Neutropenic Infection Research Articles

Pharmacodynamic Thresholds for Beta-Lactam Antibiotics: A Story of Mouse Versus Man.

Beta-lactams remain a critical member of our antibiotic armamentarium and are among the most commonly prescribed antibiotic classes in the inpatient setting. For these agents, the percentage of time that the free concentration remains above the minimum inhibitory concentration (%fT > MIC) of the pathogen has been shown to be the best predictor of antibacterial killing effects. However, debate remains about the quantity of fT > MIC exposure needed for successful clinical response. While pre-clinical animal based studies, such as the neutropenic thigh infection model, have been widely used to support dosing regimen selection for clinical development and susceptibility breakpoint evaluation, pharmacodynamic based studies in human patients are used validate exposures needed in the clinic and for guidance during therapeutic drug monitoring (TDM). For the majority of studied beta-lactams, pre-clinical animal studies routinely demonstrated the fT > MIC should exceed approximately 40–70% fT > MIC to achieve 1 log reductions in colony forming units. In contrast, clinical studies tend to suggest higher exposures may be needed, but tremendous variability exists study to study. Herein, we will review and critique pre-clinical versus human-based pharmacodynamic studies aimed at determining beta-lactam exposure thresholds, so as to determine which targets may be best suited for optimal dosage selection, TDM, and for susceptibility breakpoint determination. Based on our review of murine and clinical literature on beta-lactam pharmacodynamic thresholds, murine based targets specific to each antibiotic are most useful during dosage regimen development and susceptibility breakpoint assessment, while a range of exposures between 50 and 100% fT > MIC are reasonable to define the beta-lactam TDM therapeutic window for most infections.

SPR741, Double- or Triple-Combined With Erythromycin and Clarithromycin, Combats Drug-Resistant Klebsiella pneumoniae, Its Biofilms, and Persister Cells.

Klebsiella pneumoniae has emerged as a major clinical and public health threat owing to the increasing prevalence of healthcare-associated infections caused by multidrug-resistant or extensively drug-resistant strains. However, increasing antibiotic resistance and the absence of clinically effective antimicrobial agents make combination therapy an urgent need. This study investigated the anti-microbial activity of SPR741, a polymyxin B derivative, in combination with macrolide antibiotics (erythromycin and clarithromycin), against extensively drug-resistant and pandrug-resistant K. pneumoniae. Monotherapy, double, and triple combination therapies were performed to identify the most effective treatment combination using in vitro checkerboard, time-killing kinetics. Furthermore, we evaluated the biofilm eradication and persister cell-killing activity of these combinations using laser confocal microscopy and colony forming unit counting. In addition, a neutropenic mouse thigh infection model was used to assess the therapeutic efficacy and toxicity of the triple antibiotic combination against pandrug-resistant K. pneumoniae in vivo. Our results suggested that SPR741 combined with macrolides exhibited strong synergistic antibacterial activity against extensively drug-resistant and pandrug-resistant K. pneumoniae. These antibiotic combinations could also effectively eradicate highly resistant bacterial biofilms and persister cells in vitro and demonstrate considerable efficacy and low toxicity in vivo. In summary, our findings indicated that SPR741, in combination with macrolide antibiotics (double or triple combination), has the potential to serve as a novel treatment option against drug-resistant K. pneumoniae -related infections.

PKPD Modeling of the Inoculum Effect of Acinetobacter baumannii on Polymyxin B in vivo.

The reduction in antimicrobial activity at high bacterial counts is a microbiological phenomenon known as the inoculum effect (IE). In a previous in vitro study, a significant IE was observed for polymyxin B (PMB) against a clinical isolate of Acinetobacter baumannii, and well described by a new pharmacokinetic-pharmacodynamic model. Few in vivo studies have investigated the impact of inoculum size on survival or antibiotic efficacy. Therefore, our objective was to confirm the influence of inoculum size of this A. baumannii clinical isolate on PMB in vivo effect over time. Pharmacokinetics and pharmacodynamics of PMB after a single subcutaneous administration (1, 15 and 40 mg/kg) were studied in a neutropenic murine thigh infection model. The impact of A. baumannii inoculum size (105, 106 and 107 CFU/thigh) on PMB efficacy was also evaluated. In vivo PMB PK was well described by a two-compartment model including saturable absorption from the subcutaneous injection site and linear elimination. The previous in vitro PD model was modified to adequately describe the decrease of PMB efficacy with increased inoculum size in infected mice. The IE was modeled as a decrease of 32% in the in vivo PMB bactericidal effect when the starting inoculum increases from 105 to 107 CFU/thigh. Although not as important as previously characterized in vitro an IE was confirmed in vivo.

The disquietude of clozapine continuation during the COVID-19 pandemic.

The disquietude of clozapine continuation during the COVID-19 pandemic.

