Predictors of bacterial resistance usingin vitrodynamic models: area under the concentration–time curve related to either the minimum inhibitory or mutant prevention antibiotic concentration

Pseudomonas aeruginosa ATCC 27853 was exposed to tobramycin concentration-time profiles modelling in vivo bolus and infusion dosing. Dependence of bactericidal and bacteriostatic activity on the initial profile of peak concentration (bolus effect > infusion) and area under the antibiotic concentration-time curve was observed at peak concentration/MIC ratios of 10 or below.

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Pharmacokinetics and pharmacodynamics of enrofloxacin treatment of Escherichia coli in a murine thigh infection modeling

BMC Veterinary Research ◽

10.1186/s12917-021-02908-8 ◽

2021 ◽

Vol 17 (1) ◽

Author(s):

Xuesong Liu ◽

Qingwen Yang ◽

Yuying Fan ◽

Yuanyi Du ◽

Lei Lei ◽

...

Keyword(s):

Bacterial Resistance ◽

Compartmental Analysis ◽

Clinical Applications ◽

Infection Model ◽

Antibacterial Drug ◽

Log10 Reduction ◽

Time Curve ◽

E Coli ◽

Concentration Time ◽

Target Values

Abstract Background Enrofloxacin is an antibacterial drug with broad-spectrum activity that is widely indicated for veterinary use. We aim to develop the clinical applications of Enrofloxacin against colibacillosis by using the neutropenic mice thigh infection model. Results The minimum inhibitory concentration (MIC) distribution of 67 isolated E. coli strains to ENR was calculated using CLSI guidelines. Whereas, the MIC50 value calculation was considered as the population PD parameter for ENR against E. coli strains. The MIC values of 15 E. coli strains were found to be nearest to the MIC50 i.e., 0.25 μg/mL. Of all the tested strains, the PK-PD and E. coli disease model was established via selected E. coli strain i.e., Heilong 15. We analyzed the PK characteristics of ENR and its metabolite ciprofloxacin (CIP) following a single subcutaneous (s.c.) injection of ENR (1.25, 2.5, 5, 10 mg/kg). The concentration-time profiling of ENR within the plasma specimens was determined by considering the non-compartmental analysis (NCA). The basic PK parameters of ENR for the peak drug concentration (Cmax) and the area under the concentration-time curve (AUC) values were found to be in the range of 0.27–1.97 μg/mL and 0.62–3.14 μg.h/mL, respectively. Multiple s.c. injection over 24 h (1.25, 2.5, 5, 10 mg/kg at various time points i.e., 6, 8, 12, and 24 h respectively) were administered to assess the targeted PD values. The Akaike Information Criterion (AIC) was used to choose PD models, and the model with the lowest AIC was chosen. The inhibitory Emax model was employed to calculate the related PK-PD parameters. The results of our study indicated that there was a strong correlation between the AUC/MIC and various antibacterial activities (R2 = 0.9928). The target values of dividing AUC/MIC by 24 h for bacteriostatic action were 1-log10 reduction, 2-log10 reduction, and 3-log10 reduction 0.325, 0.4375, 0.63, and 0.95 accordingly. Conclusion The identified pharmacodynamics targets for various antibacterial effects will be crucial in enhancing ENR clinical applications and serving as a key step in reducing bacterial resistance.

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A Comparative Pharmacokinetic Profile of Trahydropalmatine After Oral Administration of its Monomer, Rhizoma Corydalis Alkaloid Extracts and Tong-Bi-Si-Wei-Fang to Rats

Current Pharmaceutical Analysis ◽

10.2174/1573412914666180314122512 ◽

2019 ◽

Vol 15 (4) ◽

pp. 338-345

Author(s):

Lijun Ni ◽

Lu Ding ◽

Liguo Zhang ◽

Shaorong Luan

Keyword(s):

