scholarly journals Traditional PK-PD Indices for Efficacy – Can We Do Better?

2017 ◽  
Vol 4 (suppl_1) ◽  
pp. S298-S298 ◽  
Author(s):  
Elizabeth A Lakota ◽  
Justin C Bader ◽  
Sujata M Bhavnani ◽  
David R Andes ◽  
Paul G Ambrose
Keyword(s):  
Dose Fractionation ◽  
Infection Model ◽  
Least Squares Regression ◽  
Dose Selection ◽  
E Coli ◽  
Colony Forming Units ◽  
Fitted Function ◽  
The Hill ◽  
The Relationship

Abstract Background The relationship between antimicrobial activity and exposure relative to MIC is typically evaluated using one of three PK-PD indices, AUC:MIC ratio, Cmax:MIC ratio, and %T>MIC. However, under certain circumstances, none of these PK-PD indices may be the most optimal. These include when the fitted Hill functions for each of the PK-PD indices do not allow for sufficient discrimination, the variability about the fitted functions is wide, and/or the pattern of dose fractionation data is non-informative. Relationships fit using the traditional PK-PD indices may be suboptimal for drugs which exhibit extreme PK characteristics such as abnormally short or long half-lives. As described herein, we explored the use of a fourth PK-PD index for such instances, AUC/τ:MIC ratio (τ = dosing interval). Methods Previously-described ceftolozane dose-fractionation data from a study using a neutropenic murine thigh-infection model were evaluated [AAC 2013; 57(4):1577–82]. In this prior study, mice were infected with E. coli ATCC 25922 (MIC = 0.5 mg/L) or K. pneumoniae ATCC 43816 (MIC = 1.4 mg/L). Ceftolozane doses ranged from 1.56 to 1600 mg/kg/24h given q3h, q6h, q12h, or q24h. Relationships between log10 colony forming units (CFU) at 24 hours and AUC:MIC ratio, Cmax:MIC ratio, %T>MIC, and AUC/τ:MIC ratio were evaluated by pathogen and pooled using Hill-type models and non-linear least squares regression. Results For evaluations of data by pathogen, AUC/τ:MIC ratio best described changes in log10 CFU at 24 hours. The coefficients of determination (r2) for these pathogens were improved by 0.20 and 0.11, respectively, relative to the highest r2 achieved using any of the traditional PK-PD indices. Similar results were observed when the data were evaluated using a pooled approach (Figure 1). Conclusion AUC/τ:MIC ratio may be useful to evaluate drugs demonstrating the extremes of PK. Accordingly, this PK-PD index best described ceftolozane PK-PD, an agent with a very short murine plasma half-life (<15 minutes). The use of the PK-PD index that allows for the best fit of the data to the Hill function and reduced variability about the fitted function will not only improve the characterization of PK-PD but will also improve the accuracy of future dose selection analyses. Disclosures All authors: No reported disclosures.

scholarly journals 1395. Defining the Magnitude of AUC:MIC Driver for Efficacy of the β-Lactamase Inhibitor VNRX-5133 When Combined with Cefepime Against KPC- and VIM/NDM-Producing Enterobacteriaceae and P. aeruginosa

2018 ◽  
Vol 5 (suppl_1) ◽  
pp. S429-S429 ◽  
Author(s):  
Denis Daigle ◽  
Salvador Vernacchio ◽  
Luigi Xerri ◽  
Daniel Pevear
Keyword(s):  
In Vitro Studies ◽  
Dose Fractionation ◽  
Infection Model ◽  
Type Model ◽  
E Coli ◽  
Dose Ranging ◽  
New Generation ◽  
Lactamase Inhibitor

