scholarly journals Cephalosporin clinical concentration–time profile modelling and in-vitro bactericidal effects on Escherichia coli

1999 ◽  
Vol 44 (4) ◽  
pp. 471-476 ◽  
Author(s):  
Kate A. Cholewka ◽  
Lisa L. Ioannides-Demos ◽  
Lisa Liolios ◽  
Phillip Paull ◽  
W. John Spicer ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Time Profile ◽  
Concentration Time ◽  
Bactericidal Effects

scholarly journals Norepinephrine in Combination with Antibiotic Therapy Increases both the Bacterial Replication Rate and Bactericidal Activity

2018 ◽  
Vol 62 (4) ◽  
Author(s):  
Paul G. Ambrose ◽  
Brian D. VanScoy ◽  
John Adams ◽  
Steven Fikes ◽  
Justin C. Bader ◽  
...  
Keyword(s):  
Chloride Concentration ◽  
Time Profile ◽  
Bacterial Density ◽  
Infection Model ◽  
Replication Rate ◽  
Time Curve ◽  
Concentration Time ◽  
Bactericidal Effects ◽  
Bacterial Replication

ABSTRACT We previously demonstrated that the rate and extent of an antimicrobial agent's bactericidal effects were coupled to the bacterial replication rate, the latter of which was modulated with the sodium chloride concentration. Herein, we describe the results from a 24-h one-compartment in vitro infection model study that was designed to demonstrate that an antimicrobial agent's bactericidal effects could be amplified when it is administered with a pharmaceutical agent that increases the bacterial replication rate. The antimicrobial and growth-promoting agents selected were levofloxacin and norepinephrine, respectively. The challenge isolate was Escherichia coli JMI 21711R (levofloxacin MIC, 8 mg/liter). Within the in vitro infection model, a human levofloxacin concentration-time profile (half-life, 7 h) was simulated and the challenge isolate was subjected to an ineffective monotherapy exposure (free-drug area under the concentration-time curve over 24 h divided by the MIC [AUC/MIC] ratio of 6) with and without norepinephrine as a continuous infusion (275 mg/liter). Samples were collected from the model during the course of the study for bacterial density determinations and drug concentration assay using liquid chromatography-tandem mass spectrometry (LC-MS/MS). As expected, the norepinephrine and no-treatment control arms failed immediately, followed by the levofloxacin monotherapy arm, which failed slowly over time. The levofloxacin-epinephrine regimen resulted in a 2-log 10 CFU reduction in bacterial density over the first 6 to 8 h of the study, which was followed by regrowth of a highly levofloxacin-resistant subpopulation (MIC, 64 mg/liter). These data demonstrate that increasing the rate of bacterial replication with a pharmaceutical product in combination with antimicrobial therapy represents an opportunity to increase the rate and magnitude of bactericidal effect.

scholarly journals Development of a Physiologically Based Pharmacokinetic Model for Prediction of Ethanol Concentration-Time Profile in Different Organs

2020 ◽  
Author(s):  
Armin Sadighi ◽  
Lorenzo Leggio ◽  
Fatemeh Akhlaghi
Keyword(s):  
Pbpk Model ◽  
Organ Damage ◽  
Time Profile ◽  
Sensitivity Analyses ◽  
Pbpk Modeling ◽  
Time Curve ◽  
Physiologically Based Pharmacokinetic ◽  
Concentration Time ◽  
Physiologically Based

Abstract Aims A physiologically based pharmacokinetic (PBPK) modeling approach was used to simulate the concentration-time profile of ethanol (EtOH) in stomach, duodenum, plasma and other tissues upon consumption of beer and whiskey under fasted and fed conditions. Methods A full PBPK model was developed for EtOH using the advanced dissolution, absorption and metabolism (ADAM) model fully integrated into the Simcyp Simulator® 15 (Simcyp Ltd., Sheffield, UK). The prediction performance of the developed model was verified and the EtOH concentration-time profile in different organs was predicted. Results Simcyp simulation showed ≤ 2-fold difference in values of EtOH area under the concentration-time curve (AUC) in stomach and duodenum as compared to the observed values. Moreover, the simulated EtOH maximum concentration (Cmax), time to reach Cmax (Tmax) and AUC in plasma were comparable to the observed values. We showed that liver is exposed to the highest EtOH concentration, faster than other organs (Cmax = 839.50 mg/L and Tmax = 0.53 h), while brain exposure of EtOH (AUC = 1139.43 mg·h/L) is the highest among all other organs. Sensitivity analyses (SAs) showed direct proportion of EtOH rate and extent of absorption with administered EtOH dose and inverse relationship with gastric emptying time (GE) and steady-state volume of distribution (Vss). Conclusions The current PBPK model approach might help with designing in vitro experiments in the area of alcohol organ damage or alcohol-drug interaction studies.