Oral Administration ◽

Panax Notoginseng ◽

Pharmacokinetic Profile ◽

Apparent Volume ◽

Bone Diseases ◽

Glycyrrhiza Uralensis ◽

Pharmacokinetic Property ◽

Time Curve ◽

Concentration Time

Background: Tong-Bi-Si-Wei-Fang (TBSWF) is a candidate formula of Traditional Chinese Medicine (TCM) for treating rheumatoid bone diseases, which is composed of rhizoma corydalis alkaloids, saponins of glycyrrhiza uralensis and panax notoginseng, flavonoids of rhizoma drynariae and glycyrrhiza uralensis. </P><P> Objective: Trahydropalmatine (THP), the main active ingredient of rhizoma corydalis alkaloids, was selected to study in vivo pharmacokinetics and druggability of TBSWF. Methods: The plasma concentration-time (C-T) profiles of THP and the pharmacokinetic property parameters after oral administration of THP monomer, extract of corydalis alkaloids (ECA) and TBSWF to rats, respectively were compared by a fully-validated HPLC method. Results: Compared to the THP monomer, the THP in TBSWF is absorbed faster, resides in the plasma longer and has a similar apparent volume of distribution Vz/F (10~20 L/kg). Compared to THP monomer and THP in TBSWF, the area under the concentration-time curve AUC 0-t of THP in ECA decreases two-third; Vz/F of THP in ECA (85.02 L/kg) is significantly higher than that of THP in TBSWF(p <0.05). Unlike THP monomer and THP in ECA, double peaks are observed in the C-T profile of THP after oral administration of TBSWF. THP in TBSWF exhibits slow release to a certain degree. Conclusion: The interactions among the ingredients of TBSWF promote the adsorption and prolong the residence time of THP in vivo, and provide an explanation for the advantages of TBSWF from the point of pharmacokinetics.

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Impact of Local Liver Irradiation Concurrent Versus Sequential with Lenvatinib on Pharmacokinetics and Biodistribution

Cancers ◽

10.3390/cancers13071598 ◽

2021 ◽

Vol 13 (7) ◽

pp. 1598

Author(s):

Tung-Hu Tsai ◽

Yu-Jen Chen ◽

Li-Ying Wang ◽

Chen-Hsi Hsieh

Keyword(s):

Radiation Therapy ◽

Rat Model ◽

Systemic Therapy ◽

Stereotactic Body Radiation Therapy ◽

Time Curve ◽

Stereotactic Body Radiation ◽

Concentration Time ◽

Sequential Regimen ◽

Freely Moving

Concurrent and sequential regimens involving radiotherapy (RT) and lenvatinib were designed with off-target or stereotactic body radiation therapy (SBRT) doses in a freely moving rat model to evaluate the effect of RT on the pharmacokinetics (PK) of lenvatinib. Liver RT concurrent with lenvatinib decreased the area under the concentration–time curve of lenvatinib concentration (AUClenvatinib) by 51.1% with three fractions of 2 Gy (RT2Gy×3f’x, p = 0.03), and 48.9% with RT9Gy×3f’x (p = 0.03). The AUClenvatinib increased by 148.8% (p = 0.008) with RT2Gy×3f’x, and 68.9% (p = 0.009) with RT9Gy×3f’x in the sequential regimen compared to the concurrent regimen. There were no differences in the AUClenvatinib between RT2Gy×3f’x and RT9Gy×3f’x in the concurrent or sequential regimen. Both the RT2Gy×3f’x and RT9Gy×3f’x concurrent regimens markedly decreased the biodistribution of lenvatinib in the heart, liver, lung, spleen, and kidneys, which ranged from 31% to 100% for RT2Gy×3f’x, and 11% to 100% for RT9Gy×3f’x, compared to the sham regimen. The PK and biodistribution of lenvatinib can be modulated by simultaneous off-target irradiation and SBRT doses. The timing of lenvatinib administration with respect to RT, impacted the PK and biodistribution of the drug. Additionally, off-target and SBRT doses had a similar ability to modulate the effect of systemic therapy.

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Effectiveness of a vancomycin dosing protocol guided by area under the concentration-time curve to minimal inhibitory concentration (AUC/MIC) with multidisciplinary team support to improve hospital-wide adherence to a vancomycin dosing protocol: A pilot study

Infection Control and Hospital Epidemiology ◽

10.1017/ice.2021.296 ◽

2021 ◽

pp. 1-6

Author(s):

Panipak Katawethiwong ◽

Anucha Apisarnthanarak ◽

Kittiya Jantarathaneewat ◽

David J. Weber ◽

David K. Warren ◽

...