Pharmacodynamic target assessment and prediction of clinically effective dosing regimen of TP0586532, a novel non-hydroxamate LpxC inhibitor, using a murine lung infection model

IntroductionTP0586532 is a novel non-hydroxamate UDP-3-O-acyl-N-acetylglucosamine deacetylase (LpxC) inhibitor. Pharmacokinetic/pharmacodynamic (PK/PD) indices and magnitude of index that correlated with the efficacy of TP0586532 were determined and used to estimate the clinically effective doses of TP0586532. MethodsDose-fractionation studies were conducted using a murine neutropenic lung infection model caused by carbapenem-resistant Enterobacteriaceae. The relationships between the efficacy and the PK/PD index (the maximum unbound plasma concentration divided by the MIC [fCmax/MIC], the area under the unbound plasma concentration-time curve from 0 to 24 h divided by the MIC, and the cumulative percentage of a 24-h period that the unbound plasma concentration exceeds the MIC) were determined using an inhibitory sigmoid maximum-effect model. In addition, the magnitudes of fCmax/MIC were evaluated using the dose-response relationships for each of the seven carbapenem-resistant strains of Enterobacteriaceae. Furthermore, the clinically effective doses of TP0586532 were estimated using the predicted human PK parameters, the geometric mean of fCmax/MIC, and the MIC90 for carbapenem-resistant Klebsiella pneumoniae. ResultsThe PK/PD index that best correlated with the efficacy was the fCmax/MIC. The geometric means of the fCmax/MIC associated with the net stasis and 1-log reduction endpoints were 2.30 and 3.28, respectively. The clinically effective doses of TP0586532 were estimated to be 1.24–2.74 g/day. ConclusionThese results indicate the potential for TP0586532 to have clinical efficacy at reasonable doses against infections caused by carbapenem-resistant Enterobacteriaceae. This study provided helpful information for a clinically effective dosing regimen of TP0586532.

Discovery of a Tricyclic β-Lactam as a Potent Antimicrobial Agent against Carbapenem-Resistant Enterobacterales, Including Strains with Reduced Membrane Permeability and Four-Amino Acid Insertion into Penicillin-Binding Protein 3: Structure-Activity-Relationships and In Vitro and In Vivo Activities.

The current worldwide emergence of carbapenem-resistant enterobacterales (CREs) constitutes an important growing clinical and public health threat. Acquired carbapenemases are the most important determinants of resistance to carbapenems. In the development of the previously reported tricyclic β-lactam skeleton which exhibits potent antibacterial activities against several problematic β-lactamase-producing CREs without a β-lactamase inhibitor, we found that these activities were reduced against clinical isolates with resistance mechanisms other than β-lactamase production. These mechanisms were the reduction of outer membrane permeability with the production of β-lactamases and the insertion of four amino acids into penicillin-binding protein 3. Here, we report the discovery of a potent compound that overcomes these resistance mechanisms by the conversion of the alkoxyimino moiety of the aminothiazole side chain in which a hydrophilic functional group is introduced and the carboxylic acid of the alkoxyimino moiety is converted to reduce the negative charge of the whole molecule from 2 to 1. This potent tricyclic β-lactam is a promising drug candidate for infectious diseases caused by CREs due to its potent therapeutic efficacy in the neutropenic mouse lung infection model and low frequency of producing spontaneously resistant mutants.

Minocycline pharmacodynamics against Stenotrophomonas maltophilia in the neutropenic murine infection model: implications for susceptibility breakpoints.

Minocycline displays high susceptibility rates against Stenotrophomonas maltophilia at the current breakpoint of 4 mg/L. However, no pharmacodynamic data are available to guide dosing or justify this breakpoint. The murine neutropenic thigh infection model was utilized to determine minocycline pharmacodynamics against four S. maltophilia through dose ranging and fractionation studies. The efficacy of a human simulated regimen (HSR) of 100 mg IV q12h was tested against 17 isolates with a range of minocycline MICs. Monte Carlo simulation was employed to assess the PTA for achieving defined pharmacodynamic thresholds in critically ill patients. The pharmacodynamic index best correlated with reductions in cfu was fAUC/MIC (R2 = 0.376). The composite fAUC/MIC required for stasis and 1 log10 reduction was 9.6 and 23.6, respectively. The minocycline 100 mg q12h HSR yielded no bacterial reduction at MICs ≥1 mg/L and mixed efficacy at 0.5 mg/L. Monte Carlo simulation of minocycline 200 mg IV q12h achieved the 1 log10 kill threshold with PTAs of 93% and 51.7% at MICs of 0.5 and 1 mg/L, respectively, but 0.1% at the current breakpoint of 4 mg/L. Clinically utilized minocycline dosing regimens fail to reach exposures predicted to be efficacious against S. maltophilia in critically ill patients at the current susceptibility breakpoint.

A naturally inspired antibiotic to target multidrug-resistant pathogens.

