Based on the current Clinical and Laboratory Standards Institute susceptible breakpoint of cefepime (minimum inhibitory concentration ≤ 8 μg/mL), cefepime definitive therapy is inferior to carbapenem therapy in treating patients with so-called cefepime-susceptible ESBL-producer bacteremia.

A retrospective study was conducted at two medical centers in Taiwan to evaluate the clinical characteristics, outcomes, and risk factors for mortality among patients treated with a carbapenem for bacteremia caused by extended-spectrum-beta-lactamase (ESBL)-producing organisms. A total of 251 patients with bacteremia caused by ESBL-producing Escherichia coli and Klebsiella pneumoniae isolates treated by a carbapenem were identified. Among these ESBL-producing isolates, rates of susceptibility to ertapenem (MICs < 0.25 g/ml) were 83.8% and 76.4%, respectively; those to meropenem were 100% and 99.3%, respectively; and those to imipenem were 100% and 97.9%, respectively. There were no significant differences in the critical illness rate (P ‫؍‬ 0.1) or sepsis-related mortality rate (P ‫؍‬ 0.2) for patients with bacteremia caused by ESBL-producing K. pneumoniae (140 isolates, 55.8%) and E. coli (111 isolates, 44.2%). Multivariate analysis of variables related to sepsis-related mortality revealed that the presence of severe sepsis (odds ratio [OR], 15.9; 95% confidence interval [CI], 5.84 to 43.34; P < 0.001), hospital-onset bacteremia (OR, 4.65; 95% CI, 1.42 to 15.24; P ‫؍‬ 0.01), and ertapenem-nonsusceptible isolates (OR, 5.12; 95% CI, 2.04 to 12.88; P ‫؍‬ 0.001) were independent risk factors. The patients receiving inappropriate therapy had a higher sepsis-related mortality than those with appropriate therapy (P ‫؍‬ 0.002), irrespective of ertapenem, imipenem, or meropenem therapy. Infections due to the ertapenem-susceptible isolates (MICs < 0.25 g/ml) were associated with a more favorable outcome than those due to ertapenem-nonsusceptible isolates (MICs > 0.25 g/ml), if treated by a carbapenem. However, the mortality for patients with bacteremic episodes due to isolates with MICs of <0.5 g/ml was similar to the mortality for those whose isolates had MICs of >0.5 g/ml (P ‫؍‬ 0.8). Such a finding supports the rationale of the current CLSI 2011 criteria for carbapenems for Enterobacteriaceae.

Background Lemzoparlimab (also known as TJC4 or TJ011133), a novel, RBC-sparing CD47 antibody with a unique epitope, is in early phase clinical development in both the U.S. and China. Like other anti-CD47 antibodies, lemzoparlimab blocks the interaction of CD47 and SIRPα, leading to phagocytosis of various CD47+ tumor cell lines and primary AML cells. Mono-treatment of lemzoparlimab inhibited tumor growth completely and extended the overall survival of treated mice in a patient-derived AML xenograft model. Here we report initial findings in the ongoing phase I trial which is to determine the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of lemzoparlimab in relapsed and/or refractory (r/r) AML and MDS patients. Methods The trial (NCT04202003) adopted a modified 3+3 dose escalation design with weekly lemzoparlimab at dose levels of 1, 3, 10, 20 and 30 mg/kg. The initial two lower dose cohorts (1 mg/kg and 3 mg/kg) was designed to enroll one patient each, and the study would escalate to the next level (10 mg/kg) if no DLT and no predefined toxicity events (e.g. grade 2 or above drug-related non hematologic toxicity, except for isolated lab abnormality with no clinical manifestation) were observed. If the first DLT or predefined toxicity event was observed, the cohort size would be expanded at the current dose level and the study would revert to the standard 3+3 design. Safety, PK/PD parameters, and preliminary efficacy were evaluated. Results As of 24 July 2020, 5 r/r AML patients (pts) including 1 relapsed, 1 relapsed/refractory and 3 primary refractory, were enrolled across 3 dose cohorts (1 at 1 mg/kg, 1 at 3 mg/kg and 3 at 10 mg/kg). Patients had 2-4 prior therapies. Median age was 45 years (range 25-66). Four of 5 pts developed treatment emergent AEs. Most of the AEs were grade 1 or 2. Treatment-related AEs that occurred in &gt; 1 patient included thrombocytopenia (2/5 pts, 1 with grade 1 and 1 with grade 3) and positive anti-erythrocyte antibody (2/5 pts). No dose dependent hematologic toxicities have been observed so far. There was no treatment-related dose interruption or dose discontinuation. No patient developed treatment-related SAE or death. The maximum tolerated dose (MTD) has not yet been reached and the drug was well tolerated in r/r AML pts in the background of significantly impaired hematopoietic function with or without supportive blood transfusion. The anti-CD47 interferences on the blood bank testing were mitigated before blood transfusion. With doses from 1 mg/kg to 10 mg/kg, lemzoparlimab exhibited a supraproportional increase in exposure, which can be attributed to target (CD47) mediated drug disposition at low doses. CD47 receptor occupancy (RO) was evaluated as a PD marker. The mean RO on peripheral T cells at Cmax was 74.0%, 82.0% and 84.9% for 1, 3 and 10 mg/kg, respectively. The mean RO on CD33+ tumor cells at Cmax was 45.9%, 75.8% and 82.2% for 1, 3 and 10 mg/kg, respectively. Of note, one patient with primary refractory AML achieved morphologic leukemia-free state (MLFS) after 2 cycles of lemzoparlimab treatment at 1 mg/kg. Conclusion Lemzoparlimab was well tolerated in r/r AML pts in the doses tested and importantly, consistent with preclinical data, there were no serious hematological AEs so far. No DLTs or MTD was observed up to 10 mg/kg weekly dosing so far. The PK/PD profile of lemzoparlimab is also consistent with preclinical findings. The preliminary efficacy observed was encouraging. Dose escalation will continue until MTD or RP2D is reached. Disclosures No relevant conflicts of interest to declare.

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A limited number of adults with community-acquired urosepsis caused by ESBL-EK in the present study had a favorable outcome. Nonetheless, clinicians should be cautious of the emergence of urinary tract infections caused by ESBL-producers in the community setting.