scholarly journals Pharmacodynamics of Isavuconazole in a DynamicIn VitroModel of Invasive Pulmonary Aspergillosis

2015 ◽  
Vol 60 (1) ◽  
pp. 278-287 ◽  
Author(s):  
Helen Box ◽  
Joanne Livermore ◽  
Adam Johnson ◽  
Laura McEntee ◽  
Timothy W. Felton ◽  
...  
Keyword(s):  
Invasive Pulmonary Aspergillosis ◽  
Pathogenic Fungi ◽  
Time Profile ◽  
Wild Type ◽  
Time Curve ◽  
Content Type ◽  
Concentration Time ◽  
Target Values ◽  
Maximal Suppression

ABSTRACTIsavuconazonium sulfate is a novel triazole prodrug that has been recently approved for the treatment of invasive aspergillosis by the FDA. The active moiety (isavuconazole) has a broad spectrum of activity against many pathogenic fungi. This study utilized a dynamicin vitromodel of the human alveolus to describe the pharmacodynamics of isavuconazole against two wild-type and two previously defined azole-resistant isolates ofAspergillus fumigatus. A human-like concentration-time profile for isavuconazole was generated. MICs were determined using CLSI and EUCAST methodologies. Galactomannan was used as a measure of fungal burden. Target values for the area under the concentration-time curve (AUC)/MIC were calculated using a population pharmacokinetics-pharmacodynamics (PK-PD) mathematical model. Isolates with higher MICs required higher AUCs in order to achieve maximal suppression of galactomannan. The AUC/MIC targets necessary to achieve 90% probability of galactomannan suppression of <1 were 11.40 and 11.20 for EUCAST and CLSI, respectively.

scholarly journals Intrapulmonary Distribution of Intravenous Telavancin in Healthy Subjects and Effect of Pulmonary Surfactant on In Vitro Activities of Telavancin and Other Antibiotics

2007 ◽  
Vol 52 (1) ◽  
pp. 92-97 ◽  
Author(s):  
Mark H. Gotfried ◽  
Jeng-Pyng Shaw ◽  
Bret M. Benton ◽  
Kevin M. Krause ◽  
Michael R. Goldberg ◽  
...  
Keyword(s):  
Healthy Subjects ◽  
Pulmonary Surfactant ◽  
Respiratory Infections ◽  
Time Profile ◽  
Epithelial Lining Fluid ◽  
Plasma Ratio ◽  
The Third ◽  
Concentration Time ◽  
In Vitro Antibacterial Activity

ABSTRACT Steady-state concentrations of telavancin, a novel, bactericidal lipoglycopeptide, were determined in the plasma, pulmonary epithelial lining fluid (ELF), and alveolar macrophages (AMs) of 20 healthy subjects. Telavancin at 10 mg of drug/kg of body weight/day was administered as a 1-h intravenous infusion on three successive days, with bronchoalveolar lavage performed on five subjects, each at 4, 8, 12, and 24 h after the last dose. Plasma samples were collected before the first and third infusions and at 1, 2, 3, 4, 8, 12, and 24 h after the third infusion. The plasma telavancin concentration-time profile was as reported previously. Telavancin (mean ± standard deviation) penetrated well into ELF (3.73 ± 1.28 μg/ml at 8 h and 0.89 ± 1.03 μg/ml at 24 h) and extensively into AMs (19.0 ± 16.8 μg/ml at 8 h, 45.0 ± 22.4 μg/ml at 12 h, and 42.0 ± 31.4 μg/ml at 24 h). Mean concentrations in AMs and plasma at 12 h were 45.0 μg/ml and 22.9 μg/ml (mean AM/plasma ratio, 1.93), respectively, and at 24 h were 42.0 μg/ml and 7.28 μg/ml (mean AM/plasma ratio, 6.67), respectively. Over the entire dosing interval, telavancin was present in ELF and AMs at concentrations up to 8-fold and 85-fold, respectively, above its MIC90 for methicillin-resistant Staphylococcus aureus (0.5 μg/ml). Pulmonary surfactant did not affect telavancin's in vitro antibacterial activity. Telavancin was well tolerated. These results support the proposal for further clinical evaluation of telavancin for treating gram-positive respiratory infections.