Gram-negative bacteria are responsible for an increasing number of deaths caused by antibiotic-resistant infections1,2. The bacterial natural product colistin is considered the last line of defence against a number of Gram-negative pathogens. The recent global spread of the plasmid-borne mobilized colistin-resistance gene mcr-1 (phosphoethanolamine transferase) threatens the usefulness of colistin3. Bacteria-derived antibiotics often appear in nature as collections of similar structures that are encoded by evolutionarily related biosynthetic gene clusters. This structural diversity is, at least in part, expected to be a response to the development of natural resistance, which often mechanistically mimics clinical resistance. Here we propose that a solution to mcr-1-mediated resistance might have evolved among naturally occurring colistin congeners. Bioinformatic analysis of sequenced bacterial genomes identified a biosynthetic gene cluster that was predicted to encode a structurally divergent colistin congener.Chemical synthesis of this structure produced macolacin, which is active against Gram-negative pathogens expressing mcr-1 and intrinsically resistant pathogens with chromosomally encoded phosphoethanolamine transferase genes. These Gram-negative bacteria include extensively drug-resistant Acinetobacter baumannii and intrinsically colistin-resistant Neisseria gonorrhoeae, which, owing to a lack of effective treatment options, are considered among thehighest level threat pathogens4. In a mouse neutropenic infection model, a biphenyl analogue of macolacin proved to be effective against extensivelydrug-resistant A. baumannii with colistin-resistance, thus providing a naturally inspired and easily produced therapeutic lead for overcoming colistin-resistant pathogens.

1241. In Vivo Efficacy of Meropenem Against Metallo-ß-Lactamase (MBL)-Harboring Pseudomonas aeruginosa and Correlation to In Vitro Susceptibility Upon Addition of EDTA

BackgroundPrior investigations evaluating the predictive value of zinc-depleted media for MBL-susceptibility testing have focused on Enterobacterales. Therein, bacterial killing observed with meropenem (MEM) in vivo was concordant with its pharmacodynamic profile using MIC values determined in zinc-depleted media compared with conventional cation-adjusted Mueller-Hinton broth (CAMHB). This study aims to evaluate the exposure-response relationship of MEM against VIM- and NDM-harboring P. aeruginosa (PSA) using the murine thigh infection model and zinc-depleted MICs.MethodsMBL-harboring PSA isolates (VIM n=11; NDM n=10) were tested both in vivo (neutropenic murine thigh infection model) and in vitro (broth microdilution). The 24h murine thigh study was conducted with treatment groups receiving a humanized MEM 2g q8h (3h infusion) dose. Six different zinc-limited media were prepared by the addition of EDTA at concentrations ranging from 3 to 300 mg/L to CAMHB. MEM MICs were determined in triplicate in conventional CAMHB and zinc-limited media. Time > MIC values (generated in each zinc-depleted media) were then plotted against the change in 24h bacterial density count in an Emax model.ResultsAverage 0 h bacterial densities were 5.21 ± 0.40 and 5.13 ± 0.81 log10 CFU/thigh for NDM and VIM isolates, respectively. MEM resulted in -0.09 CFU reduction to +3.69 CFU growth against NDM isolates. MEM resulted in -2.59 CFU reduction to +4.81 CFU growth against VIM isolates. All MEM MICs in conventional CAMHB were >64 µg/mL for NDM and ranged from 8 to >64 µg/mL for VIM isolates. Increasing EDTA concentrations resulted in several-fold MIC reductions and on average, a larger magnitude of reduction was observed among VIM- (6-fold) compared with NDM-harboring PSA (4-fold) in CAMHB-EDTA 300 mg/L relative to CAMHB. For both NDM- and VIM-harboring PSA, an Emax model with MICs generated in CAMHB+EDTA 30 mg/L (r2 = 0.88) provided the highest correlation with MEM in vivo activity compared with CAMHB (r2 = 0.55).ConclusionResults indicate that MIC values generated in conventional CAMHB do not appropriately characterize the in vivo efficacy of meropenem against MBL-harboring PSA, and addition of EDTA (30 mg/L) to CAMHB appears to be a viable option for in vitro testing of these organisms.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.)

1103. Minocycline (MIN) Pharmacodynamics (PD) against Stenotrophomonas maltophilia (STM) in a Neutropenic Murine Thigh Infection Model

BackgroundAntibiotic treatment options for serious STM infections are limited. MIN displays in vitro activity against STM; however, limited data supports optimal dosing for STM. Herein, we employed the murine neutropenic thigh infection model to assess MIN PD against STM.MethodsFour clinical STM isolates with MIN MICs 0.25 – 1 mg/L were included. Both thighs of neutropenic ICR mice were inoculated with bacterial suspensions of 107 colony forming units (CFU)/mL. Mice received uranyl nitrate on Day -3 to provide predictable renal impairment. Two hours after inoculation, MIN or control was administered subcutaneously. Pharmacokinetic (PK) studies of 2.5, 25, 50, and 100 mg/kg were conducted. Previously reported protein binding of 78.1% was used to define free exposure. Dose ranging studies were conducted on all STM to assess in vivo activity over a range of MIN exposures. MIN total daily doses (TDD) of 10, 20, and 50 mg/kg were fractionated q24h, q12h, and q6h against a single STM to determine the PD index best correlated with reductions in CFU/mL. Efficacy was measured in log10CFU/thigh at 24h compared with 0h controls. Composite CFU data were fitted to an Emax model to determine the fAUC/MIC exposure for stasis and 1 log10 reduction.ResultsMIN PK was linear up to 50 mg/kg and well described by a 1 compartment model with first order absorption and elimination. Mean PK parameters across the linear range were: Vd, 2.97 L/kg; K01, 10.62 1/h; and K10, 0.35 1/h. Mean ± SD bacterial burden at 0h across all isolates was 6.17±0.20 log10CFU/thigh. In 24h controls, bacterial growth was 7.90±0.85 log10CFU/thigh. A dose response was observed across all isolates using TDD of 2-300 mg/kg. PD indices correlated with CFU reductions as follows: fAUC/MIC (R2=0.613), fCmax/MIC (R2=0.590), and %fT >MIC (R2=0.504). The fAUC/MIC needed for stasis and 1 log10 reduction at 24h was 9.6 and 23.6, respectively. ConclusionThese are the first data describing MIN PD against STM. Against these STM, MIN fAUC/MIC was the PD index best correlated with CFU reductions. The exposure thresholds defined in this study will be useful in designing optimal MIN dosing regimens for treating STM infections and re-assessment of the current susceptibility breakpoint. The study was funded under FDA Contract 75F40120C00171.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)

