Readings in Advanced Pharmacokinetics

This book, “Readings in Advanced Pharmacokinetics - Theory, Methods and Applications”, covers up to date information and practical topics related to the study of drug pharmacokinetics in humans and in animals. The book is designed to offer scientists, clinicians and researchers a choice to logically build their knowledge in pharmacokinetics from basic concepts to advanced applications. This book is organized into two sections. The first section discusses advanced theories that include a wide range of topics; from bioequivalence studies, pharmacogenomics in relation to pharmacokinetics, computer based simulation concepts to drug interactions of herbal medicines and veterinary pharmacokinetics. The second section advances theory to practice offering several examples of methods and applications in advanced pharmacokinetics

Exploring pharmacist prescribing in hospitals in Scotland, with a focus on antimicrobials.

This aim of the research was to explore pharmacist prescribing (PP) with a focus on antimicrobials, in hospitals in Scotland. A mixed-methods approach was used to collect, generate and synthesise data. A systematic review of peer-reviewed published literature on evidence-based roles for the pharmacist as part of an antimicrobial multidisciplinary team, identified roles for pharmacists within the teams but limited evidence relating to outcomes associated with these roles. Six qualitative focus groups, with 37 hospital pharmacists in 5 Scottish Health Boards, contextualised perceptions of barriers to, and facilitators of, implementation of PP in hospitals. Key themes were: perceived lack of pharmacy management support to take on a prescribing role and little strategic attention paid to PP implementation and sustainability. These issues were discussed in relation to PP in general and not only for antimicrobials. Participants perceived successful implementation of PP to be associated with factors including ward type and patients clinical condition. None of the pharmacists were prescribing antimicrobials and consequently further studies focused on PP in general. A scoping exercise, utilising various sources of information, reinforced findings from Phase 1; it highlighted the absence of any national or Health Board frameworks to support implementation of PP in secondary care in Scotland. Consensus-based research was undertaken, therefore, to provide guidance to facilitate service redesign involving PP in secondary care in Scotland. A Delphi approach undertaken with 40 experts, mainly in strategic posts, resulted in a high level of agreement in areas relating to succession planning, rather than role development; more variability was obtained in areas relating to future orientation of service, competencies required by prescribers and potential development of non-medical prescribing teams. The guidance was developed into a self-assessment toolkit providing an analytical strategy for implementation and role development of PP in secondary care. While the results and conclusions generated through this research need to be interpreted with caution, the data generated is an original contribution to the evidence base relating to PP

Repurposing clinically approved cephalosporins for tuberculosis therapy

While modern cephalosporins developed for broad spectrum antibacterial activities have never been pursued for tuberculosis (TB) therapy, we identified first generation cephalosporins having clinically relevant inhibitory concentrations, both alone and in synergistic drug combinations. Common chemical patterns required for activity against Mycobacterium tuberculosis were identified using structure-activity relationships (SAR) studies. Numerous cephalosporins were synergistic with rifampicin, the cornerstone drug for TB therapy and ethambutol, a first-line anti-TB drug. Synergy was observed even under intracellular growth conditions where beta-lactams typically have limited activities. Cephalosporins and rifampicin were 4- to 64-fold more active in combination than either drug alone; however, limited synergy was observed with rifapentine or rifabutin. Clavulanate was a key synergistic partner in triple combinations. Cephalosporins (and other beta-lactams) together with clavulanate rescued the activity of rifampicin against a rifampicin resistant strain. Synergy was not due exclusively to increased rifampicin accumulation within the mycobacterial cells. Cephalosporins were also synergistic with new anti-TB drugs such as bedaquiline and delamanid. Studies will be needed to validate their in vivo activities. However, the fact that cephalosporins are orally bioavailable with good safety profiles, together with their anti-mycobacterial activities reported here, suggest that they could be repurposed within new combinatorial TB therapies.This work was supported by grants from the British Columbia Lung Association and The Canadian Institute of Health Research (MOP-82855) to C.J.T. and from a Grand Challenges Canada - Stars in Global Health (0030-01-04-01-01) and a People Programme (Marie Skłodowska Curie Actions) of the European Union’s Seventh Framework Programme (FP7/2007–2013) under REA agreement no. 291799 (Tres Cantos Open Lab Foundation - COFUND programme) to S.R.-G

Exploring Antibiotic Resistance and the Effect of Antimicrobial Stewardship on Physicians’ and Non-Physician Prescribing Clinicians through Knowledge, Attitudes, Practices and Beliefs (KAPB) Utilizing the Social Cognitive Theory (SCT)