Abstract Background VNRX-5133 is a cyclic boronate β-lactamase inhibitor (BLI) in clinical development with cefepime for treatment of infections caused by ESBL- and carbapenemase producing Enterobacteriaceae and P. aeruginosa. It is a new generation broad-spectrum BLI with direct inhibitory activity against serine-active site and emerging metallo-β-lactamases (e.g., VIM/NDM). In previous in vivo and in vitro studies, the PK-PD driver of efficacy of VNRX-5133 was defined as AUC:MIC. Described herein are in vitro studies to assess the magnitude of VNRX-5133 exposure (AUC:MIC) required to restore efficacy of cefepime against a broad collection of KPC- and VIM/NDM-producing Enterobacteriaceae (ENT) and P. aeruginosa (PSA) clinical isolates. Methods Dose-fractionation studies, consisting of four VNRX-5133 exposures fractionated into regimens administered every 4, 8, 12 and 24 hours, were performed in an in vitro infection model with simulated 2 g q8h dosing of cefepime against NDM-1 producing E. coli. A Hill-type model described the relationship between change in log10 CFU at 24 hours and VNRX-5133 exposure (AUC:MIC), where cefepime MIC was determined with 4 µg/mL VNRX-5133. To evaluate variability of efficacy enabled by VNRX-5133 between isolates as well as between Serine-BL and Metallo-BL producers, dose-ranging studies were completed for eight isolates (seven ENT and one PSA) producing KPC or VIM/NDM metallo-β-lactamases. Results The PK-PD exposure parameter AUC:MIC accurately described the efficacy of VNRX-5133 in rescuing cefepime activity against KPC and VIM/NDM carbapenemase-producing isolates of ENT and PSA. The AUC:MIC ratios associated with net bacterial stasis, 1-, and 2-log10 reductions in bacterial burden from baseline were 6.1, 18.4 and 45, respectively, for a collection of five VIM/NDM- and three KPC-producing isolates with cefepime MICs ranging from 4–8 µg/mL with no significant differences observed between Ser-BL and MBL producers. Conclusion These data confirm the equivalent in vitro activity of cefepime/VNRX-5133 against organisms producing serine- and metallo-β-lactamases and provides an initial PK-PD target for VNRX-5133 efficacy when used in combination with cefepime for the treatment of ESBL- and carbapenemase-producing ENT and PSA infections. Disclosures D. Daigle, VenatoRx Pharmaceuticals Inc.: Employee and Shareholder, Salary. S. Vernacchio, VenatoRx Pharmaceuticals Inc.: Employee and Shareholder, Salary. L. Xerri, VenatoRx Pharmaceuticals Inc.: Employee and Shareholder, Salary. D. Pevear, VenatoRx Pharmaceuticals Inc.: Employee, Salary.

scholarly journals Characterization of the β-lactamase specified by the resistance factor R-1818 in Escherichia coli K12 and other Gram-negative bacteria

1971 ◽  
Vol 123 (4) ◽  
pp. 501-505 ◽  
Author(s):  
J. W. Dale
Keyword(s):  
Escherichia Coli ◽  
Host Species ◽  
Host Bacterium ◽  
Gram Negative Bacteria ◽  
Gram Negative ◽  
E Coli ◽  
R Factor ◽  
Relationship Of ◽  
The Relationship

1. The amino acid composition of the β-lactamase from E. coli (R-1818) was determined. 2. The R-1818 β-lactamase is inhibited by formaldehyde, hydroxylamine, sodium azide, iodoacetamide, iodine and sodium chloride. 3. The Km values for benzylpenicillin, ampicillin and oxacillin have been determined by using the R-factor enzyme from different host species. The same values were obtained, irrespective of the host bacterium. 4. The molecular weight of the enzyme was found to be 44600, and was the same for all host species. 5. The relationship of R-1818 and R-GN238 β-lactamases is discussed.

Influence of pyrolytic seeds on ZnO nanorod growth onto rigid substrates for photocatalytic abatement of Escherichia coli in water

2014 ◽  
Vol 14 (6) ◽  
pp. 1087-1094 ◽  
Author(s):  
Luis Sanchez ◽  
Lucas Guz ◽  
Pilar García ◽  
Silvia Ponce ◽  
Silvia Goyanes ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Antibacterial Activity ◽  
Zno Nanorods ◽  
Water Disinfection ◽  
Acetate Solution ◽  
Ethanol Mixture ◽  
E Coli ◽  
The Relationship ◽  
Nanorod Growth

