scholarly journals Ceftazidime/avibactam versus standard-of-care agents against carbapenem-resistant Enterobacteriaceae harbouring blaKPC in a one-compartment pharmacokinetic/pharmacodynamic model

2018 ◽  
Vol 73 (9) ◽  
pp. 2405-2410 ◽  
Author(s):  
Katie E Barber ◽  
Jason M Pogue ◽  
Henderson D Warnock ◽  
Robert A Bonomo ◽  
Keith S Kaye
Keyword(s):  
Klebsiella Oxytoca ◽  
Growth Control ◽  
Standard Of Care ◽  
Polymyxin B ◽  
Initial Inoculum ◽  
Comparable Activity ◽  
Free Growth ◽  
Klebsiella Pneumoniae Carbapenemases ◽  
Drug Free

AbstractBackground‘Last-line’ antimicrobial usage has promoted the emergence of MDR bacteria. Production of Klebsiella pneumoniae carbapenemases (KPCs) is increasingly common and leads to resistance to most antimicrobials. However, ceftazidime/avibactam demonstrates activity against KPC-producing strains. Ceftazidime/avibactam in the empirical setting remains unknown.MethodsStrains underwent genetic analysis evaluating blaKPC presence/production and MICs were determined. Four strains were assessed in an in vitro, one-compartment pharmacokinetic (PK)/pharmacodynamic (PD) model for 96 h. The following bolus dosing exposures were tested: 2.5 g of ceftazidime/avibactam every 8 h, 2 g of meropenem every 8 h, 1.25 mg/kg polymyxin B every 12 h, amikacin ‘once-daily dosing’ (peak of 70–80 mg/L), tigecycline at 200 mg ×1 dose followed by 100 mg every 12 h, and a drug-free growth control.ResultsThirty blaKPC-producing strains were evaluated; 97% of strains were ceftazidime/avibactam susceptible with MIC50/MIC90 values of 0.38/1.5 mg/L (range 0.032–16 mg/L). Two K. pneumoniae strains, one Klebsiella oxytoca strain and one Citrobacter freundii strain underwent further analysis in PK/PD models. Ceftazidime/avibactam displayed potent activity with a reduction of 4.23 ± 0.42 cfu/mL from the initial inoculum at 96 h. Against susceptible isolates, amikacin displayed similar activity compared with ceftazidime/avibactam at 96 h, although this was not demonstrated against all strains. Polymyxin B produced comparable activity to ceftazidime/avibactam against two strains. Neither meropenem nor tigecycline produced effective killing and were comparable to the drug-free growth control at 96 h.Conclusionsbla KPC-producing organisms demonstrated susceptibility to ceftazidime/avibactam and bactericidal activity was observed in the PK/PD model. Based on these data, ceftazidime/avibactam is a valuable agent for treating KPC-producing organisms and should be considered for treatment of infections caused by these pathogens.

scholarly journals 1559. Ertapenem Plus Ceftriaxone or Ceftaroline Dual Β-Lactam Combination for Enterococcus faecalis

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S569-S569
Author(s):  
Jaclyn A Cusumano ◽  
Kathryn E Daffinee ◽  
Kerry LaPlante
Keyword(s):  
Enterococcus Faecalis ◽  
Bactericidal Activity ◽  
Half Life ◽  
Wild Type Strain ◽  
Standard Of Care ◽  
Penicillin Binding Protein ◽  
Wild Type ◽  
Initial Inoculum ◽  
Colony Forming Units