scholarly journals Preclinical Pharmacokinetics of MI-219, a Novel Human Double Minute 2 (HDM2) Inhibitor and Prediction of Human Pharmacokinetics

2012 ◽  
Vol 15 (2) ◽  
pp. 265 ◽  
Author(s):  
Peng Zou ◽  
Nan Zheng ◽  
Yanke Yu ◽  
Shanghai Yu ◽  
Wei Sun ◽  
...  
Keyword(s):  
Allometric Scaling ◽  
Human Study ◽  
Volume Of Distribution ◽  
Time Profile ◽  
In Vitro Assays ◽  
Pharmacokinetic Studies ◽  
Human Pharmacokinetics ◽  
Preclinical Pharmacokinetics ◽  
Concentration Time

Purpose. The two purposes of this study were evaluating preclinical pharmacokinetics of MI-219 and predicting clearance (CL) and volume of distribution at steady-state (Vdss) of MI-219 in humans. Methods. Pharmacokinetic studies were conducted on mice, rats, dogs, and monkeys. Human CL of MI-219 was predicted using allometric scaling (SA), multi-exponential allometric scaling (ME), rule of exponents (RoE), single species scaling, two-term power equation (TTPE), physiologically based in vitro-in vivo extrapolation (IVIVE), and fu corrected intercept method (FCIM). In vitro assays were conducted to determine in vitro intrinsic CL, protein binding, and blood-plasma partition coefficients. To estimate half-life of MI-219, plasma concentration–time profile in humans was predicted using kallynochron and apolysichron time transformation (Dedrick plots) and normalization with MRT and Vdss (Wajima’s method). In addition, simultaneous interspecies scaling of CL, Vdss and concentration–time profile were performed by using Nonlinear Mixed Effects Modeling (NONMEM). Results. Preclinical studies showed that the elimination of MI-219 was mainly through metabolism. The validation using observed monkey CL and Vdss showed that MA, IVIVE and Oie-Tozer methods were accurately than the other methods. Human CL of MI-219 predicted by ME and IVIVE was between 0.237-0.342 L*h-1*kg-1. Human Vdss predicted by Oie-Tozer method and allometric scaling of unbound volume of distribution of tissues (VT/fuT) method was between 0.93-1.40 L*kg-1. Superimposition of rat, monkey and dog data was observed in Dedrick plots and Wajima’s transformations. Conclusions. The predicted human pharmacokinetics is useful for the design of first-in-human study. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

scholarly journals Improvement of the Bioavailability and Glycaemic Metabolism of Cinnamon Oil in Rats by Liquid Loadable Tablets

2012 ◽  
Vol 2012 ◽  
pp. 1-6 ◽  
Author(s):  
Chunchao Han ◽  
Bo Cui
Keyword(s):  
Insulin Secretion ◽  
Blood Glucose ◽  
Plasma Concentration ◽  
Time Profile ◽  
Release Profile ◽  
In Vitro Dissolution ◽  
Pharmacokinetic Parameters ◽  
Cinnamon Oil ◽  
Concentration Time