ZnO nanorods (ZnO NRs) were grown on ZnO seeded fluorine doped tin oxide (FTO) substrates at low temperatures (90 °C) from Zn2+ precursors in alkaline aqueous solution. The ZnO seeds were deposited on the FTO substrate heated at 350 °C by spray pyrolysis of a zinc acetate solution in a water ethanol mixture. The structure of seeds was tuned by the ethanol water ratio, Γ, which controls the solvent evaporation rate of drops impinging the substrate. The relationship between the microstructure and optical properties of the ZnO NR films and the photocatalytic antibacterial activity for Escherichia coli abatement, was determined through a detailed characterization of the material. The higher photocatalytic antibacterial activity was performed by ZnO NR films grown on seeds deposited from solutions with Γ in the 0.0–0.03 range. With these films, the population of viable E. coli dropped more than six orders, from 8 × 108 to 4 × 102 CFU. These results show the potential of these materials in water disinfection.

scholarly journals 477. Characterization of Extended-Spectrum Β-Lactamase (ESBL) Producing Gram-negative (GN) Urinary Tract Infections (UTI) in Pediatric Patients

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S233-S233
Author(s):  
Leslie Stach ◽  
Regina Orbach ◽  
Kanokporn Mongkolrattanothai
Keyword(s):  
Urinary Tract ◽  
Pediatric Patients ◽  
Selective Pressure ◽  
Once Daily ◽  
E Coli ◽  
Colony Forming Units ◽  
Amoxicillin Clavulanate ◽  
Tract Infections ◽  
Abnormal Urinary Tract

Abstract Background There has been an increase in antimicrobial resistance among GN pathogens, not only in adults, but also pediatrics. UTIs are common in pediatrics; however, reports of pediatric UTI with ESBL producing GN are limited. Methods All urine cultures positive for ESBL producing GN from 5/1/18 to December 31/18 were retrospectively reviewed. Proven infection (PI) defined as ≥50,000 colony-forming units (CFU)/mL of bacteria plus pyuria or positive leukocyte esterase for catheterized or clean catch specimens. Relapsed infection defined as same pathogen cultured within 30 days of infection. Abnormal urinary tract systems or functions (AUTS) include neurogenic bladder, structural anomalies, or intermittent catheterization. Results A total of 107 urine cultures for ESBL producing GN, from 85 patients, were included. Majority of specimens [78/107 (73%)] were obtained from the ED or outpatient clinics. 43% of specimens were from patients with AUTS. E. coli was the majority (95%) of ESBL isolates. 57% of ESBL producing GNs were susceptible to amoxicillin/clavulanate (AC) or trimethoprim/sulfamethoxazole (TMP/SMX). 88% were nitrofurantoin susceptible. Only 1 isolate was meropenem resistant. Antibiotics (ABX) were prescribed for UTI in 67/107 episodes. However, only 52 episodes were PI. Of these, 38 were empirically treated with oral ABX and 29 with intravenous ABX. The most commonly prescribed empiric ABX was oral cephalexin (25/67, 37%.) Ineffective empiric ABX for UTI was very common, 83% (43/52). Of these, 5/43 never received effective therapy and none had relapse. Most common duration of ABX was 10 days (range 5–17 days.) 43% (23/52) of PI were treated with oral AC or TMP/SMX. 15% (8/52) of PI were treated with nitrofurantoin. 12% of PI were treated with a once-daily aminoglycoside. Only 6% of PI were treated with a carbapenem. Conclusion Many ESBL UTI isolates remain susceptible to oral ABX. Although small numbers, patients treated with ineffective ABX did not return with relapsed infection. Non-carbapenem ABX are a reasonable option to minimize selective pressure or unnecessary use. Empiric narrow-spectrum antibiotic therapy may still be appropriate. Disclosures All authors: No reported disclosures.

scholarly journals Genetic Characterization of Escherichia coli Populations from Host Sources of Fecal Pollution by Using DNA Fingerprinting

2003 ◽  
Vol 69 (5) ◽  
pp. 2587-2594 ◽  
Author(s):  
Sandra L. McLellan ◽  
Annette D. Daniels ◽  
Alissa K. Salmore
Keyword(s):  
Escherichia Coli ◽  
Pairwise Comparison ◽  
Fecal Pollution ◽  
Host Animal ◽  
Host Group ◽  
E Coli ◽  
Single Host ◽  
Relationship Of ◽  
The Relationship

