Impact of Key Components of Intensified Ceftaroline Dosing on Pharmacokinetic/Pharmacodynamic Target Attainment

Background and Objective Ceftaroline fosamil is a β-lactam antibiotic approved as a 600 mg twice daily dose (≤1 h infusion, ‘standard dosing’) or a 600 mg thrice daily dose (2 h infusion) to treat complicated skin and soft tissue infections caused by Staphylococcus aureus (minimum inhibitory concentration [MIC] 2–4 mg/L). We sought to systematically evaluate the relative impact of the three key components of the intensified dosing regimen (i.e. shortened dosing interval, prolonged infusion duration and increased total daily dose [TDD]) on the pharmacokinetic/pharmacodynamic (PK/PD) target attainment given different grades of bacterial susceptibility. Methods A population PK model was developed using data from 12 healthy volunteers (EudraCT-2012-005134-11) receiving standard or intensified dosing. PK/PD target attainment (ƒT>MIC = 35% and 100%) after 24 h was compared following systematically varied combinations of the (1) dosing interval (every 12 h [q12h]→ every 8 h [q8h]); (2) infusion duration (1 h→2 h); and (3) individual and total daily dose (400→900 mg, i.e. TDD 1200→1800 mg), as well as for varying susceptibility of S. aureus (MIC 0.032–8 mg/L). Results A two-compartment model with linear elimination adequately described ceftaroline concentrations (n = 274). The relevance of the dosing components dosing interval/infusion duration/TDD for ƒT>MIC systematically changed with pathogen susceptibility. For susceptible pathogens with MIC ≤1 mg/L, shortened dosing intervals appeared as the main driver of the improved target attainment associated with the intensified dosing regimen, followed by increased TDD and infusion duration. For less susceptible pathogens, the advantage of q8h dosing and 2 h infusions declined, and increased TDD improved ƒT>MIC the most. Conclusion The analysis calls to mind consideration of dose increases when prolonging the infusion duration in the case of low bacterial susceptibility

Population plasma and urine pharmacokinetics and the probability of target attainment of fosfomycin in healthy male volunteers

Purpose: A population pharmacokinetic model of fosfomycin was developed in healthy volunteers after intravenous administration, and different dosing regimens were evaluated in terms of the probability of target attainment for Escherichia coli using both plasma and urinary pharmacokinetic/pharmacodynamic targets. Methods: Eight healthy men received fosfomycin as both intermittent 8 g q8h and continuous infusion 1 g/h with a loading dose of 8 g in a crossover study design. Dense sampling was conducted during both regimens. Population pharmacokinetic modelling was performed using NONMEM. Monte Carlo simulations were conducted to evaluate the Probability of Target Attainment (PTA) of different dosing regimens using bactericidal (AUC24h/MIC of 83 and 75%T&gt;MIC) and bacteriostatic (AUC24h/MIC of 25) plasma targets and bacteriostatic (AUC24h/MIC of 3994) urine target. Results: A total of 176 plasma and 86 urine samples were available for PK analysis. A two-compartment model with a urine compartment best described the data. Glomerular filtration rate (GFR) showed a significant correlation with renal clearance and was implemented in the final model. Simulation results show that the dose of 4 g q8h reached 100% of PTA using bactericidal and bacteriostatic targets for MIC up to 16 mg/L. Conclusion: For the clinical breakpoint of 32 mg/L, the standard dosing regimen (4 g q8h) might not be sufficient to reach the bactericidal target. Higher dosing of 8 g q8h as an intermittent infusion or 0.75 g/h as a continuous infusion might be required. Continuous infusion resulted in better attainment of the %T&gt;MIC target than intermittent infusion.</p