The purpose of this study is to investigate the bioavailability and glycaemic metabolism of cinnamon oil (CIO) carried by liquid-loadable tablets (CIO-LLTs), the carrier of a CIO self-emulsifying formulation (CIO-LS). The results of tests performed to evaluate the physical properties of the CIO-LLT complied with Chinese Pharmacopeia (2010). The release profile suggested that the CIO-LLT preserved the enhancement of in vitro dissolution of cio. After orally administration, the plasma concentration-time profile and pharmacokinetic parameters suggested that a significant increase (P<0.0001) in theCmax, AUC andFwere observed in the CIO-LLT. The blood glucose and the HbA1c were significantly decreased in alloxan-induced hyperglycemic rats (P<0.05,P<0.01, resp.), while the level of insulin secretion was markedly elevated in alloxan-induced hyperglycemic rats (P<0.05). The alloxan-damaged pancreaticβ-cells of the rats were partly recovered gradually after the rats were administered with CIO-LLT 45 days later. CIO-LLT could improve the bioavailability and glycaemic metabolism of CIO.

scholarly journals Use of an In Vitro Pharmacodynamic Model To Derive a Linezolid Regimen That Optimizes Bacterial Kill and Prevents Emergence of Resistance in Bacillus anthracis

2008 ◽  
Vol 52 (7) ◽  
pp. 2486-2496 ◽  
Author(s):  
A. Louie ◽  
H. S. Heine ◽  
K. Kim ◽  
D. L. Brown ◽  
B. VanScoy ◽  
...  
Keyword(s):  
Bacillus Anthracis ◽  
Drug Concentration ◽  
Human Subjects ◽  
Time Profile ◽  
Pharmacodynamic Model ◽  
Dose Fractionation ◽  
Serum Drug Concentration ◽  
Maximum Serum ◽  
Concentration Time

ABSTRACT Simulating the average non-protein-bound (free) human serum drug concentration-time profiles for linezolid in an in vitro pharmacodynamic model, we characterized the pharmacodynamic parameter(s) of linezolid predictive of kill and for prevention of resistance in Bacillus anthracis. In 10-day dose-ranging studies, the average exposure for ≥700 mg of linezolid given once daily (QD) resulted in >3-log CFU/ml declines in B. anthracis without resistance selection. Linezolid at ≤600 mg QD amplified for resistance. With twice-daily (q12h) dosing, linezolid at ≥500 mg q12 h was required for resistance prevention. In dose fractionation studies, killing of B. anthracis was predicted by the area under the time-concentration curve (AUC)/MIC ratio. However, resistance prevention was linked to the maximum serum drug concentration (C max)/MIC ratio. Monte Carlo simulations predicted that linezolid at 1,100 mg QD would produce in 96.7% of human subjects a free 24-h AUC that would match or exceed the average 24-h AUC of 78.5 mg·h/liter generated by linezolid at 700 mg QD while reproducing the shape of the concentration-time profile for this pharmacodynamically optimized regimen. However, linezolid at 700 mg q12h (cumulative daily dose of 1,400 mg) would produce an exposure that would equal or exceed the average free 24-h AUC of 90 mg·h/liter generated by linezolid at 500 mg q12h in 93.8% of human subjects. In conclusion, in our in vitro studies, the QD-administered, pharmacodynamically optimized regimen for linezolid killed drug-susceptible B. anthracis and prevented resistance emergence at lower dosages than q12h regimens. The lower dosage for the pharmacodynamically optimized regimen may decrease drug toxicity. Also, the QD administration schedule may improve patient compliance.

scholarly journals Bacterial Replication Rate Modulation in Combination with Antimicrobial Therapy: Turning the Microbe against Itself

2016 ◽  
Vol 61 (1) ◽  
Author(s):  
Paul G. Ambrose ◽  
Brian VanScoy ◽  
Haley Conde ◽  
Jennifer McCauley ◽  
Christopher M. Rubino ◽  
...  
Keyword(s):  
Antimicrobial Therapy ◽  
Antimicrobial Agents ◽  
Infection Model ◽  
Replication Rate ◽  
Model Studies ◽  
Concentration Time ◽  
Bactericidal Effects ◽  
The Media ◽  
Bacterial Replication

