13 countries were determined by broth microdilution method according to CLSI guidelines. Only for CFDC, iron-depleted CAMHB was used. In a rat lung infection model, B. cepacia ATCC 25416 (CFDC MIC: ≤ 0.031 μg/mL, MEM MIC: 4 μg/mL) was used. Male CD (SD, immunocompetent, n=4-5) rats were infected by intrabronchial inoculation of the bacterial suspension including 1% nutrient agar. The humanized PK in plasma by administration of CFDC 2 g every 8 h (3-h infusion) and MEM 1 g every 8 h (0.5-h infusion) were recreated via the continuous intravenous infusion for 4 days, and the viable cfu in lungs were counted.

Results

Against 462 strains, including 185 MEM non-susceptible isolates, CFDC showed MIC50/MIC90 of ≤ 0.031/1 µg/mL, which was the lowest among the tested antibiotics. Among 185 MEM non-susceptible isolates, 94% of the isolates exhibited ≤ 4 µg/mL of CFDC MIC. In a rat lung infection model, CFDC and MEM showed bactericidal activity with 2.8 and 2.4 log10 CFU/lung decrease compared with non-treated control, respectively. By recreating the humanized PK exposure in this model, 100% and ca.35% of fT >MIC of CFDC and MEM in plasma has been achieved, respectively. The bactericidal activities of both compounds vs B. cepacia ATCC 25416 would be reasonable because the fT >MIC achieved in this model exceeds the target fT >MIC (75% for CFDC and 26% for MEM against Acinetobacter baumannii, respectively) required to cause 1 log10 reduction in murine thigh infection models1,2).

1) M. Sabet. 2019. AAC 2) R. Nakamura. 2019. AAC

In vitro activity of CFDC and comparator agents against Burkholderia spp.

Conclusion

CFDC has potential for treating respiratory tract infections caused by Burkholderia spp. In critically ill patients, the recommended dosing regimen achieves 100% of fT >MIC of ≤ 4 ug/mL3).3) N. Kawaguchi. 2021. AAC

Disclosures

Merime Oota, BSc, Shionogi TechnoAdvance Research & Co., Ltd. (Employee) Toriko Yoshitomi, -, Shionogi TechnoAdvance Research & Co., Ltd. (Employee) Rio Nakamura, BSc, Shionogi TechnoAdvance Research & Co., Ltd. (Employee) Miki Takemura, MS, SHIONOGI & CO., LTD. (Employee) Yoshinori Yamano, PhD, Shionogi (Employee) Meredith Hackel, PhD MPH, IHMA (Employee)Pfizer, Inc. (Independent Contractor) Daniel F. Sahm, PhD, IHMA (Employee)Pfizer, Inc. (Independent Contractor)
1069. In Vitro Activity of Tebipenem Against Clinically Significant Gram-Negative Bacteria Isolated from Patients with Cancer
Authors: Gerges Bahgat , Rosenblatt Joel , Hachem Ray Y , Raad Issam I , Chaftari Anne-Marie
Published: December 2021

Background

Gram negative (GN) bacterial infections are on the rise in patients with cancer and frequently require extended hospital stays that may lead to a major increase in healthcare cost. This study aimed to evaluate the in vitro activity of a novel oral carbapenem, tebipenem against recent gram-negative clinical isolates from our cancer patients.

Methods

All 173 clinical isolates from our cancer patients including 36 Extended Spectrum Beta-Lactamase (ESBL) isolates from blood cultures were tested against tebipenem and other comparators. Clinical and Laboratory Standards Institute (CLSI) approved broth microdilution method was used. Appropriate ATCC controls were included. MIC50, MIC90, MIC ranges and percent of susceptibility calculations ware made using FDA breakpoints when available. The tebipenem provisional susceptibility breakpoint for most GN organism is ≤ 0.125 mg/L.

Results

Tebipenem and comparators antibiotics susceptibility percent (S: %), and MIC90 are shown in the table below. Tebipenem demonstrated highly potent activity against Escherichia coli, Klebsiella pneumoniae (including ESBL producing strains), Enterobacter cloacae and inhibited 90% of the Enterobacter aerogenes strains screened. MIC90s ranged from 0.06-0.25 mg/L for all tested Enterobacteriaceae. At a provisional breakpoints of 0.125 mg/L, the susceptibilities, MICs and ranges were comparable to meropenem, and ertapenem.

