scholarly journals Clinical Pharmacology of Antibiotics

2019 ◽  
Vol 14 (7) ◽  
pp. 1080-1090 ◽  
Author(s):  
Rachel F. Eyler ◽  
Kristina Shvets
Keyword(s):  
Drug Exposure ◽  
Inhibitory Concentration ◽  
Dialysis Session ◽  
Development Of Resistance ◽  
Drug Concentrations ◽  
Dosing Frequency ◽  
To Receive ◽  
The Relationship ◽  
Antibiotic Dose ◽  
Volumes Of Distribution

Antimicrobial pharmacology and its effect on prescribing is quite complex. Selecting an antibiotic that will optimally treat an infection while minimizing adverse effects and the development of resistance is only the first step, as one must also consider the patient’s individual pharmacokinetic alterations and the pharmacodynamic properties of the drug when prescribing it as well. Patients with CKD may have alterations in their protein binding, volumes of distribution, kidney clearance, and nonrenal clearance that necessitates antibiotic dose adjustments to prevent the development of toxicity. Knowledge of a drug’s pharmacodynamics, defined as the relationship between drug exposure and antibacterial efficacy, provides some guidance regarding the optimal way to make dose adjustments. Different pharmacodynamic goals, such as maximizing the time that free (unbound) drug concentrations spend above the minimum inhibitory concentration (MIC) for time dependent drugs (e.g., β-lactams) or maximizing the free peak-to-MIC ratio for concentration-dependent antibiotics (e.g., aminoglycosides), require different adjustment strategies; for instance, decreasing the dose while maintaining normal dosing frequency or giving normal (or even larger) doses less frequently, respectively. Patients receiving hemodialysis have other important prescribing considerations as well. The nephrologist or patient may prefer to receive antibiotics that can be administered intravenously toward the end of a dialysis session. Additionally, newer dialysis technologies and filters can increase drug removal more than originally reported. This review will discuss the place in therapy, mechanism of action, pharmacokinetic, pharmacodynamic, and other pharmacologic considerations encountered when prescribing commonly used antibiotics in patients with chronic kidney disease or ESKD.

Methodological Approaches to Evaluate Fetal Drug Exposure

2019 ◽  
Vol 25 (5) ◽  
pp. 496-504 ◽  
Author(s):  
Naïm Bouazza ◽  
Frantz Foissac ◽  
Déborah Hirt ◽  
Saïk Urien ◽  
Sihem Benaboud ◽  
...  
Keyword(s):  
Cord Blood ◽  
Drug Exposure ◽  
Placental Transfer ◽  
Ex Vivo ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Pbpk Models ◽  
Drug Concentrations ◽  
Fetal Drug Exposure

Background: Drug prescriptions are usual during pregnancy, however, women and their fetuses still remain an orphan population with regard to drugs efficacy and safety. Most xenobiotics diffuse through the placenta and some of them can alter fetus development resulting in structural abnormalities, growth or functional deficiencies. Methods: To summarize the different methodologies developed towards the prediction of fetal drug exposure. Results: Neonatal cord blood concentration is the most specific measurement of the transplacental drug transfer at the end of pregnancy. Using the cord blood and mother drug concentrations altogether, drug exchanges between the mother and fetus can be modeled and quantified via a population pharmacokinetic analysis. Thereafter, it is possible to estimate the fetus exposure and the fetus-to-mother exposure ratio. However, the prediction of placental transfer before any administration to pregnant women is desirable. Animal studies remain difficult to interpret due to structural and functional inter-species placenta differences. The ex-vivo perfusion of the human placental cotyledon is the method of reference to study the human placental transfer of drugs because it is thought to mimic the functional placental tissue. However, extrapolation of data to in vivo situation remains difficult. Some research groups have extensively worked on physiologically based models (PBPK) to predict fetal drug exposure and showed very encouraging results. Conclusion: PBPK models appeared to be a very promising tool in order to predict fetal drug exposure in-silico. However, these models mainly picture the end of pregnancy and knowledge regarding both, development of the placental permeability and transporters is strongly needed.