ABSTRACT Exploring Antibiotic Resistance and the Effect of Antimicrobial Stewardship on Physicians’ and Non-Physician Prescribing Clinicians through Knowledge, Attitudes, Practices and Beliefs (KAPB) Utilizing the Social Cognitive Theory (SCT) Tamika Carty Seton Hall University, 2021 Dissertation Chair: Genevieve Pinto Zipp, PT, EdD, FNAP Background: Antibiotics are one of the greatest medical discoveries, revolutionizing the field of medicine. However, antimicrobial and antibiotic over usage has become a prevalent issue among outpatients, leading to antibiotic resistance (AR) (Ventola, 2015). As a result of, its widespread usage and associated concerns, the World Health Organization (WHO) has cited AR as a growing concern for many nations (WHO, 2015). This in turn has led to the development of management programs such as stewardships which are often led by health professionals and clinicians to address this growing issue. One would argue that stewardship programs are only as effective if those leading them are adequately prepared. Therefore, it is imperative to identify physicians’ and prescribing non-physician practitioners’ knowledge, attitudes, practices, and beliefs regarding AR and the incorporation of Antimicrobial Stewardship Programs (ASPs) to combat AR. Purpose: The purpose of this study was threefold: first to create, validate and test the reliability of the novel instrument “Antibiotic Resistance & Antimicrobial Stewardship Assessment Tool (ABRASAT)”. The second purpose was to test the valid and reliable tool in physicians’ and non-physician prescribing practitioners. The final purpose was to use the valid and reliable tool in the population of interest to understand physicians’ and non-physician prescribing practitioners’ knowledge, attitudes, practices, and beliefs with regard to antibiotic resistance and ASPs as combative method for AR. Methods: This study employed a mixed methods research approach, utilizing specifically an explanatory mixed methods design. The study can also further be categorized as non-experimental, descriptive, cross sectional, correlational and explanatory. The study consisted of two practitioner groups (physicians’ and non-physician prescribing practitioners) in which their knowledge, attitudes, practices, and beliefs were explored utilizing the ABRASAT instrument which was rooted in the available “evidenced based” literature, KAPBs theory and the Social Cognitive Theory (SCT). The ABRASAT consisted of 10 demographic questions and 25 questions relating to KAPBs, expectations, suggestions and thoughts on AR and ASPs. Data Collection and Analysis: Data was collected from both practitioner groups. Participants were recruited via social media (Facebook, WhatsApp, Twitter, Reddit and LinkedIn) and research platform (Research Gate), in addition to convenience sampling. The PI utilized descriptive statistics in addition to statistical analysis tests (ANOVA, T-Test, MANOVA and Pearson’s Correlation) to analyze quantitative data. The PI employed an inductive approach utilizing descriptive and in vivo coding to analyze qualitative data. Both the quantitative and qualitative data helped to form an inclusive overview of KAPBs of physicians’ and non-physician prescribing practitioners. Results: A total of 234 participants completed the survey. The study results for both the quantitative and qualitative data for descriptive research questions (RQ) 1 -5 resulted in the following: for RQ1, the quantitative and the qualitative data shows overall both practitioner groups had high knowledge on AR. For RQ2, the quantitative and the qualitative data shows overall both practitioner groups had high knowledge on what ASPs were. For RQ3, the quantitative and the qualitative data shows overall both practitioner groups had favorable attitudes with regards to ASPs. For RQ4, the quantitative and the qualitative data shows overall both practitioner groups had good ASP practices. For RQ5, the quantitative and the qualitative data shows overall both practitioner groups had favorable beliefs with regards to ASPs. The study results for both the quantitative and qualitative data for relational research questions (RQ) and hypotheses 6 -13 resulted in the following: for RQs 6 & 7, there was no significant difference in practitioner groups on knowledge, resulting in failure to reject the null hypothesis. For RQs 8 - 11, there was a significant difference in practitioner groups on attitudes and beliefs resulting in rejection of the null hypothesis. Finally, for RQ 12 & 13, like RQs 6 & 7, there was no significant difference in practitioner groups on practices, resulting in failure to reject the null hypothesis. While the overall instrument had a high reliability of .843 and successfully measured attitudes, practices and beliefs, knowledge had a poor reliability. While knowledge had poor reliability, it did not affect the overall reliability of the tool. However, it will need to be reassessed for future use as an individual construct. Conclusion: Though knowledge scored poorer in reliability it does not dispute the fact that physicians’ and non-physician prescribing clinicians have knowledge of AR, and displayed positive attitudes and beliefs towards ASPs. As a result, practitioners are generally in favor of ASPs yet improvements should still be made to ensure maximum benefits, thus society must continue to implement and refine these programs

