scholarly journals Optimal Regimens and Cutoff Evaluation of Ceftiofur Against Actinobacillus pleuropneumoniae in Swine

2020 ◽  
Author(s):  
Da Sun ◽  
Kun Mi ◽  
Haihong Hao ◽  
Shuyu Xie ◽  
Dongmei Chen ◽  
...  
Keyword(s):  
Monte Carlo Simulation ◽  
Monte Carlo ◽  
Ex Vivo ◽  
Actinobacillus Pleuropneumoniae ◽  
Cutoff Value ◽  
Gram Positive Bacteria ◽  
Cephalosporin Antibiotic ◽  
Emergence Of Resistance ◽  
Better Than

Abstract BackgroundActinobacillus pleuropneumoniae, formerly known as Haemophilus pleuropneumoniae, can cause pleuropneumoniae in pigs of different ages, leading to significant mortality. Ceftiofur was the first cephalosporin antibiotic used in animals that was effective against gram-negative and gram-positive bacteria. This study aimed to determine the breakpoint of ceftiofur against Actinobacillus pleuropneumoniae based on the investigation of the epidemiologic cutoff value (ECV), and pharmacodynamic-pharmacokinetic breakpoint.ResultsThe epidemiologic cutoff value was 0.125 µg/mL. The results of the pharmacodynamic study showed that the MICs of BW39 were 0.5 µg/mL and 1 µg/mL under in vitro and ex-vivo conditions, respectively, and the minimal bactericidal concentrations (MBCs) under in vitro and ex vivo conditions were both 1 µg/mL. The time-killing profiles of ceftiofur against BW39 were time-dependent. According to the inhibitory sigmoid Emax model, the AUC24 h/MIC values for the bacteriostatic, bactericidal, and elimination effects in serum were 45.73, 63.83, and 69.04 h for healthy pigs, respectively. Based on the Monte Carlo simulation, the COPD was calculated as 2 µg/mL, and the optimized dosage regimen of ceftiofur against Actinobacillus pleuropneumoniae to achieve bacteriostatic, bactericidal, and elimination effects over 24 h was 2.13, 2.97, and 3.42 mg/kg for the 50% target attainment rate (TAR) and 2.47, 3.21, and 3.70 mg/kg for the 90% TAR, respectively.ConclusionsIn this study, the epidemiologic cutoff value was 0.125 µg/mL, as calculated by ECOFFinder software. According to the PK/PD evaluation in vitro and ex vivo, the value of the pharmacodynamics cutoff was 2 µg/mL, as obtained by Monte Carlo simulation. The COPD suggested that the breakpoint could be better than the COWT value because COPD derived from PL/PD data was obtained in vitro and ex vivo, which was more significant. According to the PK/PD parameters, the single bactericidal dose was 3.21 mg/kg for the 90% target, which would be more available to cure Actinobacillus pleuropneumoniae and avoid the emergence of resistance for clinical ceftiofur use.

scholarly journals Optimal regimens regimens based on PK/PD cutoff evaluation of ceftiofur against Actinobacillus pleuropneumoniae in swine

2020 ◽  
Author(s):  
Da Sun ◽  
Kun Mi ◽  
Haihong Hao ◽  
Shuyu Xie ◽  
Dongmei Chen ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Actinobacillus Pleuropneumoniae ◽  
Time Dependent ◽  
Target Attainment ◽  
Cutoff Value ◽  
Gram Positive Bacteria ◽  
Cephalosporin Antibiotic ◽  
Emergence Of Resistance ◽  
Significant Mortality