ABSTRACT A major clinical challenge for treating infectious diseases is the duration of antimicrobial therapy required to eradicate the pathogen. We hypothesized that modulation of the bacterial replication rate in the context of an antimicrobial exposure is coupled with the rate and extent of bactericidal effects. Herein we describe results from in vitro infection model (one compartment, 24-h model; hollow fiber, 10-day model) studies designed to probe the relationship between the bacterial replication rate and the rate and extent of bactericidal effects in the context of an effective antibiotic exposure. The bacterial replication rate was modulated by adjusting the sodium chloride concentration (0 to 8%) in the growth media (Mueller-Hinton II broth). The study drug selected was levofloxacin, and the challenge isolate was Staphylococcus aureus ATCC 29213 (levofloxacin MIC, 0.125 mg/liter). Within each in vitro infection model, human levofloxacin concentration-time profiles (half-life, 7 h) were simulated and the challenge isolate was subjected to an effective exposure (free-drug area under the concentration-time curve over 24 h divided by the MIC [AUC/MIC ratio], 65; administered as a single dose or daily for 10 days). Over the course of each study, samples were taken from each model for bacterial density determinations and drug concentration assay using liquid chromatography-tandem mass spectrometry (LC-MS/MS). In the 24-h one-compartment in vitro infection model studies, as the bacterial replication rate increased, so too did the rate (slope, 0 to 4 h) and extent (24-h CFU count per milliliter) of bacterial killing. In the 10-day hollow-fiber infection model studies, the times until a reduction of bacterial density to 1 × 102 CFU/ml occurred were 10 days in the media in which the challenge isolate grew slowly and approximately 2 days in the media in which the challenge isolate grew rapidly. Together, these data provide a proof of concept for new adjunctive therapeutic options with respect to the use of antimicrobial agents alone that reduce treatment durations. Such adjunctive therapies hold promise for marked reductions in the tonnage of antimicrobial agents administered to patient populations and selection pressure toward antimicrobial resistance.

scholarly journals Determination of the In Vivo Pharmacodynamic Profile of Cefepime against Extended-Spectrum-Beta-Lactamase-Producing Escherichia coli at Various Inocula

2004 ◽  
Vol 48 (6) ◽  
pp. 1941-1947 ◽  
Author(s):  
Dana Maglio ◽  
Christine Ong ◽  
Mary Anne Banevicius ◽  
Qiuming Geng ◽  
Charles H. Nightingale ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Infection Model ◽  
Extended Spectrum Beta Lactamase ◽  
E Coli ◽  
Extended Spectrum ◽  
Pharmacodynamic Profile ◽  
Significant Difference ◽  
Bactericidal Effects

ABSTRACT Cefepime was evaluated in vivo against two inoculum sizes of four strains of Escherichia coli that produced extended-spectrum beta-lactamases (ESBLs) in a murine neutropenic thigh infection model to characterize the pharmacodynamic activity of cefepime in the presence of ESBL-producing bacteria and to evaluate if differences in lengths of cefepime exposure are required with various inocula. Three strains possessed a single enzyme each: TEM-10, TEM-12, and TEM-26. The fourth strain possessed two TEM-derived ESBLs and a third uncharacterized enzyme. Two non-ESBL-producing E. coli strains were included for comparison. Mice received various doses of cefepime to achieve a spectrum of percentages of time the drug was above the MIC (%T>MICs) for each isolate at both inocula. No significant difference in cefepime exposure was required to achieve similar bactericidal effects for ESBL- and non-ESBL-producing isolates when the starting inoculum was 105 CFU of E. coli per thigh. The increased MICs observed in vitro for the ESBL-producing strains at 107 CFU/ml did not predict the amount of exposure required to achieve a comparable level of bactericidal activity in vivo at the corresponding starting inoculum of 107 CFU/thigh. Compared to the cefepime exposure in tests with the lower inoculum (105 CFU/thigh), less exposure was required when the starting inoculum was 107 CFU/thigh (%T>MIC, 6% versus 26%), such that similar doses (in milligrams per kilogram of body weight) produced similar bactericidal effects with both inocula of ESBL-producing isolates. Equivalent exposures of cefepime produced similar effects against the microorganisms regardless of the presence of ESBL production. Pharmacodynamic profiling undertaken with conventional cefepime MIC determinations predicted in vivo microbial outcomes at both inoculum sizes for the ESBL-producing isolates evaluated in this study. These data support the use of conventional MIC determinations in the pharmacodynamic assessment of cefepime.

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