65. In Vivo Efficacy of Human Simulated Minocycline (MIN) against Stenotrophomonas maltophilia (STM)

BackgroundThe current susceptibility breakpoint for MIN against STM is 4mg/L, yielding >99% of isolates susceptible. Unfortunately, there are limited pre-clinical and clinical data to support this breakpoint for STM. The purpose of this study was to evaluate the efficacy of a MIN human simulated regimen (HSR) against STM across a wide range of MICs in the murine neutropenic thigh model.MethodsClinical STM with modal MIN MICS of 0.25-8mg/L were included. Confirmatory pharmacokinetic (PK) studies were performed in infected neutropenic mice to develop a MIN HSR providing an area under the curve (AUC) and maximum concentration (Cmax) exposure similar to MIN 100mg intravenous (IV) q12h at steady-state based on PK parameters from critically ill adult patients. The murine neutropenic thigh infection model was utilized to examine the antibacterial effects of the confirmed MIN HSR against 17 STM. Both thighs of neutropenic ICR mice were inoculated with bacterial suspensions of 107 colony forming units (CFU)/mL. Two hours after inoculation, the MIN HSR was administered subcutaneously (SC) over 24h. Control mice received normal saline. Efficacy was measured as the change in log10CFU/thigh at 24h compared with 0h controls.ResultsMIN 22, 10, 14, and 10mg/kg dosed SC at 0, 6, 12, and 18h best recapitulated the human Cmax and AUC profile. Mean ± standard deviation bacterial burden at 0h across all isolates was 6.03±0.32 log10CFU/thigh. Bacterial growth was 1.35±0.68 log10CFU/thigh in 24h controls. Six of 7 isolates (86%) with MIC ≤ 0.5mg/L achieved 1-log kill with MIN HSR (-1.44±1.37 log10CFU/thigh). All STM with MIC ≥ 1mg/L experienced bacterial growth (1.18±0.79 log10CFU/thigh) (Figure).Figure. Efficacy of a minocycline human simulated exposure of 100mg intravenous Q12h in the murine neutropenic thigh model against 17 clinical Stenotrophomonas maltophilia isolates ConclusionThese data describe the in vivo efficacy of a MIN HSR with exposures similar to MIN 100mg IV q12h in critically ill adults. Lack of antibacterial activity against STM with MICs ≥ 1mg/L justifies a reassessment of the current susceptibility breakpoint. The study was funded under FDA Contract 75F40120C00171. 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)

1066. In Vitro and in Vivo Antimicrobial Activity of Cefiderocol and Comparators against Achromobacter spp

Background Achromobacter spp. is intrinsically resistant to multiple antibiotics, and the treatment options are limited. Cefiderocol (CFDC), a siderophore cephalosporin approved in US and EU, is active against a wide variety of aerobic Gram-negative bacteria, including carbapenem-resistant strains. In this study, in vitro and in vivo antibacterial activity of CFDC against Achromobacter spp. was evaluated.MethodsA total of 334 global isolates collected by IHMA from 39 countries in 2015-2019 were used. Minimum inhibitory concentrations (MICs) of CFDC and comparators were determined by broth microdilution method using iron-depleted CAMHB or CAMHB, respectively, as recommended by CLSI guidelines. In vivo efficacy of CFDC was compared with meropenem (MEM), piperacillin-tazobactam (PIP/TAZ), ceftazidime (CAZ), and ciprofloxacin (CIP) in a neutropenic murine lung infection model (n=5), and compared with MEM in a immunocompetent rat lung infection model (n=3-7) caused by 2 A. xylosoxydans. In the murine model, treatment was given 2, 5, and 8 hours post-infection, and the numbers of viable cfu in lungs were determined 24 hours post-infection. In the rat model, the humanized PK in plasma resulting from CFDC 2 g every 8 h (3-h infusion) or meropenem 1 g every 8 h (0.5-h infusion) were recreated via continuous intravenous infusion for 4 days, following which cfu in lungs were determined.ResultsCFDC showed in vitro activity with MIC50/90 of 0.06/0.5 µg/mL against 334 Achromobacter spp. Only 7 isolates (2.1%) had MICs > 4 µg/mL. These were the lowest values among all compound tested (Table). In the murine model, CFDC caused > 1.5 log10 decrease of viable cfu in lungs at 100 mg/kg dose (%fT >MIC: < 50%) from baseline control against both of strains (CFDC MIC: 0.5 and 2 µg/mL) (P< 0.05). No decrease of cfu in lungs was observed for the comparators at 100 mg/kg (MEM, PIP/TAZ, CAZ, and CIP MICs were >16, >64, >32, and >8 µg/mL, respectively). In the rat model, humanized CFDC dosing reduced the viable cfu by >1 log10 CFU/lung compared with baseline controls (P< 0.05). MEM showed no significant activity.In vitro activity of CFDC and comparator agents against Achromobacter spp. 334 Achromobacter spp. isolates collected from 2015 and 2019. The majority of isolates tested were A. xylosoxidans (312/334; 93.4%), followed by A. insolitus (11/334; 3.3%), Achromobacter sp. (8/334; 2.4%), A. denitrificans (2/334; 0.6%), and A. piechaudii (1/334; 0.3%).ConclusionCFDC showed potent in vivo efficacy reflecting in vitro activity against A. xylosoxidans. The results suggested that CFDC has the potential to be an effective therapeutic option for Achromobacter spp. infections.Disclosures Ryuichiro Nakai, MSc, Shionogi TechnoAdvance Research & Co., Ltd. (Employee) Ayaka makino, BSc, Shionogi TechnoAdvance Research & Co., Ltd. (Employee) Toriko Yoshitomi, -, Shionogi TechnoAdvance Research & Co., Ltd. (Employee) Rio Nakamura, BSc, Shionogi TechnoAdvance Research & Co., Ltd. (Employee) Meredith Hackel, PhD MPH, IHMA (Employee)Pfizer, Inc. (Independent Contractor) Miki Takemura, MS, SHIONOGI & CO., LTD. (Employee) Daniel F. Sahm, PhD, IHMA (Employee)Pfizer, Inc. (Independent Contractor) Yoshinori Yamano, PhD, Shionogi (Employee)