Abstract Background Ampicillin-ceftriaxone β-lactam therapy has become the standard of care for treating serious Enterococcus faecalis infections. Alternative regimens are of interest due to ceftriaxone’s association with C. difficile infections and VRE colonization, and ampicillin’s instability and inconvenient dosing schedule. Methods E. faecalis wild-type strain JH2-2 was utilized in a 48-hour in vitro pharmacodynamic model with a starting inoculum of 106 colony-forming units (CFU)/mL. Models were performed in duplicate to triplicate. Simulated doses of ertapenem 1g every 24 hours (fCmax 12.2 μg/mL; half-life 4 hours; MIC 4 μg/mL), ceftriaxone 2 g every 12 hours (fCmax 28.5 μg/mL; half-life 6.5 hours; MIC 512 μg/mL), and ceftaroline 600 mg every 8 hours (fCmax 27.1 μg/mL; half-life 2.7 hours; MIC 2 μg/mL) were tested. Ertapenem was also combined with ceftriaxone or ceftaroline. Bacterial counts were obtained at 0, 4, 8, 24, 32, and 48 hours. Bactericidal activity was defined as ≥ 3-log10 CFU/mL reduction from the initial inoculum. MICs were assessed at 0, 24, and 48 hours using E-tests in accordance with CLSI. Results Ertapenem plus ceftriaxone, and ertapenem plus ceftaroline demonstrated bactericidal activity at 24 hours, but bacterial regrowth was observed at 48 hours (Table 1). An ertapenem MIC increase was only noted in one set of the ertapenem plus ceftriaxone models to 16mcg/mL at 48 hours, from 4mcg/mL at 0 hours. All other models did not have an increase in MIC. Conclusion Bactericidal activity of ertapenem-based dual β-lactam combinations may prove to be an alternative treatment for severe E. faecalis infections. Mechanistic understanding of penicillin-binding protein (PBP) saturation and optimization of antimicrobial pharmacodynamics must be explored. Disclosures All authors: No reported disclosures.

scholarly journals In vitro Bactericidal Activities of Combination Antibiotic Therapies Against Carbapenem-Resistant Klebsiella pneumoniae With Different Carbapenemases and Sequence Types

2021 ◽  
Vol 12 ◽  
Author(s):  
Jocelyn Qi-Min Teo ◽  
Nazira Fauzi ◽  
Jayden Jun-Yuan Ho ◽  
Si Hui Tan ◽  
Shannon Jing-Yi Lee ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Bactericidal Activity ◽  
Carbapenem Resistance ◽  
Polymyxin B ◽  
Apparent Difference ◽  
Initial Inoculum ◽  
Carbapenem Resistant ◽  
Limited Effectiveness ◽  
Sequence Types

Carbapenem-resistant Klebsiella pneumoniae (CRKP) is becoming increasingly problematic due to the limited effectiveness of new antimicrobials or other factors such as treatment cost. Thus, combination therapy remains a suitable treatment option. We aimed to evaluate the in vitro bactericidal activity of various antibiotic combinations against CRKP with different carbapenemase genotypes and sequence types (STs). Thirty-seven CRKP with various STs and carbapenemases were exposed to 11 antibiotic combinations (polymyxin B or tigecycline in combination with β-lactams including aztreonam, cefepime, piperacillin/tazobactam, doripenem, meropenem, and polymyxin B with tigecycline) in static time-kill studies (TKS) using clinically achievable concentrations. Out of the 407 isolate-combination pairs, only 146 (35.8%) were bactericidal (≥3 log10CFU/mL decrease from initial inoculum). Polymyxin B in combination with doripenem, meropenem, or cefepime was the most active, each demonstrating bactericidal activity in 27, 24, and 24 out of 37 isolates, respectively. Tigecycline in combination with β-lactams was rarely bactericidal. Aside from the lower frequency of bactericidal activity in the dual-carbapenemase producers, there was no apparent difference in combination activity among the strains with other carbapenemase types. In addition, bactericidal combinations were varied even in strains with similar STs, carbapenemases, and other genomic characteristics. Our findings demonstrate that the bactericidal activity of antibiotic combinations is highly strain-specific likely owing to the complex interplay of carbapenem-resistance mechanisms, i.e., carbapenemase genotype alone cannot predict in vitro bactericidal activity. The availability of WGS information can help rationalize the activity of certain combinations. Further studies should explore the use of genomic markers with phenotypic information to predict combination activity.

scholarly journals In Vitro Activity of Eravacycline and Comparator Antimicrobials Against 143 Strains of Bacteroides Species.