The Molecular Epidemiology of Enteric Fever in South and Southeast Asia

Typhoid fever is a life-threating systemic infection caused by Salmonella enterica sub-species enterica serovars Typhi (S. Typhi) and Paratyphi A (S. Paratyphi A). While the disease is mainly travel-associated in developed countries, it still causes significant burden in the poorest areas in developing countries where safe water and adequate sanitation and food hygiene remain limited. Typhoid management largely relies on antimicrobial therapy; however, antimicrobial resistance (AMR) in these causative pathogens has become a global threat, compromising the effectiveness of the treatment therapy and signifying the burden of this disease. Understanding the epidemiology of typhoid fever in different endemic settings as well as the impact of AMR on the disease outcome is crucial for disease control and management. First, this thesis utilized whole genome sequences of S. Typhi combined with clinical data from a randomized controlled trial to investigate the impact of AMR and bacterial genotype on the disease outcome. A novel subclade of ciprofloxacin-resistant H58 S. Typhi associated with increased treatment failure was identified and these organisms were likely widespread in Indian subcontinent. Subsequently, this study combined bacterial genomics with conventional epidemiological tools to reveal the population structure and spatiotemporal dynamics of S. Paratyphi A isolates in Nepal. The Nepalese S. Paratyphi A population was highly dynamic with evidences of regular inter-country transmission, clonal expansion and replacement of distinct genotypes during the study period. A number of localized spatiotemporal clusters of S. Paratyphi A cases were also identified. A molecular epidemiological investigation was also performed to provide insights into the AMR, epidemiological features and population structure and dynamics of S. Typhi in rural areas of Siem Reap, Cambodia. A substantial burden of pediatric typhoid fever was revealed and communes with high-risk of infection were identified. Multidrug resistant H58 S. Typhi with reduced susceptibility to fluoroquinolones was dominant in this setting. This study also investigated the phylogenetic relationship between acute and carriage S. Typhi isolates in Nepal and deciphered the genetic characteristics associated with carriage isolates. My study suggested that typhoid carriage was likely not an important source of new infections in endemic area

An Epidemiological and Pharmacokinetic-pharmacodynamic Investigation into the Impact of Carbapenem-resistant Enterobacterales

Background: According to the 2019 CDC Antibiotic Resistance Threats Report, more than 2.8 million antibiotic-resistant infections occur in the United States each year, leading to more than 35,000 deaths. Among the most urgent threats identified by the CDC are carbapenem-resistant Enterobacterales (CRE). Despite efforts to control the spread of these organisms, the number of estimated cases between 2012 and 2017 remained stable. In 2017, an estimated 13,100 hospitalized cases of CRE led to approximately 1,100 deaths and $130 million attributable healthcare costs. This dissertation seeks to address this issue from both a pharmacokinetic/pharmacodynamic and epidemiological perspective. Methods: We evaluated the susceptibility of 140 CRE clinical isolates against novel agents eravacycline and plazomicin using techniques standardized by the Clinical and Laboratory Standards Institute. We performed in-vitro static time-kill assays in 8 Verona Integron-encoded metallo-beta-lactamase (VIM)-producing CRE using single and combination exposures of cefepime, meropenem, piperacillin/tazobactam, amikacin, and plazomicin along with aztreonam and aztreonam/avibactam. Additionally, we performed a 10-year, inverse probability of treatment weighting adjusted retrospective cohort study comparing the risk in observing a composite outcome of all-cause mortality or discharge to hospice in patients having CRE vs. carbapenem-susceptible Enterobacterales (CSE) infections after 14 and 30 days. In this cohort, we also reported on the prevalence of CRE across the decade. Additionally, we compared the organism composition and susceptibilities of isolates cultured in both the CRE and CSE groups. Results: Plazomicin showed higher susceptibility than eravacycline against our CRE isolates. In time kill studies, plazomicin was bactericidal against 5/8 isolates as monotherapy. Meropenem/amikacin or meropenem/plazomicin were bactericidal in all experiments, except for one isolate which regrew against meropenem/plazomicin. Aztreonam/avibactam was bactericidal in all experiments tested. Neither cefepime nor piperacillin/tazobactam improved the activity of plazomicin against our isolates. Cefepime with amikacin showed inconsistent activity. In the retrospective cohort study, the overall incidence of CRE infections was 1.8%. CRE isolates exhibited higher resistance across all routinely tested antimicrobials classes compared to CSE. The CRE population appeared to be largely non-carbapenemase-producing given the high susceptibility of meropenem and the high prevalence of E. cloacae, a known AmpC-producer. Overall, the risk of composite outcome only appeared to be increased among patients with a bloodstream infection on the index date and could only be assessed when utilizing an exposure of carbapenem-non-susceptible Enterobacterales (CNSE) due to insufficient sample size. However, the results were inconclusive as they were not statistically significant. Conclusions: Novel antimicrobial agents plazomicin and aztreonam/avibactam were highly active against a collection of CRE including both Klebsiella pneumoniae carbapenemase (KPC) and VIM. Aztreonam/avibactam, meropenem/amikacin, and meropenem/plazomicin all exhibited comparably bactericidal activity. Furthermore, at an academic medical center in a non-endemic region for CRE, it appears that CRE infection may have increased the risk of experiencing the composite outcome after both 14 and 30 days, but definitive conclusions may not be drawn given the lack of statistical significance and imprecision in the estimation of the effect. The difficulties in drawing definitive conclusions from this study owing to limited sample size in the CRE or CNSE group stresses the importance of developing novel strategies and performing larger, multicenter studies when investigating highly resistant infections with low prevalence