Abstract Background Actinobacillus pleuropneumoniae , formerly known as Haemophilus pleuropneumoniae , can cause pleuropneumoniae in pigs of different ages, leading to significant mortality. Ceftiofur was the first cephalosporin antibiotic used in animals that was effective against gram-negative and gram-positive bacteria. This study aimed to determine epidemiologic cutoff value (ECV), and pharmacodynamic-pharmacokinetic cutoff. Establishing Clinical breakpoint of ceftiofur against Actinobacillus pleuropneumoniae based on the pharmacodynamic-pharmacokinetic cutoff. Results The epidemiologic cutoff value was 0.125 μg/mL. The results of the pharmacodynamic study showed that the MICs of BW39 were 0.5 μg/mL and 1 μg/mL under in vitro and ex-vivo conditions, respectively, and the minimal bactericidal concentrations (MBCs) under in vitro and ex vivo conditions were both 1 μg/mL. The time-killing profiles of ceftiofur against BW39 were time-dependent with a partly concentration-dependent pattern. According to the inhibitory sigmoid E max model, the AUC 24 h /MIC values for the bacteriostatic, bactericidal, and elimination effects in serum were 45.73, 63.83, and 69.04 h for healthy pigs, respectively. Based on the Monte Carlo simulation, the CO PD was calculated as 2 μg/mL, and the optimized dosage regimen of ceftiofur against Actinobacillus pleuropneumoniae to achieve bacteriostatic, bactericidal, and elimination effects over 24 h was 2.13, 2.97, and 3.42 mg/kg for the 50% target attainment rate (TAR) and 2.47, 3.21, and 3.70 mg/kg for the 90% TAR, respectively. Conclusions In conclusion, we reveal the EOFF and PK/PD cutoff values of ceftiofur against A. pleuropneumoniae in piglets. However, with the paucity of clinical data for ceftiofur to establish a clinical cutoff against A. pleuropneumoniae, the PK/PD cutoff value of 2 μg/mL will be recommended as surrogate. According to the PK/PD data and the MIC distribution in China, the single bactericidal dose was 3.21 mg/kg for the 90% target, which would be more able to cure Actinobacillus pleuropneumoniae and avoid the emergence of resistance for clinical ceftiofur use of ceftiofur in piglet.

scholarly journals Optimal regimens regimens based on PK/PD cutoff evaluation of ceftiofur against Actinobacillus pleuropneumoniae in swine

2020 ◽  
Author(s):  
Da Sun ◽  
Kun Mi ◽  
Haihong Hao ◽  
Shuyu Xie ◽  
Dongmei Chen ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Actinobacillus Pleuropneumoniae ◽  
Positive Bacterium ◽  
Target Attainment ◽  
Recommended Dosage ◽  
Cutoff Value ◽  
Cephalosporin Antibiotic ◽  
Emergence Of Resistance ◽  
Significant Mortality

Abstract Background Actinobacillus pleuropneumoniae formerly known as Haemophilus pleuropneumoniae, can cause pleuropneumoniae in pigs, which lead to significant mortality. Ceftiofur was the first cephalosporin antibiotic used in animals，which was effective against gram-negative and gram-positive bacterium. This study aimed to formulate a rational dosage strategy and review the preceding recommended dosage based on PK/PD modeling and Establish Clinical breakpoint of ceftiofur against Actinobacillus pleuropneumoniae based on the pharmacodynamic-pharmacokinetic cutoff. Results The epidemiologic cutoff value was 0.125 μg/mL. The results of the pharmacodynamic study showed that the MICs of BW39 were 0.5 μg/mL and 1 μg/mL in vitro and ex-vivo, respectively. The minimal bactericidal concentrations (MBCs) under in vitro and ex vivo conditions were both 1 μg/mL. The time-killing profiles of ceftiofur against BW39 were time-dependent with a partly concentration-dependent pattern. Based on the inhibitory sigmoid Emax model, the AUC24 h/MIC values for the bacteriostatic, bactericidal, and elimination effects in serum were 45.73, 63.83, and 69.04 h for healthy pigs separately. According to the Monte Carlo simulation, the COPD was calculated as 2 μg/mL, and the optimized dosage regimen of ceftiofur against Actinobacillus pleuropneumoniae to achieve bacteriostatic, bactericidal, and elimination effects over 24 h was 2.13, 2.97, and 3.42 mg/kg for the 50% target attainment rate (TAR) and 2.47, 3.21, and 3.70 mg/kg for the 90% TAR respectively.Conclusions In conclusion, we reveal the EOFF and PK/PD cutoff values of ceftiofur against A. pleuropneumoniae in piglets. However, with the paucity of clinical data for ceftiofur to establish a clinical cutoff against A. pleuropneumoniae, the PK/PD cutoff value of 2 μg/mL will be recommended as surrogate. According to the PK/PD data and the MIC distribution in China, the single bactericidal dose was 3.21 mg/kg for the 90% target, which would be more able to cure Actinobacillus pleuropneumoniae and avoid the emergence of resistance for clinical ceftiofur use in piglet.