2017 ◽  
Vol 4 (suppl_1) ◽  
pp. S369-S370
Author(s):  
Diane Citron ◽  
Kerin Tyrrell ◽  
E Goldstein
Keyword(s):  
Ribosomal Subunit ◽  
Growth Control ◽  
Skim Milk ◽  
Clinical Isolates ◽  
Good Growth ◽  
Serious Infections ◽  
Pure Cultures ◽  
Agar Dilution ◽  
Drug Free

Abstract Background Eravacycline (ERV is the first fully synthetic fluorocycline with activity against tetracycline (TET)-resistant organisms. In addition, it is 2–8 times more potent than tigecycline (TGC). Like other tetracyclines, it inhibits protein synthesis by binding to the 30S ribosomal subunit exhibiting a broad spectrum of activity. To further explore its activity, we tested 143 clinical isolates of Bacteroides and included TET, TGC and other drugs frequently used to treat serious infections. Methods Clinical isolates recovered during the past 3 years from patients in southern California were saved as pure cultures in 20% skim milk at −70°C. Prior to testing, they were transferred at least twice to ensure purity and good growth. Antimicrobials included ERV, TET, TGC, piperacillin-tazobactam (P-T), meropenem (MER), clindamycin (CLI), and metronidazole (MET). The method was agar dilution as described in the CLSI M11-A8 document for testing anaerobes using Brucella agar and incubation in the anaerobic chamber at 36°C for 44h. The MIC was defined as the lowest dilution that completely inhibited growth or resulted in a marked reduction compared with a drug-free growth control. Results The MIC90 values (µg/ml) for Bacteroides and Parabacteroides are presented in the table: Conclusion This study confirmed the improved activity of ERV over TGC against Bacteroides and suggests that ERV may be an appropriate choice for infections involving these organisms. Disclosures E. Goldstein, Tetraphase Pharmaceuticals: Research Contractor, Research grant

Development and Comparative Anti-Microbial Evaluation of Lipid Nanoparticles and Nanoemulsion of Polymyxin B

2006 ◽  
Vol 6 (9) ◽  
pp. 2986-2990 ◽  
Author(s):  
A. S. Pattani ◽  
S. D. Mandawgade ◽  
Vandana B. Patravale
Keyword(s):  
Polymyxin B ◽  
Lipid Nanoparticles ◽  
Polydispersity Index ◽  
Significant Activity ◽  
Dependent Manner ◽  
Potent Effect ◽  
Globule Size ◽  
Gram Negative Bacteremia ◽  
Comparable Activity ◽  
Drug Free

Polymyxin B is a decapeptide, mainly used for the treatment of gram-negative bacteremia. It was anticipated that a prolongation of release may lead to a more efficacious therapy. Lipid nanoparticles and nanoemulsion were formulated and comparatively evaluated for their properties. Lipid nanopraticles of Polymyxin B Sulphate with a mean particle size of 186.9 nm (Polydispersity Index 0.235) were prepared by nano-precipitation technique and nanoemulsion was prepared under the conditions of spontaneous formation with a mean globule size 125.0 nm (Polydispersity Index 0.291). The lipid nanoparticles were screened for lipid load from 0.1–1% along with 1–10% surfactant while in the optimization of nanoemulsion different ratios of oil, surfactant, and co-surfactant were evaluated. The developed systems were taken up for comparative anti-microbial study against a sensitive strain of E. coli using Turbidimetry as the method for monitoring the growth of microorganisms in a time dependent manner. Results of the study using ANOVA revealed an initial comparable activity with no statistical difference between the free drug, lipid nanoparticles, and the nanoemulsion. The anti-microbial effect was significantly sustained by lipid nanoparticles over a period of 18 hr but could not be sustained in case of nanoemulsion after 12 hr. Further, in order to assess anti-microbial activity of the developed delivery templates, a similar study was carried out using the lipid nanoparticles and nanoemulsion without the incorporation of drug. The results showed only a mild anti-microbial action for drug-free lipid nanoparticles but significant activity was exerted by drug-free nanoemulsion against plain drug throughout the study. It was concluded that the developed lipid nanoparticles and nanoemulsion are promising delivery vectors for the anti-microbial drugs. Further, lipid nanoparticles could give an initial as well as sustained effect while the nanoemulsion was capable of exerting potent effect for a shorter period of time.