Comparative study between Tebipenem and comparators for MIC90 (mg/L.) and Susceptibility (%) results against Gram-Negative Bacteria Isolated from Patients with Cancer

Conclusion

Our data demonstrate that oral tebipenem has promising activity against clinically significant bacterial pathogens isolated from cancer patients, and it has similar activity to that of other tested carbapenem. Further clinical evaluation for oral carbapenem treatment of bacterial infections is warranted.

Disclosures

All Authors: No reported disclosures
1070. In vitro Activity of PLG0206 Against Isolates Commonly Found in Periprosthetic Joint Infections (PJI)
Authors: Huang David , Steckbeck Jonathan , Pillar Chris , Murray Bev , Huganfel David , Shinabanger Dean
Published: December 2021

Background

PLG0206 is a novel engineered cationic antimicrobial peptide being evaluated for treatment of prosthetic joint infections. In this study, the activity of PLG0206 was evaluated by broth microdilution against 104 isolates of Staphylococcus epidermidis, 53 other coagulase-negative staphylococci (CoNS), 3 S. aureus, and 66 Gram-negative isolates consisting of Enterobacterales, Pseudomonas aeruginosa, and Acinetobacter baumannii.

Methods

Imipenem, levofloxacin, tigecycline, linezolid, vancomycin, oxacillin, ceftazidime, colistin, and amikacin were tested as comparators. Testing was conducted in accordance with guidelines from the Clinical and Laboratory Standards Institute (CLSI; M7 and M100). Test organisms consisted of reference strains from the American Type Culture Collection, the Centers for Disease Control Antibiotic Reference Bank and clinical isolates from the Micromyx repository. The media employed for testing in the broth microdilution MIC assay for all organisms were cation-adjusted Mueller Hinton Broth and for PLG0206 only included RPMI-1640 medium supplemented with 0.002% P-80.

Results

Activity of PLG0206 in RPMI against CoNS, S. aureus, and resistant Gram-negative* pathogens are shown in Table.

Activity of PLG0206 in RPMI against CoNS, S. aureus and resistant Gram-negative* pathogens

Activity of PLG0206 in RPMI against CoNS, S. aureus and resistant Gram-negative* pathogens

Conclusion

PLG0206 was found to have potent antimicrobial activity when evaluated in RPMI against

S. epidermidis, CoNS non-epidermidis, S. aureus, Enterobacterales, P. aeruginosa, and A. baumannii, including isolates with multi-drug resistance.

Disclosures

David Huang, MD, PhD, Peptilogics (Employee) Jonathan Steckbeck, PhD, Peptilogics (Employee) Chris Pillar, PhD, Micromyx (Employee) Bev Murray, BS, Micromyx (Employee) David Huganfel, BS, Micromyx (Employee) Dean Shinabanger, PhD, Micromyx (Employee)
1072. In Vitro Antibacterial Susceptibility Testing of Sulopenem Against Category A and B Bio-threat Bacterial Pathogens
Authors: Dunne Michael , Aronin Steven I , Halasohoris Stephanie A , Pysz Lisa M , Lembirik Sanae , Meinig James M
Published: December 2021

Background

Sulopenem is a thiopenem β-lactam antibiotic being developed for the treatment of infections caused by multi-drug resistant bacteria. Sulopenem possesses potent activity against species of the Enterobacterales that encode ESBLs or AmpC-type β-lactamases that confer resistance to third generation cephalosporins. It has also demonstrated good in vitro microbiological activity against a range of bacterial pathogens including penicillin resistant S. pneumoniae, β-lactamase-producing H. influenzae and M. catarrhalis. Sulopenem is available as intravenous and oral pro-drug formulations, and its activity aligns with the most urgent drug-resistant antimicrobial threats defined by the CDC.