Keyword(s):

Mortality Rate ◽

Multidisciplinary Team ◽

Kidney Injury ◽

University Hospital ◽

Routine Practice ◽

Post Intervention ◽

Coagulase Negative Staphylococci ◽

Time Curve ◽

Concentration Time ◽

Quasi Experimental

Abstract Background: Limited data are available on the implementation of an area under the concentration-time curve (AUC)–based dosing protocol with multidisciplinary team (MT) support to improve adherence with vancomycin dosing protocol. Objective: To evaluate the effectiveness of an AUC-based dosing protocol with MT support intervention with adherence to a hospital-wide vancomycin dosing protocol at Thammasat University Hospital. Method: We conducted a quasi-experimental study in patients who were prescribed intravenous vancomycin. The study was divided into 2 periods; (1) the preintervention period when the vancomycin dosing protocol was already applied in routine practice and (2) the post-intervention period when the implementation of an AUC-based dosing protocol with MT support was added to the existing vancomycin dosing protocol. The primary outcome was the rate of adherence, and the secondary outcomes included acute kidney injury events, vancomycin-related adverse events, and 30-day mortality rate. Results: In total, 240 patients were enrolled. The most common infections were skin and soft-tissue infections (24.6%) and bacteremia (24.6%). The most common pathogens were coagulase-negative staphylococci (19.6%) and Enterococcus spp (15.4%). Adherence with the vancomycin dosing protocol was significantly higher in the postintervention period (90.8% vs 55%; P ≤ .001). By multivariate analysis, an AUC-based dosing protocol with MT support was the sole predictor for adherence with the vancomycin dosing protocol (adjusted odds ratio, 10.31; 95% confidence interval, 4.54–23.45; P ≤ .001). The 30-day mortality rate was significantly lower during the postintervention period (8.3% vs 20%; P = .015). Conclusions: AUC-based dosing protocol with MT support significantly improved adherence with vancomycin dosing protocol and was associated with a lower 30-day mortality rate.

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Evidence for Establishing the Clinical Breakpoint of Cefquinome against Haemophilus Parasuis in China

Pathogens ◽

10.3390/pathogens10020105 ◽

2021 ◽

Vol 10 (2) ◽

pp. 105

Author(s):

Kun Mi ◽

Da Sun ◽

Mei Li ◽

Haihong Hao ◽

Kaixiang Zhou ◽

...

Keyword(s):

Monte Carlo Simulation ◽

Antibacterial Activity ◽

Inhibitory Concentration ◽

High Morbidity ◽

Haemophilus Parasuis ◽

Wild Type ◽

Time Curve ◽

Resistance Change ◽

Concentration Time ◽

Clinical Experiments

Haemophilus parasuis can cause high morbidity and mortality in swine. Cefquinome possesses excellent antibacterial activity against pathogens causing diseases of the respiratory tract. This study aimed to establish the clinical breakpoint (CBP) of cefquinome against H. parasuis and to monitor the resistance change. Referring to the minimum inhibitory concentration (MIC) distribution of cefquinome against 131 H. parasuis isolates, the MIC50 and MIC90 were determined to be 0.125 and 1 μg/mL, respectively. And the epidemiological cutoff (ECOFF) value was 1 μg/mL. HPS42 was selected as a representative strain for the pharmacodynamic (PD) experiment, pharmacokinetic (PK) experiment and clinical experiments. The PK/PD index values, area under concentration-time curve (AUC)/MIC, of the bacteriostatic, bactericidal, and bacterial elimination effects were 23, 41, and 51 h, respectively. The PK/PD cutoff was calculated as 0.125 μg/mL by Monte Carlo simulation (MCS), and the clinical cutoff was 0.25−4 μg/mL by WindoW. Combing these three values, the CBP of cefquinome against H. parasuis was found to be 1 μg/mL. In conclusion, this was the first study to integrate various cutoffs to establish the CBP in the laboratory. It is helpful to distinguish wild type H. parasuis and reduce the probability of treatment failure.

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1326. Vancomycin Area Under the Concentration-Time Curve (AUC) Estimation Using a Bayesian Approach Versus First-Order Pharmacokinetic Equations: A Pilot Study

Open Forum Infectious Diseases ◽

10.1093/ofid/ofaa439.1508 ◽

2020 ◽

Vol 7 (Supplement_1) ◽

pp. S673-S673

Author(s):

Jeffrey Pearson ◽

Yazed S Alsowaida ◽

B S Pharm ◽

David W Kubiak ◽

Mary P Kovacevic ◽

...