Grading Teachers: Race and Gender Differences in Low Evaluation Ratings and Teacher Employment Outcomes

2019 ◽  
Vol 56 (5) ◽  
pp. 1800-1833 ◽  
Author(s):  
Steven Drake ◽  
Amy Auletto ◽  
Joshua M. Cowen
Keyword(s):  
Charter Schools ◽  
Evaluation System ◽  
Employment Outcomes ◽  
Teachers Of Color ◽  
High Stakes ◽  
Teacher Labor Market ◽  
Race And Gender ◽  
And Gender ◽  
To Receive ◽  
The Relationship

In July 2011, the State of Michigan adopted a broad set of teacher labor market reforms, including a high-stakes evaluation system designed in part to remove low-performing teachers. We examine the characteristics of teachers rated as “minimally effective” and “ineffective,” as well as their schools, and the relationship between low effectiveness ratings and later employment outcomes. Results suggest teachers of color across traditional and charter schools are more likely to receive low effectiveness ratings than their within-school peers. These low rating risks are higher for teachers of color working in comparatively White-faculty contexts. Male and novice teachers are also rated low more frequently, and important differences appear to exist in the usage of low ratings by traditional public and charter schools.

scholarly journals 1304. Characterization of Tebipenem Pivoxil Hydrobromide Pharmacokinetics-Pharmacodynamics (PK-PD) in a Neutropenic Murine Acute Pyelonephritis (AP) Model

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S666-S666
Author(s):  
Brian D VanScoy ◽  
Steven Fikes ◽  
Christopher M Rubino ◽  
Sujata M Bhavnani ◽  
Nicole S Cotroneo ◽  
...  
Keyword(s):  
Acute Pyelonephritis ◽  
Free Drug ◽  
Research Support ◽  
Model Free ◽  
Drug Concentrations ◽  
Drug Plasma ◽  
Dose Ranging ◽  
Tebipenem Pivoxil ◽  
Tract Infections ◽  
The Relationship

Abstract Background Tebipenem pivoxil hydrobromide (tebipenem HBr), an orally (PO) bioavailable prodrug of tebipenem, is a carbapenem with broad-spectrum activity against Gram-positive and -negative bacteria that is being developed for the treatment of patients with complicated urinary tract infections, including AP. Data from a one-compartment in vitro infection model demonstrated that the ratio of free-drug plasma area under the curve (AUC) to MIC with adjustment for dosing interval (τ) (AUC:MIC ratio•1/τ) was the PK-PD index most associated with tebipenem HBr efficacy [VanScoy BD et al., IDWeek 2019, Poster 1565]. Studies were undertaken to characterize the magnitude of tebipenem HBr free-drug plasma AUC:MIC ratio•1/τ associated with efficacy for Enterobacteriaceae using a neutropenic murine AP model. Methods A single dose pharmacokinetic study was completed in neutropenic mice infected via intra-renal injection with 104 CFU/kidney of Escherichia coli NCTC 13441. Following PO administration of 4 tebipenem HBr doses (1, 15, 45 and 100 mg/kg), plasma samples were collected at 0.25, 0.5, 1, 2, 4, 6 and 8 hours post-treatment initiation and drug concentrations were determined using LC/MS/MS. Dose-ranging studies were completed using a panel of 7 Enterobacteriaceae isolates (tebipenem HBr MIC values of 0.015 to 0.5 mg/L). Mice were infected with 104 CFU/kidney via intra-renal injection. Two hours post-incubation, 8 total daily tebipenem HBr doses (0.3 to 135 mg/kg) were fractionated into regimens given every 8 hours. The relationship between change in log10 CFU/g from baseline at 24 hours and free-drug plasma AUC:MIC ratio•1/τ was fit using a Hill-type model. Free-drug plasma AUC:MIC ratio•1/τ values associated with net bacterial stasis and 1- and 2-log10 CFU/g reductions from baseline at 24 hours were determined. Results The relationship between change in log10 CFU/g from baseline at 24 hours and tebipenem HBr free-drug plasma AUC:MIC ratio•1/τ described the data well (r2 = 0.833). Free-drug plasma AUC:MIC ratio•1/τ values associated with net bacterial stasis and a 1-log10 CFU/g reduction from baseline were 26.2 and 54.1, respectively. A 2-log10 CFU/g reduction was not achieved. Relationship between change in log10 CFU/g from baseline at 24 hours and tebipenem HBr free-drug plasma AUC:MIC ratio•1/τ based on data for a panel of Enterobacteriaceae isolates evaluated in the dose-ranging studies conducted using a neutropenic murine acute pyelonephritis model Conclusion These data will be useful to support tebipenem HBr dose selection for clinical studies in patients with AP. Disclosures Brian D. VanScoy, B.S., Institute for Clinical Pharmacodynamics, Inc. (Employee)Spero Therapeutics (Grant/Research Support) Steven Fikes, BA, Institute for Clinical Pharmacodynamics, Inc. (Employee)Spero Therapeutics (Grant/Research Support) Christopher M. Rubino, PharMD, Institute for Clinical Pharmacodynamics, Inc. (Employee)Spero Therapeutics (Grant/Research Support) Sujata M. Bhavnani, PharMD, MS, FIDSA, Institute for Clinical Pharmacodynamics, Inc. (Employee)Spero Therapeutics (Grant/Research Support) Nicole S. Cotroneo, BS, Spero Therapeutics (Employee, Shareholder) Ian A. Critchley, PhD, Spero Therapeutics (Employee, Shareholder) Thomas R. Parr, PhD, Spero Therapeutics (Employee, Shareholder) Paul G. Ambrose, PharMD, FIDSA, Institute for Clinical Pharmacodynamics, Inc. (Employee)Spero Therapeutics (Grant/Research Support)