Methods

Bacterial inoculums were prepared by suspending colonies into cation adjusted Mueller Hinton broth (CAMHB) from 18-24 h (B. anthracis, B. pseudomallei and B. mallei plates incubated at 35ºC); or 36-48 h (F. tularensis and Y. pestis plates incubated at 35ºC and 28ºC, respectively). Sheep blood agar plates were used for B. anthracis and Y. pestis. Chocolate agar plates were used for F. tularensis, B. pseudomallei and B. mallei. Suspended cultures were diluted with CAMHB to achieve a turbidity equivalent to a 0.5 McFarland standard. MICs were determined by the microdilution method in 96-well microplates according to CLSI guidelines (Clinical and Laboratory Standards Institute, 2020). Antibiotic ranges used for sulopenem were 0.03 - 64 μg/mL and 0.004 - 8 μg/mL for the diversity strains of B. anthracis, F. tularensis, Y. pesis, B. mallei, and B. pseudomallei, based on a final well volume of 100 μl after inoculation.

Results

A summary of sulopenem MIC90 results versus bio-threat bacterial pathogens in presented in the table. Criteria for down selection into mice was met for all pathogens except F. tularensis.

Sulopenem MIC90 Summary for Down Selection Criteria

Conclusion

Sulopenem is active in vitro against a number of bio-threat pathogens at concentrations likely to be achieved after oral dosing in humans and meets criteria to be tested in the murine model of B. anthracis, Y. pestis, B. mallei, and B. pseudomallei.

Disclosures

Michael Dunne, MD, Iterum Therapeutics (Board Member, Consultant, Shareholder) Steven I. Aronin, MD, Iterum Therapeutics (Employee, Shareholder)
1073. Sulbactam-Durlobactam Has Potent Activity Against Multidrug-Resistant Acinetobacter baumannii Clinical Isolates From Thai Patients With Chronic Infections
Authors: Wannigama Dhammika Leshan , Higgins Paul G , Hurst Cameron , Abe Shuichi , Hongsing Parichart , Luk-In Sirirat , Kueakulpattana Naris , Laowansiri Matchima , Tanasatitchai Chanikan , Srisakul Sukrit , Kicic Anthony , Chatsuwan Tanittha , Moussa Samir , Miller Alita
Published: December 2021

Background

Due to the increase in multi-drug resistance (MDR) of Acinetobacter baumannii chronic infections with accompanying considerable morbidity and mortality, it is imperative to find effective novel treatments. Durlobactam (DUR) is a potent broad-spectrum inhibitor of Ambler classes A, C and D serine β-lactamases that effectively restores sulbactam (SUL) activity against MDR A.baumannii isolates. SUL-DUR is currently in late-stage development for the treatment of infections caused by Acinetobacter spp., including drug resistant isolates. In this study, we sought to evaluate potency of SUL-DUR against MDR A. baumannii isolates collected from Thai patients with chronic infections.

Methods

Non-duplicative clinical strains were isolated during 2016–2019 from 200 chronically infected patients in different medical wards with a variety of different infections at King Chulalongkorn Memorial Hospital, Bangkok, Thailand. Susceptibility testing of SUL-DUR and comparator agents was performed according to CLSI guidelines. SUL-DUR was also tested on a background of imipenem (IPM) therapy (SUL-IPM titrated at a 1:1 ratio plus DUR fixed at 4 mg/L). Data analysis was performed using CLSI and EUCAST breakpoint criteria where available.

Results

This collection of isolates was 92% sulbactam-resistant (using a breakpoint of 4 mg/L), 91% carbapenem-resistant, 74% amikacin resistant and 8% colistin resistant. In contrast, the SUL-DUR MIC90 was 4 mg/L compared with 64 mg/L for sulbactam alone. SUL-DUR was equally potent across antibiotic-resistant subsets. Only 6 isolates (3%) had SUL-DUR MIC values >4 mg/L. Interestingly, addition of imipenem to SUL-DUR showed similar potency as SUL-DUR alone, with an MIC90 of 2 mg/L.

Conclusion

SUL-DUR showed potent in vitro activity against contemporary clinical isolates from a hospital in Bangkok, Thailand. If successfully developed, SUL-DUR may be an important new therapeutic option for the treatment of MDR Acinetobacter infections.

Disclosures

Alita Miller, PhD, Entasis Therapeutics (Employee)
1074. The Relationship Between the Patient’s Body Mass Index and Dalbavancin’s Efficacy in the Treatment of Invasive Gram-Positive Infections
Authors: Avery Lisa , Sessa Julia , Conn Kelly M , Slish Judianne , Adamchick Lauren , Louie Ted
Published: December 2021

Background

Dalbavancin is a long-acting lipoglyopeptide antibiotic used in the treatment of invasive gram-positive infections. There is a lack of published research on the effect of obesity on dalbavancin’s pharmacokinetics. The primary objective was to determine if obesity correlates to clinical failure at 90 days for patients with gram-positive infections treated with dalbavancin.

