scholarly journals Competence Mining of Vancomycin (VAN) in the Management of Infections Due to Bacterial Strains With High VAN Minimum Inhibitory Concentrations (MICs): A Novel Dosing Strategy Based on Pharmacokinetic/Pharmacodynamic Modeling

2021 ◽  
Vol 12 ◽  
Author(s):  
Xiangqing Song ◽  
Meizi Zeng ◽  
Yi Wu ◽  
Yong Pan
Keyword(s):  
Staphylococcus Epidermidis ◽  
Pharmacodynamic Modeling ◽  
Limited Data ◽  
Bacterial Strains ◽  
Time Curve ◽  
Concentration Time ◽  
Sternal Osteomyelitis ◽  
Bacterial Pericarditis ◽  
Dosing Strategy ◽  
Old Drugs

The increasing emergence of bacterial strains with high VAN MICs (BSH–VAN–M), such as Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus, Staphylococcus epidermidis, and Streptococcus bovis, results in growing concern that VAN is not effective against these isolates. Due to the limited data on VAN against BSH–VAN–M and the application limits of drugs currently considered to be effective for BSH–VAN–M, exploration of “new usages for old drugs” is reasonable to improve and maximize the efficacy of existing antibiotics. This study aimed to construct a novel dosing strategy to mine the competence of VAN in the management of BSH–VAN–M infections. Herein, we optimized the traditional intermittent i.v. infusion (TIII) method to create an optimal two-step infusion (OTSI). With pharmacokinetic (PK)/pharmacodynamic (PD) modeling at the targeted ratio of the daily area under the concentration-time curve (AUC0–24) to the minimum inhibitory concentration (MIC) (AUC0–24/MIC) of 400, we used Monte Carlo simulations to evaluate the efficacy of 25 VAN regimens (including 15 OTSI regimens and 10 TIII regimens with daily doses of up to 6 g) to treat pneumonia, meningitis, sternal osteomyelitis, mastitis, pleuritis, bacteremia, and bacterial pericarditis resulting from isolates with MICs of ≤64 mg/L and to the current E. faecalis, E. faecium, S. aureus, S. epidermidis, and S. bovis populations with a pooled MIC distribution. Our data indicated that 4 g/day VAN, with an OTSI but not a TIII, for mastitis, pleuritis, bacteremia, and bacterial pericarditis due to isolates with MICs of ≤4 mg/L or to the current E. faecalis, S. aureus, S. epidermidis, and S. bovis populations achieved the desired PK/PD exposure at the AUC0–24/MIC target of 400. This study suggests the superiority and feasibility of OTSI relative to TIII for the competence mining of VAN against BSH–VAN–M from the perspective of PK/PD and provides a new resource for understanding how PK/PD modeling shapes the performance of VAN to meet the growing challenges of BSH–VAN–M infections.

scholarly journals Clinical Pharmacodynamic Index Identification for Micafungin in Esophageal Candidiasis: Dosing Strategy Optimization

2013 ◽  
Vol 57 (11) ◽  
pp. 5714-5716 ◽  
Author(s):  
David R. Andes ◽  
Daniel K. Reynolds ◽  
Scott A. Van Wart ◽  
Alexander J. Lepak ◽  
Laura L. Kovanda ◽  
...  
Keyword(s):  
Dose Level ◽  
Randomized Trials ◽  
Clinical Investigation ◽  
Time Curve ◽  
Content Type ◽  
Dosing Interval ◽  
Concentration Time ◽  
Dosing Regimens ◽  
Dosing Strategy ◽  
Current Report

ABSTRACTEchinocandins exhibit concentration-dependent effects onCandidaspecies, and preclinical studies support the administration of large, infrequent doses. The current report examines the pharmacokinetics/pharmacodynamics of two multicenter, randomized trials of micafungin dosing regimens that differed in both dose level and dosing interval. Analysis demonstrates the clinical relevance of the dose level and area under the concentration-time curve (AUC). Better, although not statistically significant (P= 0.056), outcomes were seen with higher maximum concentrations of drug in serum (Cmax) and large, infrequent doses. The results support further clinical investigation of novel micafungin dosing regimens with large doses but less than daily administration. (These studies have been registered at ClinicalTrials.gov under registration no. NCT00666185 and NCT00665639.)

scholarly journals Determinants of Rifampin, Isoniazid, Pyrazinamide, and Ethambutol Pharmacokinetics in a Cohort of Tuberculosis Patients