ABSTRACT Escherichia coli isolates were obtained from common host sources of fecal pollution and characterized by using repetitive extragenic palindromic (REP) PCR fingerprinting. The genetic relationship of strains within each host group was assessed as was the relationship of strains among different host groups. Multiple isolates from a single host animal (gull, human, or dog) were found to be identical; however, in some of the animals, additional strains occurred at a lower frequency. REP PCR fingerprint patterns of isolates from sewage (n = 180), gulls (n = 133), and dairy cattle (n = 121) were diverse; within a host group, pairwise comparison similarity indices ranged from 98% to as low as 15%. A composite dendrogram of E. coli fingerprint patterns did not cluster the isolates into distinct host groups but rather produced numerous subclusters (approximately >80% similarity scores calculated with the cosine coefficient) that were nearly exclusive for a host group. Approximately 65% of the isolates analyzed were arranged into host-specific groups. Comparable results were obtained by using enterobacterial repetitive intergenic consensus PCR and pulsed-field gel electrophoresis (PFGE), where PFGE gave a higher differentiation of closely related strains than both PCR techniques. These results demonstrate that environmental studies with genetic comparisons to detect sources of E. coli contamination will require extensive isolation of strains to encompass E. coli strain diversity found in host sources of contamination. These findings will assist in the development of approaches to determine sources of fecal pollution, an effort important for protecting water resources and public health.

scholarly journals Pharmacokinetics-Pharmacodynamics of Enmetazobactam Combined with Cefepime in a Neutropenic Murine Thigh Infection Model

2020 ◽  
Vol 64 (6) ◽  
Author(s):  
Fabian Bernhard ◽  
Rajesh Odedra ◽  
Sylvie Sordello ◽  
Rossella Cardin ◽  
Samantha Franzoni ◽  
...  
Keyword(s):  
Generation Cephalosporin ◽  
Threshold Concentration ◽  
Dose Fractionation ◽  
Infection Model ◽  
Dose Selection ◽  
Content Type ◽  
Clinical Dose ◽  
Sigmoid Curve ◽  
Dose Ranging ◽  
Tract Infections

ABSTRACT Third-generation cephalosporin (3GC)-resistant Enterobacteriaceae are classified as critical priority pathogens, with extended-spectrum β-lactamases (ESBLs) as principal resistance determinants. Enmetazobactam (formerly AAI101) is a novel ESBL inhibitor developed in combination with cefepime for empirical treatment of serious Gram-negative infections in settings where ESBLs are prevalent. Cefepime-enmetazobactam has been investigated in a phase 3 trial in patients with complicated urinary tract infections or acute pyelonephritis. This study examined pharmacokinetic-pharmacodynamic (PK-PD) relationships of enmetazobactam, in combination with cefepime, for ESBL-producing isolates of Klebsiella pneumoniae in 26-h murine neutropenic thigh infection models. Enmetazobactam dose fractionation identified the time above a free threshold concentration (fT > CT) as the PK-PD index predictive of efficacy. Nine ESBL-producing isolates of K. pneumoniae, resistant to cefepime and piperacillin-tazobactam, were included in enmetazobactam dose-ranging studies. The isolates encoded CTX-M-type, SHV-12, DHA-1, and OXA-48 β-lactamases and covered a cefepime-enmetazobactam MIC range from 0.06 to 2 μg/ml. Enmetazobactam restored the efficacy of cefepime against all isolates tested. Sigmoid curve fitting across the combined set of isolates identified enmetazobactam PK-PD targets for stasis and for a 1-log10 bioburden reduction of 8% and 44% fT > 2 μg/ml, respectively, with a concomitant cefepime PK-PD target of 40 to 60% fT > cefepime-enmetazobactam MIC. These findings support clinical dose selection and breakpoint setting for cefepime-enmetazobactam.

scholarly journals Relationship between Fosfomycin Exposure and Amplification of Escherichia coli Subpopulations with Reduced Susceptibility in a Hollow-Fiber Infection Model

2016 ◽  
Vol 60 (9) ◽  
pp. 5141-5145 ◽  
Author(s):  
Brian VanScoy ◽  
Jennifer McCauley ◽  
Sujata M. Bhavnani ◽  
Evelyn J. Ellis-Grosse ◽  
Paul G. Ambrose
Keyword(s):  
Escherichia Coli ◽  
Hollow Fiber ◽  
Drug Exposure ◽  
Drug Susceptibility ◽  
Infection Model ◽  
Content Type ◽  
E Coli ◽  
Control Regimen ◽  
Dosing Regimens ◽  
The Relationship