Prebiotics and Probiotics

Currently, new health benefits of probiotics have been identified, and new strains with probiotic potential have been discovered and continue to be investigated. Likewise, prebiotics and their interaction with the microbiota have been the focus of research in human and animal health, as well as to counteract zoonotic pathogenic microorganisms. Probiotics and prebiotics can be found in food and are isolated or synthesized to be supplemented as functional ingredients for the benefit of humans or animals. The volume contains thirteen chapters that explain the mechanisms of probiotics, prebiotics, and symbiotics from their interaction with the intestinal microbiota as antimicrobials and immunomodulators and their effect on human and animal health

Un nouvel agent antibactérien : caractérisation bactériologique in vitro et performance des formulations à libération prolongée in vitro/in vivo

Introduction: Antibiotic resistance is a major threat to public health and new antimicrobials are urgently needed. CIN-102, a new antibacterial agent which resembles cinnamon essential oils composition, was developed by a pharmaceutical company. CIN-102 had a broad-spectrum of action and resistance was not developed until now. Between all the possible therapeutic applications for CIN-102, a future utilization against Inflammatory Bowel Diseases (IBD) is aimed. IBD are chronic pathologies with a multifactorial etiology. In this context, enteric bacteria are well-known to have an important role, and higher bacterial concentrations are found in the intestine under inflammatory conditions. The objectives of this work were: to characterize the bacteriological activity of CIN-102, to analyze the bacteriological activity of anti-inflammatory agents and antibiotics used in IBD and to fabricate multiparticulate CIN-102 pharmaceutical forms for colonic targeted drug release. The idea is to use CIN-102 to reduce colonic bacterial loads and improve the state of intestinal inflammation. Methodology: The Minimal Inhibitory Concentration (MIC), the Post-Antibiotic Effect (PAE) and the logarithmic reduction time of CIN-102 were determined against several aerobic and anaerobic bacterial isolates. The interactions between CIN-102 and commercialized antibiotics were evaluated. The MIC of 5-aminosalicilyc acid, GED-0507-34 and antibiotics were determined for anaerobic bacterial isolates. Concerning sustained released formulations: CIN-102 pellet cores were fabricated by extrusion-spheronization and subsequently coated with blends of insoluble polymers and natural biodegradable polysaccharides. CIN-102 mini-tablets were fabricated by direct compression. In vitro drug released was measured in simulated gastric and intestinal fluid. The efficacy of best sustained release formulations was assessed in a murine model of colitis. Samples of luminal contents and sections of the colon were taken to perform a bacteriological analysis. Expression of cytokines was analyzed from colonic tissues.Results and discussion: The broad-spectrum activity of CIN-102 was confirmed. All aerobic and anaerobic strains were susceptible to CIN-102. Furthermore, CIN-102 had an important PAE and exerted a fast logarithmic reduction of bacterial inoculum. It interacts synergistically with several antibiotics, mostly with colistin and aminoglycosides, restoring the antibiotic activity against multi-resistant bacteria. The promising in vitro activity of CIN-102 has to be further confirmed by animal studies. Anti-inflammatory agents used against IBD were not provided of antibacterial activity and neither of the antibiotics tested possessed a broad-spectrum of action against anaerobic isolates commonly found in the intestine. These results confirm the need of a broad-spectrum antibiotic capable of reduced increased bacterial loads during inflammation. Following this aim, oral dosage forms able to deliver CIN-102 into the colon were studied. Concerning the sustained release forms, in vitro CIN-102 release from coated-pellets and mini-tablets was reduced in simulated gastric and intestinal fluids. Colitic mice treated with CIN-102 controlled release formulations had less diarrhea and bloody stools. Furthermore, the concentrations of enterobacteria in colonic tissue and stool were significantly reduced in CIN-102 treated mice. These results show that sustained