2006 ◽  
Vol 50 (4) ◽  
pp. 1170-1177 ◽  
Author(s):  
Helen McIlleron ◽  
Peter Wash ◽  
André Burger ◽  
Jennifer Norman ◽  
Peter I. Folb ◽  
...  
Keyword(s):  
Antituberculosis Drug ◽  
Time Curve ◽  
Tuberculosis Patients ◽  
Treatment Regimens ◽  
Concentration Time ◽  
Antituberculosis Treatment ◽  
Drug Concentrations ◽  
Patients At Risk ◽  
History Of ◽  
Dosing Strategy

ABSTRACT Evaluation of sources of pharmacokinetic variation can facilitate optimization of tuberculosis treatment regimens by identification of avoidable sources of variation and of risk factors for low or high drug concentrations in patients. Our objective was to describe the pharmacokinetics of rifampin, isoniazid, pyrazinamide, and ethambutol in a cohort of tuberculosis patients established on first-line treatment regimens and to evaluate the determinants of pharmacokinetic variation. Plasma concentration-time profiles were determined for each of the drugs in 142 patients with drug-sensitive pulmonary tuberculosis after 2 months of daily treatment in hospital. Pharmacokinetic measures were described by noncompartmental analysis. Multiple linear regression was used to evaluate the patient and the treatment factors associated with variation of the area under the concentration-time curve from 0 to 8 h. Several factors independently associated with variations in antituberculosis drug concentrations were identified: human immunodeficiency virus infection was associated with 39% and 27% reductions for rifampin and ethambutol, respectively; formulation factors were determinants of rifampin and isoniazid bioavailability; female patients had increased rifampin and isoniazid concentrations but reduced ethambutol concentrations; older patients had higher levels of isoniazid and ethambutol; patients with a history of previous antituberculosis treatment had lower ethambutol concentrations; and the dose per kilogram of body weight was associated with the concentrations of all four agents. Further studies are required to assess the implications of variations in antituberculosis drug concentrations for efficacy and safety before decisions are made to change the dosing strategy in patients at risk.

scholarly journals Population Pharmacokinetic Assessment of Vancomycin Dosing in the Large Pediatric Patient

2019 ◽  
Vol 63 (4) ◽  
Author(s):  
Brady S. Moffett ◽  
Vijay Ivaturi ◽  
Jennifer Morris ◽  
Ayse Akcan Arikan ◽  
Ankhi Dutta
Keyword(s):  
Pediatric Patients ◽  
Population Pharmacokinetic Analysis ◽  
Fat Free Mass ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Kidney Dysfunction ◽  
Time Curve ◽  
Concentration Time ◽  
Pharmacokinetic Assessment ◽  
Dosing Strategy

ABSTRACT The most appropriate vancomycin dosing strategy in pediatric patients weighing ≥70 kg (weight based versus non-weight based) to achieve an area under the concentration-time curve (AUC) of ≥400 mg·liter/h and a trough concentration of <20 mg/liter is not known. Population pharmacokinetic analysis determined that dosing of vancomycin should be weight based using fat-free mass, with appropriate adjustment for kidney dysfunction.

scholarly journals Pharmacokinetic/Pharmacodynamic Modeling of Spiramycin against Mycoplasma synoviae in Chickens

Pathogens ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 1238
Author(s):  
Sara T. Elazab ◽  
Nahla S. Elshater ◽  
Yousreya H. Hashem ◽  
Nayera M. Al-Atfeehy ◽  
Eon-Bee Lee ◽  
...  
Keyword(s):  
Oral Dose ◽  
Inhibitory Concentration ◽  
Oral Treatment ◽  
Pharmacodynamic Modeling ◽  
Parallel Study ◽  
Withdrawal Period ◽  
Time Curve ◽  
Mycoplasma Synoviae ◽  
Concentration Time ◽  
Plasma Concentration Time Curve

This research aimed to assess the pharmacokinetics/pharmacodynamics (PK/PD) and tissue residues of spiramycin in chickens. The PK of spiramycin were determined in 12 chickens using a parallel study design in which each group of chickens (n = 6) received a single dose of spiramycin at 17 mg/kg intravenously (IV) or orally. Plasma samples were collected at assigned times for up to 48 h to measure spiramycin concentrations. Additionally, a tissue depletion study was performed in 42 chickens receiving spiramycin at 17 mg/kg/day orally for 7 days. The area under the plasma concentration–time curve values were 29.94 ± 4.74 and 23.11 ± 1.83 µg*h/mL after IV and oral administrations, respectively. The oral bioavailability was 77.18%. The computed withdrawal periods of spiramycin were 11, 10, and 7 days for liver, muscle, and skin and fat, respectively. The minimum inhibitory concentration for spiramycin against Mycoplasma synoviae (M. synoviae) strain 1853 was 0.0625 µg/mL. Using the PK/PD integration, the appropriate oral dose of spiramycin against M. synoviae was estimated to be 15.6 mg/kg. Thus, we recommend an oral dose of 15.6 mg spiramycin/kg against M. synoviae in chickens and a withdrawal period of 11 days following oral treatment with 17 mg spiramycin/kg/day for 7 days.