Opiophobia in Cancer Biology- Justified? - The Role of Perioperative Use of Opioids in Cancer Recurrence

2019 ◽  
Vol 25 (28) ◽  
pp. 3020-3027 ◽  
Author(s):  
Mir W. Sekandarzad ◽  
Chris Doornebal ◽  
Markus W. Hollmann
Keyword(s):  
Pain Management ◽  
Cancer Biology ◽  
Tumor Biology ◽  
Cancer Recurrence ◽  
Standard Of Care ◽  
Cancer Surgery ◽  
Perioperative Pain Management ◽  
Tumor Growth And Metastasis

: Opioids remain the standard of care in the provision of analgesia in the patient undergoing cancer surgery preoperatively. : The effects of opioids on tumor growth and metastasis have been discussed for many years. In recent years their use as part of the perioperative pain management bundle in the patients undergoing cancer surgery has been thought to promote cancer recurrence and metastasis. : This narrative review highlights earlier and more recent in vitro, in vivo and human retrospective studies that yield conflicting results as to the immune-modulatory effects of morphine on tumor biology. The article examines and explains the discrepancies with regards to the seemingly opposite results of morphine in the tumor milieu. The results of both, earlier studies that demonstrated procarcinogenic effects versus the data of more recent refined rodent studies that yielded neutral or even anti-carcinogenic effects are presented here. : Until the results of prospective randomized controlled trials are available to clarify this important question, it is currently not warranted to support opiophobia and opioids continue to constitute a pivotal role in the pain management of cancer patients.

scholarly journals Direct antivirals working against the novel coronavirus: azithromycin (DAWn-AZITHRO), a randomized, multicenter, open-label, adaptive, proof-of-concept clinical trial of new antivirals working against SARS-CoV-2—azithromycin trial

Trials ◽  
2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Iwein Gyselinck ◽  
◽  
Laurens Liesenborghs ◽  
Ewout Landeloos ◽  
Ann Belmans ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Standard Of Care ◽  
Ordinal Scale ◽  
Cytokine Signaling ◽  
Nasopharyngeal Swab ◽  
The Novel ◽  
Proof Of Concept ◽  
Open Label ◽  
Novel Coronavirus

Abstract Background The rapid emergence and the high disease burden of the novel coronavirus SARS-CoV-2 have created a medical need for readily available drugs that can decrease viral replication or blunt the hyperinflammatory state leading to severe COVID-19 disease. Azithromycin is a macrolide antibiotic, known for its immunomodulatory properties. It has shown antiviral effect specifically against SARS-CoV-2 in vitro and acts on cytokine signaling pathways that have been implicated in COVID-19. Methods DAWn-AZITHRO is a randomized, open-label, phase 2 proof-of-concept, multicenter clinical trial, evaluating the safety and efficacy of azithromycin for treating hospitalized patients with COVID-19. It is part of a series of trials testing promising interventions for COVID-19, running in parallel and grouped under the name DAWn-studies. Patients hospitalized on dedicated COVID wards are eligible for study inclusion when they are symptomatic (i.e., clinical or radiological signs) and have been diagnosed with COVID-19 within the last 72 h through PCR (nasopharyngeal swab or bronchoalveolar lavage) or chest CT scan showing typical features of COVID-19 and without alternate diagnosis. Patients are block-randomized (9 patients) with a 2:1 allocation to receive azithromycin plus standard of care versus standard of care alone. Standard of care is mostly supportive, but may comprise hydroxychloroquine, up to the treating physician’s discretion and depending on local policy and national health regulations. The treatment group receives azithromycin qd 500 mg during the first 5 consecutive days after inclusion. The trial will include 284 patients and recruits from 15 centers across Belgium. The primary outcome is time from admission (day 0) to life discharge or to sustained clinical improvement, defined as an improvement of two points on the WHO 7-category ordinal scale sustained for at least 3 days. Discussion The trial investigates the urgent and still unmet global need for drugs that may impact the disease course of COVID-19. It will either provide support or else justify the discouragement of the current widespread, uncontrolled use of azithromycin in patients with COVID-19. The analogous design of other parallel trials of the DAWN consortium will amplify the chance of identifying successful treatment strategies and allow comparison of treatment effects within an identical clinical context. Trial registration EU Clinical trials register EudraCT Nb 2020-001614-38. Registered on 22 April 2020