New Approaches in Pharmacokinetics and Pharmacodynamics of Antimicrobial Drugs

Die moderne antimikrobielle Therapie steht zwei großen Herausforderungen gegenüber: Mangel an neu entwickelten antimikrobiellen Substanzen und Ausbreitung multiresistenter Erreger. Der Bedarf an neuen Strategien zur Verbesserung der Therapieoptionen gegen potentiell lebensbedrohliche Infektionen und zur Unterbrechung des Teufelskreises aus steigenden bakteriellen Resistenzen und Knappheit an neuen Antibiotika ist größer denn je. Diese Dissertation untersucht zwei verschiedene Ansätze, um die beschriebenen Probleme zu umgehen: einerseits den Versuch, die Wirksamkeit von Antibiotika durch die gemeinsame Verabreichung mit anderen Medikamenten zu steigern; andererseits die Wiederentdeckung bereits entwickelter und vorübergehend verlassener Substanzen. Der erste Teil der vorliegenden Arbeit befasst sich mit dem Konzept der gemeinsamen Verabreichung von Antibiotika und Effluxpumpen-Inhibitoren. Abgesehen von ihrem Vorkommen in Bakterienzellen, wo sie als einer der Schlüsselmechanismen bakterieller Resistenz gelten, werden Effluxpumpen-Proteine auch im menschlichen Körper exprimiert und können dort die pharmakokinetische Disposition vieler Medikamente, auch von Antibiotika, maßgeblich beeinflussen. Basierend auf der Hypothese, dass eine Hemmung dieser Effluxpumpen die Wirksamkeit von Antibiotika sowohl durch verbessertes Eindringen in Bakterien als auch durch Veränderung ihrer Pharmakokinetik steigern könnte, untersucht diese Arbeit den Einfluss von Effluxpumpen-Inhibitoren auf die antimikrobielle Aktivität des Antibiotikums Ciprofloxacin. Der zweite Teil dieser Dissertation betrifft das Polymyxin-Antibiotikum Colistin, welches kürzlich als wichtige therapeutische Option gegen multiresistente Gram-negative Infektionen wiederentdeckt wurde. Der Satz an im Rahmen dieses Projekts durchgeführten in vitro - und in vivo - Experimenten soll einen Beitrag zur besseren Beschreibung verschiedener pharmakokinetischer und pharmakodynamischer Eigenschaften dieses Medikaments darstellen, welche bis vor kurzem nur fragmentarisch bekannt waren. In Summe sollen die in der vorliegenden Dissertation zusammengetragenen Daten den Wissensstand zu beiden untersuchten Ansätzen erweitern, mit dem Ziel, in der Zukunft die zur Verfügung stehenden Behandlungsoptionen gegen potentiell lebensbedrohliche Infektionskrankheiten zu verbessern.Antimicrobial drug development faces two worrying phenomena: paucity of new antimicrobial agents and bacterial multi-drug resistance. The need for new strategies to improve treatment options for potentially life-threatening infections and to break the vicious circle caused by growing bacterial resistance and the dry antibiotic pipeline is bigger than ever. The present thesis investigated two different approaches which may be useful to circumvent the described problems: on the one hand, the attempt to enhance the efficacy of antibiotics by co-administration with another drug; on the other hand, the reintroduction of previously developed, but temporarily abandoned drugs into clinical practice. The first part of this work focused on the co-administration of antibiotics and efflux-pump inhibitors. Apart from their occurrence in bacterial cells, where they are among the key mechanisms of bacterial multidrug resistance, efflux pump proteins are also expressed in the human body, where they may have a profound impact on the pharmacokinetic disposition of numerous drugs, including antibiotics. Thus, based on the hypothesis that efflux pump inhibition might improve the efficacy of antimicrobial drugs by enhancing their intracellular uptake both in bacteria and immune cells and by modifying their pharmacokinetic disposition, the present thesis investigated the impact of co-administration of efflux pump inhibitors on the antimicrobial efficacy of the antibiotic ciprofloxacin. The second part of this work concerns the polymyxin antibiotic colistin, recently reintroduced into clinical practice as precious therapeutic option against multi-drug resistant Gram-negative infections. The set of in vitro and in vivo experiments conducted within this project elucidated different aspects of the pharmacokinetics and pharmacodynamics of this drug, many features of which were hitherto described only fragmentarily. In summary, data retrieved within this thesis project is meant to generate an increase of information on both investigated approaches in antimicrobial drug development and might accordingly contribute to improve and/or optimize treatment options against infectious diseases in the future.Abweichender Titel laut Übersetzung der Verfasserin/des VerfassersArbeit an der Bibliothek noch nicht eingelangt - Daten nicht geprüftMedizinische Universität Wien, Diss., 2018(VLID)361995

Rifaximin Reduces Number and Severity of Intestinal Lesions Associated With use of Non-steroidal Anti-inflammatory Drugs in Humans

The intestinal microbiota might contribute to enteropathy associated with use of nonsteroidal anti-inflammatory drugs (NSAIDs), but there have been few human studies of this association. We performed a placebo-controlled study to determine whether a delayed-release antibiotic formulation (rifaximin-extended intestinal release [EIR]) prevents the development of intestinal lesions in subjects taking daily NSAIDs. Sixty healthy volunteers (median age, 26 y; 42% female) were given the NSAID diclofenac (75 mg twice daily) plus omeprazole (20 mg once daily), and either rifaximin-EIR (400 mg) or placebo, twice daily for 14 days. Subjects were assessed by videocapsule endoscopy at baseline and after 2 weeks of treatment. The primary end point was the proportion of subjects developing at least 1 small-bowel mucosal break at week 2. Secondary end points were the change in the mean number of mucosal lesions and the number of subjects with large erosions and/or ulcers after 14 days of exposure. We detected mucosal breaks in 20% of subjects given rifaximin and in 43% of subjects given placebo (P =.05 in the post hoc sensitivity analysis). None of the subjects in the rifaximin group developed large lesions, compared with 9 subjects in the placebo group (P <.001). Our findings indicate that intestinal bacteria contribute to the development of NSAID-associated enteropathy in human beings. Clinical trial no: EudraCT 2013-000730-36