scholarly journals Moderate levels of 5-fluorocytosine cause the emergence of high frequency resistance in cryptococci

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yun C. Chang ◽  
Ami Khanal Lamichhane ◽  
Hongyi Cai ◽  
Peter J. Walter ◽  
John E. Bennett ◽  
...  
Keyword(s):  
Cellular Uptake ◽  
High Frequency ◽  
Antifungal Agent ◽  
Inhibitory Concentration ◽  
Glucuronic Acid ◽  
Rapid Development ◽  
Acid Synthesis ◽  
Transcriptional Factor ◽  
Development Of Resistance ◽  
Acid Accumulation

AbstractThe antifungal agent 5-fluorocytosine (5-FC) is used for the treatment of several mycoses, but is unsuitable for monotherapy due to the rapid development of resistance. Here, we show that cryptococci develop resistance to 5-FC at a high frequency when exposed to concentrations several fold above the minimal inhibitory concentration. The genomes of resistant clones contain alterations in genes relevant as well as irrelevant for 5-FC resistance, suggesting that 5-FC may be mutagenic at moderate concentrations. Mutations in FCY2 (encoding a known permease for 5-FC uptake), FCY1, FUR1, UXS1 (encoding an enzyme that converts UDP-glucuronic acid to UDP-xylose) and URA6 contribute to 5-FC resistance. The uxs1 mutants accumulate UDP-glucuronic acid, which appears to down-regulate expression of permease FCY2 and reduce cellular uptake of the drug. Additional mutations in genes known to be required for UDP-glucuronic acid synthesis (UGD1) or a transcriptional factor NRG1 suppress UDP-glucuronic acid accumulation and 5-FC resistance in the uxs1 mutants.

scholarly journals Pharmacodynamics of Moxifloxacin and Levofloxacin at Simulated Epithelial Lining Fluid Drug Concentrations against Streptococcus pneumoniae

2004 ◽  
Vol 48 (4) ◽  
pp. 1215-1221 ◽  
Author(s):  
Naomi R. Florea ◽  
Pamela R. Tessier ◽  
Cuilian Zhang ◽  
Charles H. Nightingale ◽  
David P. Nicolau
Keyword(s):  
Streptococcus Pneumoniae ◽  
Fluoroquinolone Resistance ◽  
Epithelial Lining ◽  
Time Curve ◽  
Bacterial Killing ◽  
Epithelial Lining Fluid ◽  
Log Reduction ◽  
Development Of Resistance ◽  
Drug Concentrations