Methods

This retrospective observational study reviewed the use of dalbavancin from 1/1/2015- 3/31/2021 at 2 community hospitals. Patients were included if ≥ 18 years and received at least one dose of dalbavancin as an inpatient or at an outpatient infusion center. Patients were excluded if not seen by a provider within 90 days post last infusion. The primary outcome was clinical failure (CF). CF at 90 days was a composite of one or more of the following: need for additional antibiotics, dalbavancin intolerance, hospital readmission for same indication, need for additional surgery/debridement, or death. Clinical cure (CC) was defined as not meeting the criteria for CF. Patient demographics, BMI, indication, achievement of source control, Charlson Comorbidity Index (CCM) were collected. Descriptive statistics were used. To determine if a BMI cut-point exists between CC and CF, a classification & regression tree (CART) analysis was performed.

Results

A total of 81 patients received dalbavancin with 19 patients excluded for lack of follow up. Patient demographics: mean age (SD) 45.3 (15.8) years, 50% male; CCM 2.6 (3.1). Indications included osteomyelitis n=22, endovascular n=12, diabetic foot/skin soft tissue n=9, septic joint n=8, other n=11. A total of 29 (47%) of patients were bacteremic; 34 (55%) having source control. CF occurred in 15 of 62 (24%) patients. CF was compared with weight, BMI, CCM, albumin and source control. A difference existed in the median (IQR) BMI between CF 32.5 kg/m2 (25.1 – 42.8) and CC 25.5 kg/m2 (22.1 – 28.2); p=.029. A BMI cutpoint was not identified in CART analysis.

Conclusion

There is a relationship between increased BMI and 90-day CF in patients treated with dalbavancin. A higher BMI was found among those with with CF. Future studies are necessary to determine if a BMI based weight adjustment is necessary.

Disclosures

Lisa Avery, PharmD, BCPS, BCIDP, Merck (Other Financial or Material Support, Spouse Employer)
1077. In Vitro Activity of Delafloxacin Agent Against Bacterial Isolates Recovered from Patients with Cancer
Authors: Gerges Bahgat , Raad Issam I , Rosenblatt Joel , Shelbume Samuel , Prince Randal , Rolston Kenneth
Published: December 2021

Background

Fluoroquinolones have been used for infection prevention in patients with cancer (PWC). They are active against many Gram-negative bacilli (GNB) but are less active against Gram-positive organisms (GPO). Quinolone resistance is increasing and many institutions are using combination regimens for antimicrobial prophylaxis. We evaluated the in vitro activity of delafloxacin (DLX), a novel fluoroquinolone, and selected comparators against 560 bacterial isolates from PWC.

Methods

Isolates were from recent blood cultures. Susceptibility testing and time kill studies (TKS) were performed using CLSI approved methodology. Appropriate ATCC control strains were used. We calculated MIC50, MIC90, MIC ranges and percent susceptibility using FDA breakpoints when available. TKS were performed on 4 streptococcus mitis isolates at concentrations of MIC, 4x MIC, and 8x MIC.

Results

DLX was more active than ciprofloxacin (CIP) and levofloxacin (LEV) against methicillin-susceptible (MSSA), and resistant (MRSA) S. aureus, coagulase-negative staphylococci (CoNS), and viridans group streptococci (VGS), and had similar activity against beta-hemolytic streptococci. It also had low MICs for Bacillus species (SPP.), Listeria monocytogenes, Micrococcus spp., and Rothia spp. Overall GPO susceptibility was 73% to DLX, 42% to CIP, and 52% to LEV. The activity of DLX against Enterobacterales was similar to CIP and LEV. All 3 agents had moderate activity against Citrobacter spp., and non-MDR P. aeruginosa. Notably, all 3 quinolones had poor activity against E. coli, P. mirabilis, and MDR P. aeruginosa, all common pathogens in PWC. All 3 had low MICs for Acinetobacter spp. DLX and LEV achieved peak bactericidal activity at 6-8 h against all 4 VGS isolates (maximum activity at 8x MIC) but this was not always sustained at 24 h.