Improved risk prediction of chemotherapy-induced neutropenia-model development and validation with real-world data.

BackgroundThe existing risk prediction models for chemotherapy‐induced febrile neutropenia (FN) do not necessarily apply to real‐life patients in different healthcare systems and the external validation of these models are often lacking. Our study evaluates whether a machine learning‐based risk prediction model could outperform the previously introduced models, especially when validated against real‐world patient data from another institution not used for model training.MethodsUsing Turku University Hospital electronic medical records, we identified all patients who received chemotherapy for non‐hematological cancer between the years 2010 and 2017 (N = 5879). An experimental surrogate endpoint was first‐cycle neutropenic infection (NI), defined as grade IV neutropenia with serum C‐reactive protein >10 mg/l. For predicting the risk of NI, a penalized regression model (Lasso) was developed. The model was externally validated in an independent dataset (N = 4594) from Tampere University Hospital.ResultsLasso model accurately predicted NI risk with good accuracy (AUROC 0.84). In the validation cohort, the Lasso model outperformed two previously introduced, widely approved models, with AUROC 0.75. The variables selected by Lasso included granulocyte colony‐stimulating factor (G‐CSF) use, cancer type, pre‐treatment neutrophil and thrombocyte count, intravenous treatment regimen, and the planned dose intensity. The same model predicted also FN, with AUROC 0.77, supporting the validity of NI as an endpoint.ConclusionsOur study demonstrates that real‐world NI risk prediction can be improved with machine learning and that every difference in patient or treatment characteristics can have a significant impact on model performance. Here we outline a novel, externally validated approach which may hold potential to facilitate more targeted use of G‐CSFs in the future.

Lintuzumab-Ac225 in Combination with CLAG-M Yields High MRD (-) Responses in R/R AML with Adverse Features: Interim Results of a Phase I Study