ABSTRACTUnderstanding the relationship between antibiotic exposure and amplification of bacterial subpopulations with reduced drug susceptibility over time is important for evaluating the adequacy of dosing regimens. We utilized a hollow-fiber infection model to identify the fosfomycin intravenous dosing regimens that prevented the amplification ofEscherichia colibacterial subpopulations with reduced fosfomycin susceptibility. The challenge isolate wasE. coliATCC 25922 (agar MIC with glucose-6-phosphate, 1 mg/liter; agar MIC without glucose-6-phosphate, 32 mg/liter). The fosfomycin dosing regimens studied were 1 to 12 g every 8 h for 10 days to approximate that planned for clinical use. The studies included a no-treatment control regimen. Two bacterial subpopulations were identified, one with reduced susceptibility with agar MIC values ranging from 32 to 128 mg/liter and the other resistant with agar MIC values of 256 to >1,024 mg/liter on plates containing 5× and 256× the baseline MIC value, respectively. An inverted-U-shaped function best described the relationship between the amplification of the two bacterial subpopulations and drug exposure. The lowest fosfomycin dosing regimen that did not amplify a bacterial subpopulation with reduced susceptibility was 4 g administered every 8 h. Nearly immediate amplification of bacterial subpopulations with reduced susceptibility was observed with fosfomycin dosing regimens consisting of 1 to 2 g every 8 h. These data will be useful to support the selection of fosfomycin dosing regimens that minimize the potential for on-therapy amplification of bacterial subpopulations with reduced susceptibility.

scholarly journals In Vivo Pharmacokinetics and Pharmacodynamics of ZTI-01 (Fosfomycin for Injection) in the Neutropenic Murine Thigh Infection Model against Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa

2017 ◽  
Vol 61 (6) ◽  
Author(s):  
Alexander J. Lepak ◽  
Miao Zhao ◽  
Brian VanScoy ◽  
Daniel S. Taylor ◽  
Evelyn Ellis-Grosse ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Pseudomonas Aeruginosa ◽  
Klebsiella Pneumoniae ◽  
Subcutaneous Administration ◽  
Dose Fractionation ◽  
Infection Model ◽  
Time Curve ◽  
Gram Negative ◽  
Content Type ◽  
E Coli

ABSTRACT Fosfomycin is a broad-spectrum agent with activity against Gram-positive and Gram-negative bacteria, including drug-resistant strains, such as extended-spectrum-beta-lactamase (ESBL)-producing and carbapenem-resistant (CR) Gram-negative rods. In the present study, the pharmacokinetic/pharmacodynamic (PK/PD) activity of ZTI-01 (fosfomycin for injection) was evaluated in the neutropenic murine thigh infection model against 5 Escherichia coli, 3 Klebsiella pneumoniae, and 2 Pseudomonas aeruginosa strains, including a subset with ESBL and CR phenotypes. The pharmacokinetics of ZTI-01 were examined in mice after subcutaneous administration of 3.125, 12.5, 50, 200, 400, and 800 mg/kg of body weight. The half-life ranged from 0.51 to 1.1 h, area under the concentration-time curve (AUC0–∞) ranged from 1.4 to 87 mg · h/liter, and maximum concentrations ranged from 0.6 to 42.4 mg/liter. Dose fractionation demonstrated the AUC/MIC ratio to be the PK/PD index most closely linked to efficacy (R 2 = 0.70). Net stasis and bactericidal activity were observed against all strains. Net stasis was observed at 24-h AUC/MIC ratio values of 24, 21, and 15 for E. coli, K., pneumoniae and P. aeruginosa, respectively. For the Enterobacteriaceae group, stasis was noted at mean 24-h AUC/MIC ratio targets of 23 and 1-log kill at 83. Survival in mice infected with E. coli 145 was maximal at 24-h AUC/MIC ratio exposures of 9 to 43, which is comparable to the stasis exposures identified in the PK/PD studies. These results should prove useful for the design of clinical dosing regimens for ZTI-01 in the treatment of serious infections due to Enterobacteriaceae and Pseudomonas.