Table 1. Percent Susceptibility of selected Gram-positive isolates to Delafloxacin, Ciprofloxacin and Levofloxacin

Table 2. Percent Susceptibility of selected Gram-negative isolates to Delafloxacin, Ciprofloxacin and Levofloxacin

Figure 1. Bactericidal Activity of DLX at 1x , 4x, and 8x MIC against VGS - Time Kill Study

Conclusion

DLX is more active than CIP and LEV against many GPO from PWC (including S. aureus and VGS), but like these agents there are significant gaps in its coverage against GNB. It is probably not suitable as a single agent for antimicrobial prophylaxis in high-risk PWC. The current practice of combining a quinolone with a beta-lactam probably still represents the best option in PWC who need prophylaxis.

Disclosures

Kenneth Rolston, MD, Tetraphase Pharmaceuticals (Grant/Research Support)
1079. Development of Tebipenem MIC Antimicrobial Susceptibility Test for Gram-negative Bacteria on MicroScan Dried Gram-negative MIC Panels
Authors: Fernandez Jose Enrique , Williams Robert L , Carr Vasna , Miller Renae
Published: December 2021

Background

Development of a tebipenem antimicrobial susceptibility test was completed for the MicroScan Dried Gram-negative MIC (MSDGN) Panel when compared to CLSI broth microdilution reference panels.

Methods

Development was conducted by comparing MICs obtained using the MSDGN panel to MICs using a CLSI broth microdilution reference panel. A total of 669 Enterobacterales isolates were tested at 16, 18, and 20 hour incubation times using the turbidity and Prompt®* methods of inoculation. MSDGN panels were incubated at 35 ± 2ºC and read on the WalkAway System, the autoSCAN-4 instrument, and read visually. Frozen reference panels, prepared according to ISO/CLSI methodology, were inoculated using the turbidity inoculation method. All frozen reference panels were incubated at 35 ± 2ºC and read visually. Dilution sequence evaluated is 0.03-32 µg/mL.

Results

When compared to frozen reference panel results, essential agreement for all isolates tested during development are as follows:

Conclusion

The development data showed that tebipenem MIC results for Enterobacterales obtained with the MSDGN panel correlate well with MICs obtained using frozen reference panels. Essential agreement is > 90% for all inoculation and read methods.

For Investigational Use Only. The performance characteristics of this product have not been established.

* Prompt® is a registered trademark of 3M Company, St. Paul, MN USA.

© 2021 Beckman Coulter. All rights reserved. Beckman Coulter, the stylized logo, and the Beckman Coulter product and service marks mentioned herein are trademarks or registered trademarks of Beckman Coulter, Inc. in the United States and other countries.

Disclosures

Jose Enrique Fernandez, n/a, Beckman Coulter (Employee) Vasna Carr, n/a, Beckman Coulter (Employee) Renae Miller, n/a, Beckman Coulter (Employee)
1082. Real-World Experience with Omadacycline for Nontuberculous Mycobacterial Infections: A Multicenter Evaluation
Authors: Morrisette Taylor , Alosaimy Sara , Lagnf Abdalhamid M , Philley Julie V , Sigler Carly , Butt Saira , Kaip Emily A , MacDougall Conan , Mejia-Chew Carlos , Bouchard Jeannette , Frens Jeremy J , Gore Tristan , Hamad Yasir , Howard Catessa , Barger Melissa , Gabriela Cabanilla M , Ong Aaron , Veve Michael P , Webb Andrew J , Stevens Ryan W , Cohen Keira A , Rybak Michael J
Published: December 2021

Background

Nontuberculous mycobacteria (NTM) are resistant to numerous antibiotics and lead to significant morbidity and mortality. Omadacycline (OMC) is an aminomethylcycline antibiotic that is Food and Drug Administration-approved for acute bacterial skin and skin structure infections and community-acquired bacterial pneumonia. Furthermore, OMC has shown in vitro activity against NTM. Given that real-world evidence is lacking, our primary objective was to evaluate the clinical success and tolerability of OMC when used for a variety of NTM infections.