Background:Lintuzumab-Ac225 (Actimab-A) is a humanized CD33 antibody, lintuzumab, conjugated to an alpha emitting isotope, actinium (Ac225), with potent single agent activity against AML. We hypothesized that a low dose infusion of lintuzumab-Ac225, after salvage chemotherapy, would effectively eliminate residual leukemia and improve remission rates, and depth of remission.Patients and Methods:Adult patients with relapsed/refractory AML (RR-AML), and with adequate organ function and performance status were eligible for screening. On screening, we assessed CD33 expression, greater than 25% of leukemic blasts must have expressed CD33 antigen by flow cytometry for inclusion. Induction consisted of G-CSF, 300mcg/d, given D1-6, cladribine 5mg/m2, given D2-6, cytarabine 2g/m2, given D2-6, and mitoxantrone 10mg/m2, given D2-4. Lintuzumab-Ac225 was administered as a single dose on either day 7, 8, or 9. This trial enrolled to 4 cohorts, administering lintuzumab-ac225 at a dose of 0.25uCi/kg, 0.50uCi/kg, 0.75uCi/kg, and 1.0uCi/kg. Treatment consisted of one induction cycle. Disease assessment, including MRD assessment by flow, was performed between Days 29-42.Results:Sixteen patients with a median age of 64 yrs were evaluable for toxicity and response. Three pts were treated in cohort 1 (0.25uCi/kg), nine pts were treated in cohort 2 (0.5uCi/kg), three pts were treated in cohort 3 (0.75uCi/kg), and one pt was treated in cohort 4 (1.0uCi/kg). Patient characteristics include 63% (n=10) pts with adverse cytogenetics, mutations involving TP53 in 44% (n=7) pts, and secondary/therapy-related AML in 50% (n=8) of patients. Patients received a median 2 lines of therapy, and 50% (n=8) received a venetoclax combination regimen prior to enrollment. Table 1 summarizes patient characteristics.No undue non-hematologic toxicities were observed in this trial. Commonest AEs were neutropenic fever and infection. Among responders, an ANC>1000 was achieved in 9/10 patients, at a median of 33 days, and a platelet count >50k was achieved in 6/10 patients at a median of 37 days. Of note, two patients proceeded to HCT prior to platelet recovery.Overall, among patients enrolled in cohorts 1-3, CR/CRi was observed in 67% (n=10) pts. One patient enrolled in cohort 4 achieved an aplastic marrow by D+42, with subsequent stem cell boost and neutrophil recovery. Of responders, 70% (7/10) had no measurable disease (MRD(-)) by flow cytometry. Among patients receiving <4 lines of prior therapy, 71% (n=5) pts with adverse cytogenetics, 80% (n=4) pts with TP53 mutation, and 80% (n=4) pts receiving a prior venetoclax combination achieved a remission. Estimated 6-month OS was 60%.Conclusions:Lintuzumab-Ac225 at a low dose appears to be safe in combination with the salvage chemotherapy regimen CLAG-M. Furthermore, this combination has demonstrated promising efficacy results among high risk RR-AML patients, namely patients with adverse molecular/cytogenetic features and patients previously receiving venetoclax. Updated Cohort 4 results will be presented at ASH.Upon determination of MTD, we plan to explore the combination of lintuzumab-Ac225 with other salvage regimens (e.g. FLAG, FLAG-Ida, MEC) to determine whether adding this novel agent can generally improve salvage outcomes in hard to treat patients. [Display omitted] DisclosuresAbedin: Helsinn: Research Funding; Agios: Honoraria; AltruBio: Research Funding; Pfizer: Research Funding; Amgen: Honoraria; Actinium: Research Funding; Astellas Pharma Inc.: Research Funding. Guru Murthy: Guidepoint: Consultancy; Cancerexpertnow: Honoraria; Techspert: Consultancy; Qessential: Consultancy; Cardinal Health Inc.: Honoraria; TG therapeutics: Other: Advisory board. Hamadani: Sanofi, Genzyme, AstraZeneca, BeiGene: Speakers Bureau; Takeda, Spectrum Pharmaceuticals and Astellas Pharma: Research Funding; Janssen, Incyte, ADC Therapeutics, Omeros, Morphosys, Kite: Consultancy. Atallah: Pfizer: Consultancy, Research Funding; BMS: Honoraria, Speakers Bureau; Takeda: Consultancy, Research Funding; Abbvie: Consultancy, Speakers Bureau; Amgen: Consultancy; Novartis: Consultancy, Honoraria, Research Funding.

Outcomes of High-Intensity Versus Low-Intensity Induction in Elderly Patients with AML: A Retrospective Analysis of Real-World Outcomes

Background: The optimal induction strategy for patients with acute myeloid leukemia (AML) older than 65 years remains unknown. The use of lower intensity therapies in this population has become routine. The inclusion of venetoclax to intensify a hypomethylating agent backbone has efficacy outcomes approaching those of anthracycline-based inductions in elderly adults. This retrospective analysis sought to compare venetoclax-based induction combinations to anthracycline-based regimens.Patients & Methods: We retrospectively analyzed all patients with AML older than 65 treated with 7+3 or liposomal daunorubicin and cytarabine (CPX-351) versus venetoclax with either decitabine or azacitidine from June 2018 to December 2020 at our institution. Patients were included in the analysis only if ECOG performance status prior to induction supported intensive induction (≤2). Baseline patient demographics, cytogenetic risk, molecular profiling (through next-generation sequencing), toxicity, responses, and MRD analysis were obtained. Kaplan-Meier curves were constructed using censoring at date of last contact for those that did not have a death event in the specified time period.Results: The intensive cohort included 28 patients, 15 (53.6%) males and 13 (46.4%) females. The median age at diagnosis was 69 (range: 65 - 76), the median ECOG score was 1, and the median CCI score was 6. The anthracycline in the 7+3 cohort was daunorubicin in 15 patients (53.6%) and idarubicin in 1 (3.6%) patient. This cohort also included 12 (42.9%) patients treated with CPX-351. Two (7.1%) patients had favorable cytogenetics, 6 (21.4%) had intermediate cytogenetics, and 20 (71.4%) had adverse cytogenetics. The most common non-hematological toxicities that Grade 1 or higher were neutropenic fever (85.7%), infection (71.4%), GI/hepatobiliary (42.9%), cardiovascular (35.7%), and acute kidney injury (32.1%). One (3.8%) of the 26 evaluable patients died within 30 days and one (3.8%) died within 60 days. Fourteen patients (50.0%) achieved CR and 3 (10.7%) achieved CRi for an ORR of 60.7%. Six of the 17 patients with CR or CRi were analyzed for MRD and two (33.3%) were MRD-negative. Six (21.4%) received an allogenic stem cell transplant (SCT). The median OS in the intensive cohort was not reached at a median follow-up of 711 days (23.4 months).The lower intensity cohort totaled 28 patients, 18 (64.3%) males and 10 (35.7%) females. The median age at diagnosis was 75 (range: 65 - 85), median ECOG score was 1, and the median CCI score was 6. There were no differences in ECOG score (p = 0.930), CCI (p = 0.195), or cytogenetic risk (p = 0.924) between the two groups. Venetoclax was given in combination with 5-day decitabine (78.6%) or azacitidine (21.4%). Of the 28 patients with evaluable cytogenetics, 2 (7.1%) were favorable, 5 (17.9%) were intermediate, and 19 (67.9%) were adverse. The most common non-hematological toxicities were infection (57.1%), neutropenic fever (50.0%), GI/hepatobiliary (28.5%), cardiovascular (25.0%), and acute kidney injury (21.4%). Of the 28 evaluable patients, one (3.6%) died within 30 days and 7 (25.0%) died within 60 days, though not statistically significant compared to the intensive group (p = 0.103). Two (7.1%) achieved CR and 12 (39.3%) achieved CRi for an ORR of 46.4%. Two of the 13 patients were evaluated for MRD and none were MRD-negative after induction. Two (7.1%) patients received allogeneic SCT. The median OS in the venetoclax cohort was 354 days (11.6 months), though no statistically significant difference was detected when compared to the intensive cohort (p = 0.0735). However, when the two cohorts were selected for adverse cytogenetic risk and compared, the median OS was not reached in the intensive group at a median follow-up of 636 days but was 91 days in the venetoclax group (p = 0.025).Conclusion: Elderly patients had superior responses and survival to intensive induction when compared to venetoclax-based strategies when analyzed with respect to cytogenetic risk. Additionally, though the rates of toxicities were higher in the intensive cohort, the mortality during induction appeared to be lower, but did not reach statistical significance. Our work indicates that careful selection of intensive induction candidates is warranted, as those who can tolerate intensive regimens may be undertreated by selecting a less-intensive therapeutic strategy. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Cefmetazole as an Alternative to Carbapenems Against Extended-Spectrum Beta-Lactamase-Producing Escherichia coli Infections Based on In Vitro and In Vivo Pharmacokinetics/Pharmacodynamics Experiments.