ABSTRACT Recent clinical failures associated with levofloxacin treatment for Streptococcus pneumoniae infections and growing evidence of frequent mutations in the isolate population have led to increased concerns regarding fluoroquinolone resistance. Our objective was to characterize the efficacies of levofloxacin and moxifloxacin against various genotypes of S. pneumoniae after simulated bronchopulmonary exposures. An in vitro model was used to simulate a levofloxacin concentration of 500 mg and a moxifloxacin concentration of 400 mg, which were previously determined to be the concentrations in the epithelial lining fluid of older adults receiving once-daily dosing. The effects of the drugs were tested against six S. pneumoniae containing various mutations. Bacterial density and resistance were quantitatively assessed over 48 h. The S. pneumoniae isolate with no mutation displayed a 4-log reduction in CFU after treatment with both agents and did not develop resistance. Isolates containing the parC or parE mutation or both mutations regrew and developed resistance when they were exposed to levofloxacin, despite an unbound area under the concentration-time curve (AUC):MIC ratio of ∼100. When the isolate containing the parC and gyrA mutations was exposed to levofloxacin, there was a half-log reduction in the number of CFU compared to that for the control, but the isolate subsequently regrew. Likewise, levofloxacin did not kill the isolate containing the parC, gyrA, and parE mutations. Moxifloxacin sustained the killing of all bacterial isolates tested without the development of resistance. Levofloxacin did not sustain bacterial killing and did not prevent the emergence of further resistance in mutants with the parC or parE mutation or both mutations, even though an unbound AUC:MIC ratio for exposure well above the breakpoint of 30 to 40 established in the literature for S. pneumoniae was maintained. Moxifloxacin was effective against all isolates tested, despite the presence of isolates with two- and three-step mutations, for which the MICs were increased.

scholarly journals The influence of drug-exposure conditions on the development of resistance to methotrexate or ZD1694 in cultured human leukaemia cells

1996 ◽  
Vol 66 (1) ◽  
pp. 29-36 ◽  
Author(s):  
Yuzuru Takemura ◽  
Hiroyuki Kobayashi ◽  
William Gibson ◽  
Rosemary Kimbell ◽  
Hayato Miyachi ◽  
...  
Keyword(s):  
Drug Exposure ◽  
Development Of Resistance ◽  
Human Leukaemia ◽  
Exposure Conditions

scholarly journals Scheduling Chemotherapy: Catch 22 between Cell Kill and Resistance Evolution

2000 ◽  
Vol 2 (3) ◽  
pp. 215-232 ◽  
Author(s):  
Shea N. Gardner
Keyword(s):  
Cell Cycle ◽  
Cell Division ◽  
Drug Exposure ◽  
Drug Application ◽  
Growth Fraction ◽  
Cycle Phase ◽  
Response Curves ◽  
Division Rate ◽  
Drug Concentrations ◽  
Cns Drugs

Dose response curves show that prolonged drug exposure at a low concentration may kill more cells than short exposures at higher drug concentrations, particularly for cell cycle phase specific drugs. Applying drugs at low concentrations for prolonged periods, however, allows cells with partial resistance to evolve higher levels of resistance through stepwise processes such as gene amplification. Models are developed for cell cycle specific (CS) and cell cycle nonspecific (CNS) drugs to identify the schedule of drug application that balances this tradeoff.The models predict that a CS drug may be applied most effectively by splitting the cumulative dose into many (>40) fractions applied by long-term chemotherapy, while CNS drugs may be better applied in fewer than 10 fractions applied over a shorter term. The model suggests that administering each fraction by continuous infusion may be more effective than giving the drug as a bolus, whether the drug is CS or CNS. In addition, tumors with a low growth fraction or slow rate of cell division are predicted to be controlled more easily with CNS drugs, while those with a high proliferative fraction or fast cell division rate may respond better to CS drugs.

scholarly journals SHAMANEN, JOMFRUEN OG SKATTEVÆSENET: Portræt af en mirakelmager fra det sydlige Chile

2008 ◽  
Author(s):  
Dorthe Brogaard Kristensen
Keyword(s):  
Social Environment ◽  
Roman Catholic ◽  
Southern Chile ◽  
Political Reality ◽  
Local Taxation ◽  
National Symbols ◽  
Healing Power ◽  
Historical Past ◽  
To Receive ◽  
The Relationship