Methods

This was a multicenter, retrospective, observational study conducted from January 2020 to June 2021. We included all patients ≥ 18 years of age that received OMC of any indication for Mycobacterium spp. The primary outcome was clinical success, defined as a lack of all-cause mortality, lack of persistence or re-emergence of infection during or after therapy, and lack of alteration of OMC. Incidence of adverse effects potentially attributable to OMC and reasons for OMC utilization were also analyzed.

Results

A total of 31 patients were included from 12 geographically distinct academic health systems (median age: 57 (IQR, 45-63) years; 45% male; 81% Caucasian). The majority of isolated pathogens were Mycobacterium abscessus complex (84%) and of those with subspeciation performed (54%), the majority (86%) were subsp. abscessus. The primary infections were of pulmonary origin (67%) and the median (IQR) duration of OMC therapy was 5.3 (3.2-9.4) months. Most isolates did not have OMC susceptibility conducted (87%), while the majority did for tigecycline (90%). Clinical success was reported in 81% of the population. Most patients were on combination antimicrobial therapy, and 39% of patients reported an adverse effect while on OMC (58% gastrointestinal distress). The majority of patients were prescribed OMC due to ease of administration (61%) and antimicrobial resistance to previous antibiotics (42%).

Conclusion

OMC may be a potential option for the therapy of NTM infections. Prospective, randomized clinical trials are needed to confirm our preliminary findings.

Disclosures

Julie V. Philley, MD, Paratek Pharmaceuticals (Advisor or Review Panel member)Paratek Pharmaceuticals, Inc. (Consultant) Michael P. Veve, Pharm.D., Cumberland (Grant/Research Support)Paratek Pharmaceuticals (Research Grant or Support) Michael J. Rybak, PharmD, MPH, PhD, Paratek Pharmaceuticals (Research Grant or Support)
1083. Phase 1b Results of Pharmacokinetics, Pharmacodynamics, and Safety for LBP-EC01, a CRISPR-Cas3 Enhanced Bacteriophage Cocktail Targeting Escherichia coli that Cause Urinary Tract Infections
Authors: Kim Paul , Sanchez Ana , Kime Jamie , ousterout Dave
Published: December 2021

Background

LBP-EC01 is the first CRISPR-engineered bacteriophage product to successfully complete Phase 1b testing in a clinical program designed to address infections caused by E. coli initially targeting urinary tract infections (UTIs). Thirty-six subjects were enrolled in this randomized, double blind study to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of LBP-EC01 in patients with lower urinary tract colonization caused by E. coli.

Methods

Results

No drug-related Treatment Emergent Adverse Events (TEAEs) were observed. All nondrug related TEAEs were Grade 2 or below and there were no tolerability signals associated with LBP-EC01.A modified ITT (mITT) population was defined to assess PK in subjects treated with LBP-EC01 (n=17). Subjects were removed from the PK analysis who had missing or insufficient colonization at baseline (n=3), were exposed to antibiotics during screening or study conduct (n=3) or exhibited a non-drug related SAE (n=1). Of these subjects, 12 were found to be sensitive to LBP-EC01 and of these, 10 (83%) showed phage amplification. A PD analysis compared the mITT populations of LBP-EC01 vs. placebo (n=6) and showed that the LBP-EC01 arm had a decrease in E. coli that was greatest within 24 hours of initial treatment and remained below baseline across the entire treatment period. The placebo arm showed increased levels of E. coli and higher variability over the treatment period. An average difference of 2-3 log (100x to 1,000x) existed in urine E. coli concentration (CFU/mL) between the LBP-EC01 and placebo arms across the duration of the treatment period.

Conclusion

LBP-EC01 has proved to be safe and well-tolerated in this Phase 1b study of subjects colonized by E. coli. In addition, phage amplification was observed in patients with E. coli isolates sensitive to LBP-EC01, demonstrating a clear proof of mechanism. Finally, the apparent difference in PD effect between LBP-EC01 and placebo which was irrespective of MDR status, provides promise that LBP-EC01 may someday be an excellent option for patients suffering from UTIs caused by E. coli, especially in strains that are resistant to conventional antibiotics.