scholarly journals TMOD-12. ESTABLISHING A CLINICALLY RELEVANT MODEL OF MESENCHYMAL GLIOBLASTOMA (GBM) TO STUDY RESPONSE TO STANDARD OF CARE TREATMENT AND IMMUNE CHECKPOINT INHIBITION (ICI).

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii230-ii230
Author(s):  
James Clerkin ◽  
Kate Connor ◽  
Kieron Sweeney ◽  
Kieron White ◽  
Liam Shiels ◽  
...  
Keyword(s):  
Surgical Resection ◽  
Standard Of Care ◽  
Resistance Mechanisms ◽  
Orthotopic Model ◽  
Aged Mice ◽  
Gl261 Cell ◽  
Standard Of Care Treatment ◽  
Clinical Models ◽  
Immune Contexture

Abstract GBM is a devastating disease with peak incidence in the seventh decade. Pre-clinical models are essential for studying resistance mechanisms and screening novel therapies. However, historically these models have failed to predict response in humans. Current models seldom incorporate surgical resection, and commonly use young animals whose immune contexture differs from older patients. Here, we have established an orthotopic model employing the syngeneic mesenchymal-NFpp10a-cell line which incorporates surgical resection in aged mice. We further characterise response to ICI and temozolomide monotherapy. NFpp10a and GL261-cell lines were exposed in vitro to irradiation (0Gy/2Gy/5Gy) and response assessed using colony formation assays. NFpp10a formed significantly more colonies at 5Gy compared to GL261 at both day 10 (NFpp10a 5.167 vs GL261 1.4; p=0.0017) and day 14 (NFpp10a 3.5 vs GL261 0; p< 0.0001). Hence, NFpp10a displays increased radioresistance. Next, NFpp10a-luciferin expressing cells were orthotopically implanted into young (6-8weeks;n=16) and aged (18months;n=16) C57BL/6-mice. Weekly bioluminescence imaging (BLI) was performed to monitor growth. Mice undergoing resection showed a median 18.47-fold drop in BLI signal. We demonstrated resection survival advantage in aged mice (Resection:33.5 days vs Non-Resection:18 days, p= 0.0166) and showed young age to be a positive prognostic factor (Young:62 days vs Aged:22 days, p=0.0002). Subsequently, we orthotopically implanted NFpp10a-Luc2 cells into C57BL/6 mice and treated with temozolomide (n=24) or PBS control (n=23), and anti-PD1 (n=24) or IgG (n=23). We observed that temozolomide and anti-PD1 monotherapy had no impact on NFpp10-Luc2 growth (temozolomide-overall:p=0.9001, anti-PD1-overall:p=0.7933) or survival (temozolomide-overall:p=0.3035, anti-PD1-overall:p=0.6328). Overall, we have established an NFpp10-Luc2 mesenchymal-GBM model in aged mice which incorporates surgical resection and accurately displays significant resistance to temozolomide and anti-PD1 monotherapy. We are currently employing this model to study the efficacy of neoadjuvant anti-PD1 therapy. Mechanistic analyses with multiplex-immunohistochemistry, scRNA and whole exome sequencing are planned to interrogate treatment effects on the tumor microenvironment.