scholarly journals Optimal regimens regimens based on PK/PD cutoff evaluation of ceftiofur against Actinobacillus pleuropneumoniae in swine

2020 ◽  
Author(s):  
Da Sun ◽  
Kun Mi ◽  
Haihong Hao ◽  
Shuyu Xie ◽  
Dongmei Chen ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Actinobacillus Pleuropneumoniae ◽  
Positive Bacterium ◽  
Target Attainment ◽  
Recommended Dosage ◽  
Cutoff Value ◽  
Cephalosporin Antibiotic ◽  
Emergence Of Resistance ◽  
Significant Mortality

Abstract BackgroundActinobacillus pleuropneumoniae formerly known as Haemophilus pleuropneumoniae, can cause pleuropneumoniae in pigs, which lead to significant mortality. Ceftiofur was the first cephalosporin antibiotic used in animals，which was effective against gram-negative and gram-positive bacterium. This study aimed to formulate a rational dosage strategy and review the preceding recommended dosage based on PK/PD modeling and Establish Clinical breakpoint of ceftiofur against Actinobacillus pleuropneumoniae based on the pharmacodynamic-pharmacokinetic cutoff. ResultsThe epidemiologic cutoff value was 0.125 μg/mL. The results of the pharmacodynamic study showed that the MICs of BW39 were 0.5 μg/mL and 1 μg/mL in vitro and ex-vivo, respectively. The minimal bactericidal concentrations (MBCs) under in vitro and ex vivo conditions were both 1 μg/mL. The time-killing profiles of ceftiofur against BW39 were time-dependent with a partly concentration-dependent pattern. Based on the inhibitory sigmoid Emax model, the AUC24 h/MIC values for the bacteriostatic, bactericidal, and elimination effects in serum were 45.73, 63.83, and 69.04 h for healthy pigs separately. According to the Monte Carlo simulation, the COPD was calculated as 2 μg/mL, and the optimized dosage regimen of ceftiofur against Actinobacillus pleuropneumoniae to achieve bacteriostatic, bactericidal, and elimination effects over 24 h was 2.13, 2.97, and 3.42 mg/kg for the 50% target attainment rate (TAR) and 2.47, 3.21, and 3.70 mg/kg for the 90% TAR respectively.ConclusionsIn conclusion, we reveal the EOFF and PK/PD cutoff values of ceftiofur against A. pleuropneumoniae in piglets. However, with the paucity of clinical data for ceftiofur to establish a clinical cutoff against A. pleuropneumoniae, the PK/PD cutoff value of 2 μg/mL will be recommended as surrogate. According to the PK/PD data and the MIC distribution in China, the single bactericidal dose was 3.21 mg/kg for the 90% target, which would be more able to cure Actinobacillus pleuropneumoniae and avoid the emergence of resistance for clinical ceftiofur use in piglet.

scholarly journals Optimal regimens based on PK/PD cutoff evaluation of ceftiofur against Actinobacillus pleuropneumoniae in swine

2020 ◽  
Vol 16 (1) ◽  
Author(s):  
Da Sun ◽  
Kun Mi ◽  
Haihong Hao ◽  
Shuyu Xie ◽  
Dongmei Chen ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Actinobacillus Pleuropneumoniae ◽  
Positive Bacterium ◽  
Target Attainment ◽  
Recommended Dosage ◽  
Cutoff Value ◽  
Cephalosporin Antibiotic ◽  
Emergence Of Resistance ◽  
Significant Mortality