Disclosures

Dave ousterout, PhD, InceptorBio (Advisor or Review Panel member, Shareholder)Locus Biosciences (Employee, Shareholder)
1084. Comparative Outcomes Among Patients Receiving Varying Daptomycin Dosing Regimens in Hemodialysis
Authors: Maxwell Tyler , Orban James E , Kufel Wesley D , Destache Christopher , Williams Karen S , Velagapudi Manasa , Brandon Bookstaver P , Tatem Luis , McCracken James A , Carpenter Bethanne , Sharma Roopali
Published: December 2021

Background

Daptomycin (DAP) has become an appealing treatment option for gram-positive infections, which are common in patients receiving hemodialysis (HD), due to frequent access and manipulation. The approved DAP dosing of 4 to 6 mg/kg every 48 hours (q48h) quickly becomes desynchronized from the patient’s HD schedule and requires the burden of additional IV access. Previous pharmacokinetic studies have suggested that DAP can be dosed three-times weekly following HD, but no studies have evaluated clinical outcomes of this regimen.

Methods

This was a multi-center, retrospective cohort study across 6 hospitals in the United States. Adult, nonpregnant patients who received HD and DAP between 2015 and 2020 were screened for inclusion. Electronic medical records were reviewed for relevant study data. The primary outcome was clinical and microbiological outcomes among patients who received DAP thrice weekly versus q48h dosing. Microbiological Failure was defined as positive cultures after 7 days and further study definitions are included under Table 3.

Results

Baseline characteristics are summarized in Table 1. Length of stay was similar between both groups at a median of 25 days and patients had a median QPitt score of 0 on admission. The average DAP dose used was 7 mg/kg and 7mg-7mg-9mg on HD days in the q48h dosing and thrice weekly dosing regimens, respectively. The majority of patients had bacteremia and the most commonly isolated bacteria was methicillin-resistant Staphylococcus aureus. No differences in clinical outcomes were observed (p=0.87). Microbiological failure was higher among patients who received DAP thrice weekly compared to q48h dosing (69.2% vs 34.8%, p=0.047).

Conclusion

DAP dosed thrice weekly on HD days offers similar clinical resolution compared to q48h dosing. While the thrice weekly dosing regimen did have a significantly higher rate of microbiological failure, the analysis was limited by a small sample size. As this is a retrospective analysis not accounting for confounding variables, additional prospective studies are warranted to confirm these findings.

Disclosures

Wesley D. Kufel, PharmD, Melinta (Research Grant or Support)Merck (Research Grant or Support)Theratechnologies, Inc. (Advisor or Review Panel member) P. Brandon Bookstaver, Pharm D, ALK Abello, Inc. (Grant/Research Support, Advisor or Review Panel member)Biomerieux (Speaker's Bureau)Kedrion Biopharma (Grant/Research Support, Advisor or Review Panel member)
1085. Comparison of the Incidence of AKI in Vancomycin AUC Based Goal Trough Dosing vs. Traditional Trough Dosing in the Outpatient Setting
Authors: Rees Marissa , Bremmer Derek N , Carr Dustin R , Trienski Tamara , Buchanan Carley , White Kara M
Published: December 2021

Background

Recent changes to vancomycin guidelines recommend dosing by targeting an AUC of 400-600 in most patients, due to similar effectiveness and reduced rates of acute kidney injury (AKI). AKI was defined as an increase in serum creatinine of ≥ 0.5 mg/dl, a 50% increase in serum creatinine from baseline on two consecutive readings, or a decrease in creatinine clearance from 50% from baseline on two consecutive readings. The purpose of this study was to assess the incidence of AKI in patients receiving vancomycin dosed by AUC based trough goals and vancomycin dosed by traditional trough goals (15-20 mcg/mL) in the outpatient setting.

Methods

This study was performed by retrospective chart review using the electronic health record. Patients receiving vancomycin outpatient as continuation of therapy after discharge from December 1, 2018 through March 24, 2021 were reviewed. The primary objective was incidence of AKI in patients receiving vancomycin outpatient with trough goals derived from patient specific AUC calculations compared to patients receiving vancomycin by traditional goal troughs. Secondary objectives included rate of treatment failure, average AUC estimated trough range, and number of regimen changes required.