Cefmetazole (CMZ) has received attention as a pharmaceutical intervention for extended-spectrum beta-lactamase-producing Escherichia coli (ESBL-EC) infections. This study aimed to investigate the pharmacokinetics/pharmacodynamics (PK/PD) characteristics of CMZ against ESBL-EC. The susceptibility and time-killing activity of CMZ against clinically isolated ESBL-EC (EC9 and EC19) were determined in vitro. The optimal PK/PD index and its target value were calculated based on the results of a PK study in healthy mice and PD study in neutropenic murine thigh infection model mice. The minimum inhibitory concentrations (MICs) of CMZ against EC9 and EC19 were 2.0 and 1.0µg/mL, respectively. Time-kill studies showed that colony-forming units decreased in a time-dependent manner at CMZ concentrations in the range of 4-64 × MIC. In in vivo PK/PD studies, the antibacterial effect of CMZ showed the better correlation with the time that the free drug concentration remaining above the MIC (fT>MIC), with the target values for a static effect and 1 log10 kill reduction calculated as 57.6% and 69.6%, respectively. CMZ possesses time-dependent bactericidal activities against ESBL-EC and is required to achieve "fT>MIC" ≥ 69.6% for the treatment of ESBL-EC infections.

Grade 4 Neutropenia Secondary to Immune Checkpoint Inhibition - A Descriptive Observational Retrospective Multicenter Analysis.

IntroductionImmune checkpoint inhibitors (ICI) are increasingly being used to treat numerous cancer types. Together with improved recognition of toxicities, this has led to more frequent identification of rare immune-related adverse events (irAE), for which specific treatment strategies are needed. Neutropenia is a rare hematological irAE that has a potential for a high mortality rate because of its associated risk of sepsis. Prompt recognition and timely treatment of this life-threatening irAE are therefore critical to the outcome of patients with immune-related neutropenia.MethodsThis multicenter international retrospective study was conducted at 17 melanoma centers to evaluate the clinical characteristics, diagnostics, treatment, and outcomes of melanoma patients with grade 4 neutropenia (<500 neutrophils/µl blood) treated with ICI between 2014 and 2020. Some of these patients received metamizole in addition to ICI (ICI+/met+). Bone marrow biopsies (BMB) of these patients were compared to BMB from non-ICI treated patients with metamizole-induced grade 4 neutropenia (ICI-/met+).ResultsIn total, 10 patients (median age at neutropenia onset: 66 years; seven men) with neutropenia were identified, equating to an incidence of 0.14%. Median onset of neutropenia was 6.4 weeks after starting ICI (range 1.4–49.1 weeks). Six patients showed inflammatory symptoms, including fever (n=3), erysipelas (n=1), pharyngeal abscess (n=1), and mucositis (n=1). Neutropenia was diagnosed in all patients by a differential blood count and additionally performed procedures including BMB (n=5). Nine of 10 patients received granulocyte colony-stimulating factors (G-CSF) to treat their grade 4 neutropenia. Four patients received systemic steroids (including two in combination with G-CSF, and one in combination with G-CSF and additional ciclosporin A). Four patients were treated with one or more antibiotic treatment lines, two with antimycotic treatment, and one with additional antiviral therapy. Five patients received metamizole concomitantly with ICI. One fatal outcome was reported. BMB indicated a numerically lower CD4+ to CD8+ T cells ratio in patients with irNeutropenia than in those with metamizole-induced neutropenia.ConclusionGrade 4 neutropenia is a rare but potentially life-threatening side effect of ICI treatment. Most cases were sufficiently managed using G-CSF; however, adequate empiric antibiotic, antiviral, and antimycotic treatments should be administered if neutropenic infections are suspected. Immunosuppression using corticosteroids may be considered after other causes of neutropenia have been excluded.