Keyword(s):

Pilot Study ◽

Median Time ◽

Bayesian Modeling ◽

Surgical Prophylaxis ◽

Time Curve ◽

Team Members ◽

First Order ◽

Concentration Time ◽

Study Team ◽

Auc Estimation

Abstract Background Current guidelines endorse area under the concentration-time curve (AUC)-based monitoring over trough-only monitoring for systemic vancomycin. Vancomycin AUC can be estimated using either Bayesian modeling software or first-order pharmacokinetic (PK) calculations. The objective of this pilot study was to evaluate and compare the efficiency and feasibility of these two approaches for calculating the estimated vancomycin AUC. Methods A single-center crossover study was conducted in four medical/surgical units at Brigham and Women’s Hospital over a 3-month time period. All adult patients who received vancomycin were included. Patients were excluded if they were receiving vancomycin for surgical prophylaxis, were on hemodialysis, if vancomycin was being dosed by level, or if vancomycin levels were never drawn. The primary endpoint was the amount of time study team members spent calculating the estimated AUC and determining regimen adjustments with Bayesian modeling compared to first-order PK calculations. Secondary endpoints included the number of vancomycin levels drawn and the percent of those drawn that were usable for AUC calculations. Results One hundred twenty-four patients received vancomycin during the study, of whom 47 met inclusion criteria. The most likely reasons for exclusion were receiving vancomycin for surgical prophylaxis (n=40) or never having vancomycin levels drawn (n=32). The median time taken to assess levels in the Bayesian arm was 9.3 minutes [interquartile range (IQR) 7.8-12.4] versus 6.8 minutes (IQR 4.8-8.0) in the 2-level PK arm (p=0.004). However, if Bayesian software is integrated into the electronic health record (EHR), the median time to assess levels was 3.8 minutes (IQR 2.3-6.8, p=0.019). In the Bayesian arm, 30 of 34 vancomycin levels (88.2%) were usable for AUC calculations, compared to 28 of 58 (48.3%) in the 2-level PK arm. Conclusion With EHR integration, the use of Bayesian software to calculate the AUC was more efficient than first-order PK calculations. Additionally, vancomycin levels were more likely to be usable in the Bayesian arm, thereby avoiding delays in estimating the vancomycin AUC. Disclosures All Authors: No reported disclosures

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Ginsenoside Absorption Rate and Extent Enhancement of Black Ginseng (CJ EnerG) over Red Ginseng in Healthy Adults

Pharmaceutics ◽

10.3390/pharmaceutics13040487 ◽

2021 ◽

Vol 13 (4) ◽

pp. 487

Author(s):

Saebyul Yoo ◽

Bom-I Park ◽

Do-hyun Kim ◽

Sooyoung Lee ◽

Seung-hoon Lee ◽

...

Keyword(s):

Clinical Trial ◽

Molecular Weight ◽

Absorption Rate ◽

Systemic Exposure ◽

Red Ginseng ◽

Double Blind ◽

Time Curve ◽

Concentration Time ◽

Black Ginseng ◽

Clinically Significant

Red ginseng (RG) and black ginseng (BG, CJ EnerG) were prepared from fresh ginseng using one and nine cycles of steaming and drying, respectively. This process reduces the molecular weight (MW) of ginsenoside-active compounds in ginseng by removing sugar moieties from their dammaranes. We compared the pharmacokinetic characteristics of ginsenosides between BG comprising mainly low-MW ginsenosides (Rg3, Rg5, Rk1, and Rh1) and RG that predominantly contains high-MW ginsenosides (Rb1, Rb2, Rc, Rd, Re, and Rg1). The safety profiles and tolerability were also studied using a randomized, double-blind, single-dose, crossover clinical trial. A combination of Rb1, Rg1, and Rg3, well-known representative and functional RG components, exhibited a 1-h faster absorption rate (Tmax) and 58% higher exposure (24-h area under the concentration–time curve, AUC24) in BG than in RG. Furthermore, the combination of Rg3, Rg5, and Rk1, the major and most efficient components in BG, displayed 824% higher absorption (AUC24) in BG than in RG. The total ginsenoside showed a 5-h rapid intestinal absorption (Tmax) and 79% greater systemic exposure (AUC24) in BG than in RG. No clinically significant findings were observed in terms of safety or tolerability. Thus, BG extract was more effective than RG extract.