Vancomycin Advanced Therapeutic Drug Monitoring: Exercise in Futility or Virtuous Endeavor to Improve Drug Efficacy and Safety?

2020 ◽  
Author(s):  
Thomas J Dilworth ◽  
Lucas T Schulz ◽  
Warren E Rose
Keyword(s):  
Therapeutic Drug Monitoring ◽  
Drug Monitoring ◽  
Inhibitory Concentration ◽  
Drug Efficacy ◽  
Therapeutic Drug ◽  
Limited Data ◽  
Considerable Effort ◽  
Time Curve ◽  
Concentration Time ◽  
High Level

Abstract Vancomycin is commonly prescribed to hospitalized patients. Decades of pharmacokinetic/pharmacodynamic research culminated in recommendations to monitor the ratio of the area under the concentration-time curve (AUC) to the minimum inhibitory concentration in order to optimize vancomycin exposure and minimize toxicity in the revised 2020 guidelines. These guideline recommendations are based on limited data without high-quality evidence and limitations in strength. Despite considerable effort placed on vancomycin therapeutic drug monitoring (TDM), clinicians should recognize that the majority of vancomycin use is empiric. Most patients prescribed empiric vancomycin do not require it beyond a few days. For these patients, AUC determinations during the initial days of vancomycin exposure are futile. This added workload may detract from high-level patient care activities. Loading doses likely achieve AUC targets, so AUC monitoring after a loading dose is largely unnecessary for broad application. The excessive vancomycin TDM for decades has been propagated with limitations in evidence, and it should raise caution on contemporary vancomycin TDM recommendations.

scholarly journals Pharmacokinetics and Safety Profile of Artesunate-Amodiaquine Coadministered with Antiretroviral Therapy in Malaria-Uninfected HIV-Positive Malawian Adults

2018 ◽  
Vol 62 (7) ◽  
Author(s):  
Clifford G. Banda ◽  
Fraction Dzinjalamala ◽  
Mavuto Mukaka ◽  
Jane Mallewa ◽  
Victor Maiden ◽  
...  
Keyword(s):  
Antiretroviral Therapy ◽  
Active Metabolite ◽  
Risk Difference ◽  
Hiv Positive ◽  
Limited Data ◽  
Time Curve ◽  
Geometric Means ◽  
Concentration Time ◽  
Intensive Sampling ◽  
Safety Signals

ABSTRACT There are limited data on the pharmacokinetic and safety profiles of artesunate-amodiaquine in human immnunodeficiency virus-infected (HIV + ) individuals receiving antiretroviral therapy. In a two-step intensive sampling pharmacokinetic trial, we compared the area under the concentration-time curve from 0 to 28 days (AUC 0–28 ) of an active metabolite of amodiaquine, desethylamodiaquine, and treatment-emergent adverse events between antiretroviral therapy-naive HIV + adults and those taking nevirapine and ritonavir-boosted lopinavir-based antiretroviral therapy. In step 1, malaria-uninfected adults ( n = 6/arm) received half the standard adult treatment regimen of artesunate-amodiaquine. In step 2, another cohort ( n = 25/arm) received the full regimen. In step 1, there were no safety signals or significant differences in desethylamodiaquine AUC 0–28 among participants in the ritonavir-boosted lopinavir, nevirapine, and antiretroviral therapy-naive arms. In step 2, compared with those in the antiretroviral therapy-naive arm, participants in the ritonavir-boosted lopinavir arm had 51% lower desethylamodiaquine AUC 0–28 , with the following geometric means (95% confidence intervals [CIs]): 23,822 (17,458 to 32,506) versus 48,617 (40,787 to 57,950) ng · h/ml ( P < 0.001). No significant differences in AUC 0–28 were observed between nevirapine and antiretroviral therapy-naive arms. Treatment-emergent transaminitis was higher in the nevirapine (20% [5/25]) than the antiretroviral therapy-naive (0.0% [0/25]) arm (risk difference, 20% [95% CI, 4.3 to 35.7]; P = 0.018). The ritonavir-boosted lopinavir antiretroviral regimen was associated with reduced desethylamodiaquine exposure, which may compromise artesunate-amodiaquine's efficacy. Coadministration of nevirapine and artesunate-amodiaquine may be associated with hepatoxicity.

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

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.

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

Cancers ◽  
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.

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

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.

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

Pathogens ◽  
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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