scholarly journals Two Ecdysteroids Isolated from Micropropagated Lychnis flos-cuculi and the Biological Activity of Plant Material

Molecules ◽  
2021 ◽  
Vol 26 (4) ◽  
pp. 904
Author(s):  
Michał P. Maliński ◽  
Jaromir Budzianowski ◽  
Małgorzata Kikowska ◽  
Monika Derda ◽  
Marcelina M. Jaworska ◽  
...  
Keyword(s):  
Biological Activity ◽  
Acute Toxicity ◽  
Plant Material ◽  
Present Report ◽  
Root Extract ◽  
Methanolic Extracts ◽  
Comparable Activity ◽  
Antiamoebic Activity ◽  
Amoebicidal Activity

Genetically uniform plant material, derived from Lychnis flos-cuculi propagated in vitro, was used for the isolation of 20-hydroxyecdysone and polypodine B and subjected to an evaluation of the antifungal and antiamoebic activity. The activity of 80% aqueous methanolic extracts, their fractions, and isolated ecdysteroids were studied against pathogenic Acanthamoeba castellani. Additionally, a Microtox® acute toxicity assay was performed. It was found that an 80% methanolic fraction of root extract exerts the most potent amoebicidal activity at IC50 of 0.06 mg/mL at the 3rd day of treatment. Both ecdysteroids show comparable activity at IC50 of 0.07 mg/mL. The acute toxicity of 80% fractions at similar concentrations is significantly higher than that of 40% fractions. Crude extracts exhibited moderate antifungal activity, with a minimum inhibitory concentration (MIC) within the range of 1.25–2.5 mg/mL. To the best of our knowledge, the present report is the first to show the biological activity of L. flos-cuculi in terms of the antifungal and antiamoebic activities and acute toxicity. It is also the first isolation of the main ecdysteroids from L. flos-cuculi micropropagated, ecdysteroid-rich plant material.

scholarly journals EXTH-51. ANTI-INVASIVE EFFICACY AND SURVIVAL BENEFIT OF THE YAP-TEAD INHIBITOR VERTEPORFIN IN PRECLINICAL GLIOBLASTOMA MODELS

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii98-ii98
Author(s):  
Anne Marie Barrette ◽  
Alexandros Bouras ◽  
German Nudelman ◽  
Zarmeen Mussa ◽  
Elena Zaslavsky ◽  
...  
Keyword(s):  
Survival Benefit ◽  
De Novo ◽  
Epithelial Mesenchymal Transition ◽  
Intraperitoneal Administration ◽  
Standard Of Care ◽  
Tumor Burden ◽  
Mesenchymal Transition ◽  
Protein Levels

Abstract Glioblastoma (GBM) remains an incurable disease, in large part due to its malignant infiltrative spread, and current clinical therapy fails to target the invasive nature of tumor cells in disease progression and recurrence. Here, we use the YAP-TEAD inhibitor Verteporfin to target a convergence point for regulating tumor invasion/metastasis and establish the robust anti-invasive therapeutic efficacy of this FDA-approved drug and its survival benefit across several preclinical glioma models. Using patient-derived GBM cells and orthotopic xenograft models (PDX), we show that Verteporfin treatment disrupts YAP/TAZ-TEAD activity and processes related to cell adhesion, migration and epithelial-mesenchymal transition. In-vitro, Verteporfin impairs tumor migration, invasion and motility dynamics. In-vivo, intraperitoneal administration of Verteporfin in mice with orthotopic PDX tumors shows consistent drug accumulation within the brain and decreased infiltrative tumor burden, across three independent experiments. Interestingly, PDX tumors with impaired invasion after Verteporfin treatment downregulate CDH2 and ITGB1 adhesion protein levels within the tumor microenvironment. Finally, Verteporfin treatment confers survival benefit in two independent PDX models: as monotherapy in de-novo GBM and in combination with standard-of-care chemoradiation in recurrent GBM. These findings indicate potential therapeutic value of this FDA-approved drug if repurposed for GBM patients.

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