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Pharmacodynamics of Daptomycin against Enterococcus faecium and Enterococcus faecalis in the Murine Thigh Infection Model

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00506-18 ◽

2018 ◽

Vol 62 (10) ◽

Cited By ~ 9

Author(s):

James M. Kidd ◽

Kamilia Abdelraouf ◽

Tomefa E. Asempa ◽

Romney M. Humphries ◽

David P. Nicolau

Keyword(s):

Enterococcus Faecalis ◽

Enterococcus Faecium ◽

Hill Equation ◽

Infection Model ◽

Free Drug Concentration ◽

Time Curve ◽

Content Type ◽

Concentration Time ◽

The Hill ◽

Susceptibility Breakpoint

ABSTRACT The Clinical and Laboratory Standards Institute (CLSI) daptomycin MIC susceptibility breakpoint for the treatment of enterococcal infections is ≤4 μg/ml. However, patients receiving daptomycin for the treatment of infections caused by enterococci with MICs of ≤4 μg/ml may experience treatment failures. We assessed the pharmacodynamics of daptomycin against enterococci in a neutropenic murine thigh infection model and determined the exposures necessary for bacteriostasis and a 1-log10-CFU reduction of Enterococcus faecalis and Enterococcus faecium. We further characterized daptomycin efficacy at clinically achievable exposures. Six E. faecium and 6 E. faecalis isolates (daptomycin MICs, 0.5 to 32 μg/ml) were studied. Daptomycin was administered at various doses over 24 h to achieve area under the free drug concentration-time curve-to-MIC ratios (fAUC0–24/MIC) ranging from 1 to 148. Daptomycin regimens that simulate mean human exposures following doses of 6, 8, and 10 mg/kg of body weight/day were also studied. Efficacy was assessed by the differences in the number of log10 CFU per thigh at 24 h. The Hill equation was used to estimate the fAUC0–24/MIC required to achieve bacteriostasis and a 1-log10-CFU reduction. For E. faecium, a 1-log10-CFU reduction required an fAUC0–24/MIC of 12.9 (R2 = 0.71). For E. faecalis, a 1-log10-CFU reduction was not achieved, while the fAUC0–24/MIC required for stasis was 7.2 (R2 = 0.8). With a human-simulated regimen of 6 mg/kg/day, a 1-log10-CFU reduction was observed in 3/3 E. faecium isolates with MICs of <4 μg/ml and 0/3 E. faecium isolates with MICs of ≥4 μg/ml; however, a 1-log10-CFU reduction was not achieved for any of the 6 E. faecalis isolates. These results, alongside clinical data, prompt a reevaluation of the current breakpoint.

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Voriconazole Pharmacokinetics and Safety in Immunocompromised Children Compared to Adult Patients

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01731-09 ◽

2010 ◽

Vol 54 (8) ◽

pp. 3225-3232 ◽

Cited By ~ 50

Author(s):

Claudia Michael ◽

Uta Bierbach ◽

Katrin Frenzel ◽

Thoralf Lange ◽

Nadezda Basara ◽

...

Keyword(s):

Pediatric Patients ◽

Fungal Infections ◽

Adult Patients ◽

European Medicines Agency ◽

Pharmacokinetic Parameters ◽

Time Curve ◽

Entire Study ◽

Interindividual Variations ◽

Concentration Time ◽

Days Of Therapy

ABSTRACT The aim of this study was to investigate the pharmacokinetics and safety of voriconazole after intravenous (i.v.) administration in immunocompromised children (2 to 11 years old) and adults (20 to 60 years old) who required treatment for the prevention or therapy of systemic fungal infections. Nine pediatric patients were treated with a dose of 7 mg/kg i.v. every 12 h for a period of 10 days. Three children and 12 adults received two loading doses of 6 mg/kg i.v. every 12 h, followed by a maintenance dose of 5 mg/kg (children) or 4 mg/kg (adults) twice a day during the entire study period. Trough voriconazole levels in blood over 10 days of therapy and regular voriconazole levels in blood for up to 12 h postdose on day 3 were examined. Wide intra- and interindividual variations in plasma voriconazole levels were noted in each dose group and were most pronounced in the children receiving the 7-mg/kg dose. Five (56%) of them frequently had trough voriconazole levels in plasma below 1 μg/ml or above 6 μg/ml. The recommended dose of 7 mg/kg i.v. in children provides exposure (area under the concentration-time curve) comparable to that observed in adults receiving 4 mg/kg i.v. The children had significantly higher C max values; other pharmacokinetic parameters were not significantly different from those of adults. Voriconazole exhibits nonlinear pharmacokinetics in the majority of children. Voriconazole therapy was safe and well tolerated in pediatric and adult patients. The European Medicines Agency-approved i.v. dose of 7 mg/kg can be recommended for children aged 2 to <12 years.

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