English

BACKGROUND Breast cancer is a systemic disease that requires treatment with surgery, chemotherapy, radiation, endocrine therapy and biological therapy. Neoadjuvant chemotherapy is the recent treatment of locally advanced breast cancer. The purpose of this study was to assess the acute toxicity of paclitaxel-based dose-dense and conventional neoadjuvant chemotherapy in locally advanced female breast cancer patients. METHODS In this study, neoadjuvant paclitaxel was given to a hundred locally advanced breast malignancies of female patients. Three weekly paclitaxel 200 mg/m2 ( 4 courses) was given for fifty patients and weekly paclitaxel 80 mg/m2 (10 courses) was given for fifty patients along with four-course of three weekly doxorubicin 50 mg/m2 given in both arms. Chemotherapy-induced acute toxicities in both arms were assessed weekly. RESULTS There was a significant increase in the incidence of anaemia in weekly chemotherapy patients at 7th week (28 % verse 10 %, P - value 0.022) and neutropenic infection at 11th week (28 % verse 10 %, P - value 0.022). There was a non-statistically significant increase in the incidence of leukopenia, thrombocytopenia and paraesthesia and myalgia in the weekly arm. There was a significant increase in the incidence of gastrointestinal toxicity like grade 3 stomatitis (at 4th - week), nausea and vomiting (at 4th, 7th, and 11th week ) in three weekly chemotherapy patients. CONCLUSIONS In this study, acute neurological and haematological toxicities were more in the weekly neoadjuvant chemotherapy arm and acute gastrointestinal toxicities were more in the three weekly neoadjuvant chemotherapy arm. KEYWORDS Acute Toxicity, Neoadjuvant Paclitaxel Chemotherapy, Locally Advanced Breast Malignancy.

Levofloxacin pharmacodynamics against Stenotrophomonasmaltophilia in a neutropenic murine thigh infection model: implications for susceptibility breakpoint revision.

Levofloxacin displays in vitro activity against Stenotrophomonas maltophilia (STM); however, current susceptibility breakpoints are supported by limited data. We employed the murine neutropenic thigh infection model to assess levofloxacin pharmacodynamics against STM. Twenty-six clinical STM were studied using the neutropenic murine thigh infection model. Human simulated regimens (HSR) of levofloxacin 750 mg q24h were administered over 24 h. Efficacy was measured as the change in log10 cfu/thigh at 24 h compared with 0 h. Composite cfu data were fitted to an Emax model to determine the fAUC/MIC needed for stasis and 1 log10 reduction at 24 h. Monte Carlo simulation was performed to determine PTA. Levofloxacin MICs ranged from 0.5-8 mg/L. Mean bacterial burden at 0 h was 6.21 ± 0.20 log10 cfu/thigh. In the 24 h controls, bacterial growth was 1.64 ± 0.66 log10 cfu/thigh. In isolates with levofloxacin MICs ≤1, 2 and ≥4 mg/L, changes in bacterial density following levofloxacin HSR were -1.66 ± 0.89, 0.13 ± 0.97 and 1.54 ± 0.43 log10 cfu/thigh, respectively. The Emax model demonstrated strong agreement between fAUC/MIC and change in bacterial density (R2 = 0.82). The fAUC/MIC exposure needed for stasis and 1 log10 reduction was 39.9 and 54.9, respectively. PTAs for the 1 log10 reduction threshold were 95.8, 72.2, and 26.6% at MICs of 0.5, 1 and 2 mg/L, respectively. These are the first data to describe fAUC/MIC thresholds predictive of cfu reductions for levofloxacin against STM. Due to poor in vivo efficacy and PTA at MICs ≥2 mg/L, reassessment of the current susceptibility breakpoint is warranted.

A novel tricyclic β-lactam exhibiting potent antibacterial activities against carbapenem-resistant Enterobacterales: Synthesis and structure-activity-relationships

A series of tricyclic β-lactams were synthesized and evaluated for in vitro antibacterial activities against carbapenem-resistant Enterobacterales (CREs). Starting from a reported tricyclic β-lactam that combined the cephalosporin skeleton having a γ-lactone ring with a carboxylic acid group, which was reported as a unique partial structure of Lactivicin, we identified the compound which shows potent antibacterial activities against all tested CREs by introducing sulfoxide. In addition, the sulfoxide-introduced tricyclic β-lactam also shows a strong therapeutic efficacy in the neutropenic mouse lung infection model. These results indicate that the tricyclic β-lactam skeleton will show sufficient therapeutic performance in clinical use and therefore can serve as a scaffold in the search for new antibacterial agents against CREs.