Results

There were a total of 65 patients in the traditional trough dosing group and 53 patients in the AUC trough dosing group. The incidence of AKI was higher in the traditional trough dosing group compared to the AUC trough group (23.1% vs 5.7%; p=0.01). There were no differences in incidence of treatment failure. The mean AUC estimated trough range was 11.4-16.9 mcg/mL. There were significantly less average regimen changes required in the AUC dosing group (1.64 vs 1.13; p=0.006). Patients receiving AUC trough dosing were 78% less likely to develop AKI as patients receiving traditional trough dosing (HR 0.221, 95%CI 0.051 – 0.968).

Conclusion

There was a significantly lower incidence of AKI in patients receiving vancomycin dosed by AUC based troughs compared to traditional trough dosing. Continuing AUC trough based dosing for vancomycin in the outpatient setting is convenient and may lead to reduced rates of AKI.

Disclosures

Dustin R. Carr, PharmD, BCPS, BCIDP, AAHIVP, Merck (Speaker’s Bureau)
1087. Imipenem-Cilastatin-Relebactam (I/R) Pharmacokinetics (PK) in Critically Ill Patients with Augmented Renal Clearance (ARC)
Authors: Fratoni Andrew J , Mah John W , Nicolau David P , Kuti Joseph L
Published: December 2021

Background

Imipenem (IMI) and relebactam (REL) are predominantly excreted via glomerular filtration. ARC is a common syndrome in critically ill patients with sepsis, whereby increased renal blood flow may result in enhanced solute clearance; therefore, sub-therapeutic antibiotic concentrations are of concern. Herein, we describe the PK of I/R in critically-ill patients with confirmed ARC.

Methods

Infected patients in the intensive care unit with ARC (CrCl ≥130 mL/min) received a single dose of I/R 1.25g as a 30min infusion. Blood samples were collected over 6 hours (hr) for IMI and REL concentration determination by a validated LC/MS/MS assay. Protein binding was assessed at 0.5hr by ultrafiltration (UF). An 8hr urine creatinine (UCr) collection was performed to confirm ARC. IMI and REL plasma concentrations were fitted to compartmental models in WinNonlin. Simulated concentration vs time profiles were used to assess attainment of pharmacodynamic (PD) targets for IMI (30%fT >MIC) and REL (fAUC:MIC 18) at the susceptibility breakpoint of 2 mg/L.

Results

Five patients (60% female) completed the study. Mean (SD) age, weight, and APACHE II were 43 (14) years, 90 (15) kg, and 16 (6), respectively. All patients had confirmed ARC with CrCl of 160.6 ± 47.0 mL/min (range: 135-244mL/min) based on UCr. Both IMI and REL concentrations fitted a 2-compartment better than 1-compartment model. IMI PK was: clearance, 17.9 ± 8.7 L/hr; volume of central compartment, 15.6 ± 11.2 L; volume of peripheral compartment, 10.6 ± 5.4 L; and intercompartmental clearance, 16.6 ± 14.5 L/hr. REL PK parameters were 11.9 ± 7.5 L/hr, 17.0 ± 11.3 L, 13.5 ± 9.9 L, and 13.4 ± 11.1 L/hr, respectively. Half-life was 1.5 ± 0.5 for IMI and 2.8 ± 2.2 hr for REL. Protein binding for IMI ranged from 0-10%, while REL was 0-14%. IMI fT >MIC ranged from 40-90%, and REL fAUC:MIC ranged from 22.6-59.0.

Conclusion

These are the first data to describe IMI and REL PK in critically-ill infected patients with ARC. Despite plasma clearance values greater than those reported in healthy volunteers and patients in clinical trials, I/R 1.25g as a 30 minute infusion provided optimal exposure in all patients for isolates with MICs ≤2 mg/L.

Disclosures

David P. Nicolau, PharmD, Abbvie, Cepheid, Merck, Paratek, Pfizer, Wockhardt, Shionogi, Tetraphase (Other Financial or Material Support, I have been a consultant, speakers bureau member, or have received research funding from the above listed companies.) Joseph L. Kuti, PharmD, Allergan (Speaker’s Bureau)BioMérieux (Consultant, Research Grant or Support, Speaker’s Bureau)Contrafect (Scientific Research Study Investigator)GSK (Consultant)Merck (Research Grant or Support)Paratek (Speaker’s Bureau)Roche Diagnostics (Research Grant or Support)Shionogi (Research Grant or Support)Summit (Scientific Research Study Investigator)