This article presents the case of the shaman José Karipan, who is considered one of the most powerful and popular shamans in southern Chile. The article explores the success of his practice as a healer, by analyzing the relationship between healing, identity and the socio-economic and political context of Southern Chile. It is argued that shamanistic medical practice is so popular among patients in Southern Chile due to its sensitivity to their historical past and socio-political reality. The shaman’s practice and figure build upon symbols and aspects of his social environment; the shaman is Roman Catholic and claims to receive his healing power from the Virgin of Carmen, the national saint of Chile. Furthermore, he is publicly known for a conflict with the local taxation authorities, who accuse him of failing to claim tax for his income as a healer. These factors serve to challenge the logic of the Chilean state but also show how the shaman’s personal practices are embedded inside the logic of the state, and draw upon national symbols as a source of power.  

scholarly journals Is It All a Conspiracy? Conspiracy Theories and People’s Attitude to COVID-19 Vaccination

Vaccines ◽  
2021 ◽  
Vol 9 (10) ◽  
pp. 1051 ◽  
Author(s):  
Zheng Yang ◽  
Xi Luo ◽  
Hepeng Jia
Keyword(s):  
Infectious Diseases ◽  
Health Behaviors ◽  
Large Body ◽  
Pharmaceutical Companies ◽  
Conspiracy Theories ◽  
Conspiracy Beliefs ◽  
Quota Sampling ◽  
To Receive ◽  
The Relationship ◽  
Vaccination Hesitancy

A large body of research has found that people’s beliefs in conspiracy theories about infectious diseases negatively impacts their health behaviors concerning vaccination. Conspiracy belief-based vaccination hesitancy has become more rampant after the global outbreak of COVID-19. However, some important questions remain unanswered. For instance, do different versions of conspiracy theories—particularly conspiracy theories about the origin of the epidemic (e.g., that the SARS-CoV-2 leaked from a Wuhan virology laboratory or that the virus was of foreign origin) and the general theories about vaccine conspiracies (e.g., pharmaceutical companies covered up the danger of vaccines or people are being deceived about the effectiveness of vaccines)—have the same effect on vaccination intentions? Through a national survey adopting quota sampling in China, the current study tested the relationship between people’s conspiracy beliefs and their intention to receive the COVID-19 vaccination. The findings show that people’s embrace of conspiracy theories did indeed affect their intention to take COVID-19 shots. However, only conspiracy theories related to vaccines had a significant impact, while belief in more general theories about COVID-19 did not significantly affect vaccination intentions. People’s knowledge of vaccines (vaccine literacy) played an important role in this relationship. People with lower beliefs in vaccines conspiracy theories and higher levels of vaccine literacy were more likely to receive the COVID-19 vaccination.

scholarly journals Akibat Hukum dalam Pewarisan dari Pelaksanaan Pengangkatan Anak oleh Orang Tua Tunggal

2020 ◽  
Vol 1 (2) ◽  
pp. 181-185
Author(s):  
Condro Putri Dewi Hartaka
Keyword(s):  
Foster Parents ◽  
Birth Certificate ◽  
Single Parents ◽  
Foster Child ◽  
Whole Person ◽  
The Family ◽  
The Right ◽  
To Receive ◽  
The Relationship ◽  
General Adoption

The child is the mandate of the Grace Of God Almighty, and inside there is something that is attached as the dignity and status as a whole person. Along with the time on it right now is the mindset of society as it advances and growing, such as the parents who are unable to finance the future of the child and that’s why the purpose of adoption the child is not only to get the child but also for the welfare of children. And in Indonesia allow the implementation of the adoption by single parents, a woman or a man who is not married and who have been married but no longer bound in wedlock (widow or widower). Adoption of the child by single parents can only be done by the Citizens Of Indonesia after obtaining permission from ministers and the granting of permission can be ordered to agencies in the province. Adoption by single parents same thing with the adoption of children by parents in general. Adoption does not cause the relationship between children with real parents to be disconected, because most of the child who is in was from the family. Adoption of the child must be listed in a birth certificate, by not eliminate the identity of the beginning. Foster child are entitled to receive heir from the foster parents and also have the right heir from the real parents.

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