release formulations can effectively deliver CIN-102 in the lower part of the gastrointestinal tract, where the reduction of enterobacteria seems to ameliorate the course of colitis.Conclusion: CIN-102 is novel broad-spectrum antibacterial and sustained release formulations can effectively deliver this agent into the colon, reducing bacterial loads which might influence the state of intestinal inflammation.Introduction : La résistance aux antibiotiques est une menace de santé, il est donc urgent de développer de nouveaux antibactériens. CIN-102, est un nouvel antibactérien développé par une industrie pharmaceutique. Il possède un large-spectre d’action et aucune résistance n’a été développée jusqu’à présent. Parmi les possibles applications thérapeutiques du CIN-102, notre recherche s’est focalisée sur les Maladies Inflammatoires Chroniques de l’Intestin (MICIs). Plusieurs facteurs contribuent à l’étiologie des MICIs. Les bactéries intestinales jouent un rôle important dans ces maladies et une augmentation de la charge bactérienne est observée pendant l’inflammation. Les objectifs de ce travail ont été : la caractérisation de l’activité antibactérienne du CIN-102, l’analyse de l’activité antibactérienne des agents anti-inflammatoires et antibiotiques utilisés en cas de MICI et la fabrication des formulations à ciblage colique pour le CIN-102. Le but est de diminuer la charge bactérienne colique par moyen du CIN-102 et améliorer, de cette façon, l’état de l’inflammation.Méthodes: La Concentration Minimale Inhibitrice (CMI), l’Effet Post-Antibiotique (EPA) et le temps de réduction logarithmique du CIN-102 ont été déterminés pour des bactéries aérobies et anaérobies. Les interactions entre le CIN-102 et des antibiotiques sur le marché ont été évaluées. La CMI de l’acide 5-aminosalicylique (5-ASA), GED-0507-34 et antibiotiques ont été déterminées pour des souches anaérobiques. Par rapport aux formulations à libération prolongée : des mini-granules contenant le CIN-102 ont été fabriqués par extrusion-sphéronisation puis pelliculés avec des mélanges de polymères insolubles et polysaccharides. Parallèlement, des mini-comprimés de CIN-102 ont été fabriqués par compression directe. La libération du CIN-102 in vitro, a été mesurée dans des milieux simulant l’estomac et l’intestin grêle. L’efficacité des systèmes à libération prolongée a été évaluée dans un modèle de colite chez la souris. Des prélèvements de selles et tissus coliques ont été soumis à des études bactériologiques. L’expression des cytokines a été mesurée à partir des tissus coliques.Résultats et discussion : Le large-spectre d’action du CIN-102 a été confirmé. Toutes les souches ont été inhibées par le CIN-102. CIN-102 présente un EPA et un temps de réduction logarithmique court. Il présente des interactions synergiques avec plusieurs antibiotiques, notamment la colistine et les aminoglycosides, en les rendant actifs contre des bactéries multirésistantes. Ces résultats in vitro doivent être poursuivis par des études chez l’animal. Des agents anti-inflammatoires utilisés contre les MICIs ne possèdent pas d’activité antibactérienne. Par ailleurs, les antibiotiques testés n’ont pas un large-spectre d’action contre des bactéries anaérobies généralement retrouvées dans l’intestin. Cela confirme le besoin d’un antibiotique à large spectre capable de réduire des charges bactériennes en cas d’inflammation. Dans ce but, des formulations capables de délivrer CIN-102 au niveau du colon ont été étudiées. La libération du CIN-102 des mini-granules pelliculés et mini-comprimés a été réduite dans des milieux simulant l’estomac et l’intestin grêle. Des souris atteintes de colite et traitées avec les formulations du CIN-102 ont eu une diminution des diarrhées et du sang dans les selles. Les concentrations d’entérobactéries adhérentes à la muqueuse colique et dans les selles ont été significativement réduites chez les souris traitées avec le CIN-102. Ces résultats montrent que ces formulations peuvent délivrer CIN-102 dans le tractus gastro-intestinal inferieur, et que la diminution d’entérobactéries semble réduire les symptômes de la colite.Conclusion : CIN-102 est un nouvel antibactérien a large-spectre et des formulations à libération prolongée peuvent délivrer cet agent dans le colon, diminuant la charge d’entérobactéries qui pourrait influencer l’état de l’inflammation