Abstract Background Actinobacillus pleuropneumoniae formerly known as Haemophilus pleuropneumoniae, can cause pleuropneumoniae in pigs, which lead to significant mortality. Ceftiofur was the first cephalosporin antibiotic used in animals, which was effective against gram-negative and gram-positive bacterium. This study aimed to formulate a rational dosage strategy and review the preceding recommended dosage based on PK/PD modeling and Establish Clinical breakpoint of ceftiofur against Actinobacillus pleuropneumoniae based on the pharmacodynamic-pharmacokinetic cutoff. Results The epidemiologic cutoff value was 0.125 μg/mL. The results of the pharmacodynamic study showed that the MICs of BW39 were 0.5 μg/mL and 1 μg/mL in vitro and ex-vivo, respectively. The minimal bactericidal concentrations (MBCs) under in vitro and ex vivo conditions were both 1 μg/mL. The time-killing profiles of ceftiofur against BW39 were time-dependent with a partly concentration-dependent pattern. Based on the inhibitory sigmoid Emax model, the AUC24 h/MIC values for the bacteriostatic, bactericidal, and elimination effects in serum were 45.73, 63.83, and 69.04 h for healthy pigs separately. According to the Monte Carlo simulation, the COPD was calculated as 2 μg/mL, and the optimized dosage regimen of ceftiofur against Actinobacillus pleuropneumoniae to achieve bacteriostatic, bactericidal, and elimination effects over 24 h was 2.13, 2.97, and 3.42 mg/kg for the 50% target attainment rate (TAR) and 2.47, 3.21, and 3.70 mg/kg for the 90% TAR respectively. Conclusions In conclusion, we reveal the EOFF and PK/PD cutoff values of ceftiofur against A. pleuropneumoniae in piglets. However, with the paucity of clinical data for ceftiofur to establish a clinical cutoff against A. pleuropneumoniae, the PK/PD cutoff value of 2 μg/mL will be recommended as surrogate. According to the PK/PD data and the MIC distribution in China, the single bactericidal dose was 3.21 mg/kg for the 90% target, which would be more able to cure Actinobacillus pleuropneumoniae and avoid the emergence of resistance for clinical ceftiofur use in piglet.

BeO-OSL detectors for dose measurements in cell cultures

2009 ◽  
Vol 48 (06) ◽  
pp. 227-232
Author(s):  
D. Sommer ◽  
R. Freudenberg ◽  
U. Reichelt ◽  
J. Henniger ◽  
J. Kotzerke ◽  
...  
Keyword(s):  
Cell Culture ◽  
Monte Carlo Simulation ◽  
Monte Carlo ◽  
Cell Cultures ◽  
Rate Sensitivity ◽  
Culture Vessel ◽  
Qualitative Properties ◽  
Dose Profile ◽  
Ambient Lighting

Summary Aim: The absorbed dose is an important parameter in experiments involving irradiation of cells in vitro with unsealed radionuclides. Typically, this is estimated with a model calculation, although the results thus obtained cannot be verified. Generally used real-time measurement methods are not applicable in this setting. A new detector material with in vitro suitability is the subject of this work. Methods: Optically-stimulated luminescence (OSL) dosimeters based on beryllium oxide (BeO) were used for dose measurement in cell cultures exposed to unsealed radionuclides. Their qualitative properties (e. g. energy-dependent count rate sensitivity, fading, contamination by radioactive liquids) were determined and compared to the results of a Monte Carlo simulation (using AMOS software). OSL dosimeters were tested in common cell culture setups with a known geometry. Results: Dose reproducibility of the OSL dosimeters was ± 1.5%. Fading at room temperature was 0.07% per day. Dose loss (optically-stimulated deletion) under ambient lighting conditions was 0.5% per minute. The Monte Carlo simulation for the relative sensitivity at different beta energies provided corresponding results to those obtained with the OSL dosimeters. Dose profile measurements using a 6 well plate and 14 ml PP tube showed that the geometry of the cell culture vessel has a marked influence on dose distribution with 188Re. Conclusion: A new dosimeter system was calibrated with β-emitters of different energy. It turned out as suitable for measuring dose in liquids. The dose profile measurements obtained are suitably precise to be used as a check against theoretical dose calculations.

scholarly journals Antistaphylococcal Activity of TD-1792, a Multivalent Glycopeptide-Cephalosporin Antibiotic

2011 ◽  
Vol 56 (3) ◽  
pp. 1584-1587 ◽  
Author(s):  
Johanne Blais ◽  
Stacey R. Lewis ◽  
Kevin M. Krause ◽  
Bret M. Benton
Keyword(s):  
Staphylococcus Aureus ◽  
Multidrug Resistant ◽  
Postantibiotic Effect ◽  
Content Type ◽  
Gram Positive Bacteria ◽  
Highly Active ◽  
Antistaphylococcal Activity ◽  
Cephalosporin Antibiotic ◽  
Time Kill