scholarly journals Gepotidacin Pharmacokinetics-Pharmacodynamics Against Escherichia coli in the One-Compartment and Hollow-Fiber In Vitro Infection Model Systems

2021 ◽  
Author(s):  
Brian D. VanScoy ◽  
Elizabeth A. Lakota ◽  
Haley Conde ◽  
Steven Fikes ◽  
Sujata M. Bhavnani ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Hollow Fiber ◽  
Free Drug ◽  
Model Systems ◽  
Dose Fractionation ◽  
Infection Model ◽  
Bacterial Reduction ◽  
Time Curve ◽  
E Coli

Gepotidacin is a novel, first-in-class triazaacenaphthylene antibiotic that inhibits bacterial DNA replication by a distinct mechanism of action with an in vitro spectrum of activity that includes Escherichia coli . Our objectives herein were the following: 1) to identify the pharmacokinetic-pharmacodynamics (PK-PD) index associated with efficacy for gepotidacin against E. coli ; 2) to determine the magnitude of the above-described PK-PD index associated with various bacterial reduction endpoints for E. coli ; and 3) to characterize the relationship between gepotidacin exposure and on-therapy E. coli resistance amplification. A 24-hour one-compartment in vitro infection model was used to investigate the first two study objectives and a 10-day hollow-fiber in vitro infection model was used to evaluate the third objective. For the dose-fractionation studies (objective 1), in which E. coli NCTC 13441 (gepotidacin MIC, 2 mg/L) was evaluated, free-drug gepotidacin area under the concentration-time curve (AUC) from 0 to 24 h to the MIC (AUC/MIC ratio) was identified as PK-PD index most closely associated with change in bacterial burden ( R 2 = 0.925). For the dose-ranging studies (objective 2), in which four E. coli isolates (gepotidacin MIC range, 1 to 4 mg/L) were studied, the magnitude of the median free-drug gepotidacin AUC/MIC ratio associated with net bacterial stasis and 1- and 2-log 10 CFU reductions for the pooled dataset was 33.9, 43.7, and 60.7, respectively. For the hollow-fiber in vitro infection model studies (objective 3), in which one isolate ( E. coli NCTC 13441 gepotidacin MIC, 2 mg/L) was evaluated, free-drug gepotidacin AUC/MIC ratios 275 and greater were sufficient to suppress on-therapy resistance amplification. Together, the data generated from these studies will be useful to support discrimination among candidate dosing regimens for future clinical study.

Efficacy of Xyloglucan against Escherichia coli Extraintestinal Urinary Tract Infection: An in vivo Study

2020 ◽  
Vol 30 (1-6) ◽  
pp. 50-60
Author(s):  
Emanuela Esposito ◽  
Michela Campolo ◽  
Giovanna Casili ◽  
Marika Lanza ◽  
Domenico Franco ◽  
...  
Keyword(s):  
Urinary Tract ◽  
Neutrophil Infiltration ◽  
Infection Model ◽  
Histological Changes ◽  
E Coli ◽  
Colony Forming Units ◽  
Tight Junction Permeability ◽  
Tract Infections

Natural approaches to conventional pharmaceutical treatments for urinary tract infections (UTIs) have focused attention toward reducing the colonization of intestinal <i>Escheri­chia coli</i> reservoirs, the cause of ascending and hematogenous UTIs. In this study, we evaluated the protective effect of xyloglucan and xyloglucan plus gelose on intestinal and urinary epithelia in an in vivo <i>E. coli</i> infection model. Preventative xyloglucan and xyloglucan plus gelose oral treatments were performed by gavage 2 days before <i>E. coli</i> administration and every day until day 7. In vitro, xyloglucan had no effect on bacterial growth, cell morphology, or integrity. The results clearly demonstrated the protective barrier effect of xyloglucan in the bladder and intestine, as evidenced by a reduction in histological changes, neutrophil infiltration, and tight junction permeability in the intestine following <i>E. coli</i> infection. The potential beneficial effect of xyloglucan in preventing UTIs was supported by a reduction of <i>E. coli</i>-positive colony-forming units in the urinary tract. We consider xyloglucan in association with gelose to be an effective oral medical device for the prevention of extraintestinal UTIs.

Sign in / Sign up

Export Citation Format

Share Document