ABSTRACTTD-1792 is a new multivalent glycopeptide-cephalosporin antibiotic with potent activity against Gram-positive bacteria. Thein vitroactivity of TD-1792 was tested against 527Staphylococcus aureusisolates, including multidrug-resistant isolates. TD-1792 was highly active against methicillin-susceptibleS. aureus(MIC90, 0.015 μg/ml), methicillin-resistantS. aureus, and heterogeneous vancomycin-intermediateS. aureus(MIC90, 0.03 μg/ml). Time-kill studies demonstrated the potent bactericidal activity of TD-1792 at concentrations of ≤0.12 μg/ml. A postantibiotic effect of >2 h was observed after exposure to TD-1792.

scholarly journals Combination of Pantothenamides with Vanin Inhibitors as a Novel Antibiotic Strategy against Gram-Positive Bacteria

2013 ◽  
Vol 57 (10) ◽  
pp. 4794-4800 ◽  
Author(s):  
Patrick A. M. Jansen ◽  
Pedro H. H. Hermkens ◽  
Patrick L. J. M. Zeeuwen ◽  
Peter N. M. Botman ◽  
Richard H. Blaauw ◽  
...  
Keyword(s):  
Antimicrobial Agents ◽  
Acid Synthesis ◽  
Spectrometric Analysis ◽  
Gram Positive ◽  
Content Type ◽  
Gram Positive Bacteria ◽  
New Compounds ◽  
Emergence Of Resistance ◽  
Hydrolysis Of

ABSTRACTThe emergence of resistance against current antibiotics calls for the development of new compounds to treat infectious diseases. Synthetic pantothenamides are pantothenate analogs that possess broad-spectrum antibacterial activityin vitroin minimal media. Pantothenamides were shown to be substrates of the bacterial coenzyme A (CoA) biosynthetic pathway, causing cellular CoA depletion and interference with fatty acid synthesis. In spite of their potential use and selectivity for bacterial metabolic routes, these compounds have never made it to the clinic. In the present study, we show that pantothenamides are not active as antibiotics in the presence of serum, and we found that they were hydrolyzed by ubiquitous pantetheinases of the vanin family. To address this further, we synthesized a series of pantetheinase inhibitors based on a pantothenate scaffold that inhibited serum pantetheinase activity in the nanomolar range. Mass spectrometric analysis showed that addition of these pantetheinase inhibitors prevented hydrolysis of pantothenamides by serum. We found that combinations of these novel pantetheinase inhibitors and prototypic pantothenamides like N5-Pan and N7-Pan exerted antimicrobial activityin vitro, particularly against Gram-positive bacteria (Staphylococcus aureus,Staphylococcus epidermidis,Streptococcus pneumoniae, andStreptococcus pyogenes) even in the presence of serum. These results indicate that pantothenamides, when protected against degradation by host pantetheinases, are potentially useful antimicrobial agents.

ULTRASOUND ENHANCED SKIN OPTICAL CLEARING: MICROSTRUCTURAL CHANGES

2010 ◽  
Vol 03 (03) ◽  
pp. 189-194 ◽  
Author(s):  
XIANGQUN XU ◽  
CHAOJIE SUN
Keyword(s):  
Lipid Bilayers ◽  
Ex Vivo ◽  
Skin Surface ◽  
Glycerol Solution ◽  
Porcine Skin ◽  
Intact Skin ◽  
Sem Images ◽  
Optical Clearing ◽  
Better Than

Our previous studies demonstrated the ultrasound-induced skin optical clearing enhancement with topical application of optical clearing agents on in vitro porcine skin and in vivohuman skin. The objective of this study was to investigate the possible mechanisms of the enhanced skin optical clearing by ultrasound medications. Optical clearing effects of ex vivo guinea pig abdomen skin topically applied with 60% glycerol or the combination of 60% glycerol and ultrasound were studied by optical coherence tomography (OCT). Microstructure of skin surface was examined by scanning electron microscopy (SEM). Ultrasound with a frequency of 1 MHz and a power of 0.75 W over a 3-cm probe was simultaneously applied with glycerol solution for 15 min. The combination of 60% glycerol and ultrasound results in a 19% increase in OCT 1/e light penetration depth after 30 min, which is much better than 60% glycerol alone. SEM images demonstrated that changes in skin microstructure due to the tight order of the lipid bilayers in the stratum corneum disrupted and the separation of keratinocytes by the application of ultrasound contribute to the ultrasound-enhanced intact skin optical clearing effects.

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