Monte Carlo simulations: maximizing antibiotic pharmacokinetic data to optimize clinical practice for critically ill patients

Infections in critically ill patients continue to result in unacceptably high morbidity and mortality. Although few data exist for correlating antibiotic exposure with outcome, antibiotic dosing is likely to be highly important for maximizing resolution of infection in many patients. The practical and financial difficulties of performing pharmacokinetic (PK) studies in critically ill patients mean that analyses to maximize data such as Monte Carlo simulation (MCS) are highly valuable. MCS uses computer software to perform virtual clinical trials. The building blocks for MCS are: firstly, a robust population PK model from the patient population of interest; secondly, descriptors of the effect of covariates that influence the PK parameters; thirdly, description of the susceptibility of bacteria to the antibiotic and finally a PK/pharmacodynamic (PD) target associated with antibiotic efficacy. Probability of target attainment (PTA) outputs can then be generated that describe the proportion of patients that will achieve a pre-specified PD target for an MIC distribution. Such analyses can then inform dosing requirements, which can be used to have a high likelihood of achieving PK/PD targets for organisms with different MICs. In this issue of JAC, Zelenitsky et al. provide a very useful example of MCS for interpreting the optimal methods for dosing meropenem, piperacillin/tazobactam, cefepime and ceftobiprole in critically ill patients

Textstrukturen und weibliche Subjektivität in Texten von Leslie Kaplan

Zu Beginn der 80er Jahre macht sich in Frankreich eine innovative Prosaliteratur bemerkbar, die sich sowohl von der vorangegangenen theorieorientierten Avantgarde als auch vom konventionellen Roman unterscheidet. Die Autorin Leslie Kaplan hat diese von der Literaturkritik provisorisch als autre roman bezeichnete Strömung maßgeblich mitgeprägt. Ihre frühen Texte stehen mit ihrer experimentellen, nicht-narrativen Form noch deutlich unter dem Einfluss der theoriefreudigen 70er Jahre. Allmählich vollzieht sie jedoch die für die innovative Literatur der 80er als charakteristisch geltende \u27Rückkehr zum Erzählen\u27. Die Arbeit beschäftigt sich mit der Frage, welche Impulse Leslie Kaplan aus den feministischen Debatten der 70er Jahre bezieht. Untersucht werden die literaturästhetischen Erklärungen der Autorin, sowie die drei frühen Texte L\u27excès-l\u27usine (1982), Le criminel (1985) und Le Pont de Brooklyn (1987). Mit ihrem literarischen Programm eines \u27Schreibens ohne Machtausübung\u27 knüpft Kaplan implizit an die Diskussionen und Erkenntnisse der feministischen Kritik an, so eine These der Arbeit. Die literarischen Texte Kaplans kreisen um den Entwurf weiblicher Subjektivität, was ebenfalls ein zentrales Thema der Neuen Frauenliteratur war. Weibliche Subjektivität ist in den drei Texten als Offenheit entworfen. In L\u27excès-l\u27usine ist Offenheit noch negativ konstruiert als eine schmerzhafte Selbstauflösung, in Le criminel als ein Schwanken zwischen lustvoller Selbstentgrenzung und bedrohlichem Selbstverlust und in Le Pont de Brooklyn schließlich uneingeschränkt positiv als Aufgeschlossenheit und Fähigkeit, sich selbst in Frage zu stellen. Die Konstruktion einer nicht-hierarchischen Erzählstruktur erscheint dabei als Voraussetzung für den Entwurf von freien, selbstbestimmten weiblichen Figuren

The AllWISE Motion Survey and the Quest for Cold Subdwarfs

The AllWISE processing pipeline has measured motions for all objects detected on Wide-field Infrared Survey Explorer (WISE) images taken between 2010 January and 2011 February. In this paper, we discuss new capabilities made to the software pipeline in order to make motion measurements possible, and we characterize the resulting data products for use by future researchers. Using a stringent set of selection criteria, we find 22,445 objects that have significant AllWISE motions, of which 3525 have motions that can be independently confirmed from earlier Two Micron All Sky Survey (2MASS) images, yet lack any published motions in SIMBAD. Another 58 sources lack 2MASS counterparts and are presented as motion candidates only. Limited spectroscopic follow-up of this list has already revealed eight new L subdwarfs. These may provide the first hints of a “subdwarf gap” at mid-L types that would indicate the break between the stellar and substellar populations at low metallicities (i.e., old ages). Another object in the motion list--WISEA J154045.67-510139.3--is a bright (J ≈ 9 mag) object of type M6; both the spectrophotometric distance and a crude preliminary parallax place it ~6 pc from the Sun. We also compare our list of motion objects to the recently published list of 762 WISE motion objects from Luhman. While these first large motion studies with WISE data have been very successful in revealing previously overlooked nearby dwarfs, both studies missed objects that the other found, demonstrating that many other nearby objects likely await discovery in the AllWISE data products

Population pharmacokinetics and pharmacodynamics of Ofloxacin in South African patients with multidrug-resistant tuberculosis.

Despite the important role of fluoroquinolones and the predominant use of ofloxacin for treating multidrug-resistant tuberculosis in South Africa, there are limited data on ofloxacin pharmacokinetics in patients with multidrug-resistant tuberculosis, no ofloxacin pharmacokinetic data from South African patients, and no direct assessment of the relationship between ofloxacin pharmacokinetics and the MIC of ofloxacin of patient isolates. Our objectives are to describe ofloxacin pharmacokinetics in South African patients being treated for multidrug-resistant tuberculosis and assess the adequacy of ofloxacin drug exposure with respect to the probability of pharmacodynamic target attainment (area under the time curve/MIC ratio of at least 100). Sixty-five patients with multidrug-resistant tuberculosis were recruited from 2 hospitals in South Africa. We determined the ofloxacin MICs for the Mycobacterium tuberculosis isolates from baseline sputum specimens. Patients received daily doses of 800 mg ofloxacin, in addition to other antitubercular drugs. Patients underwent pharmacokinetic sampling at steady state. NONMEM was used for data analysis. The population pharmacokinetics of ofloxacin in this study has been adequately described. The probability of target attainment expectation in the study population was 0.45. Doubling the dose to 1,600 mg could increase this to only 0.77. The currently recommended ofloxacin dose appeared inadequate for the majority of this study population. Studies to assess the tolerability of higher doses are warranted. Alternatively, ofloxacin should be replaced with more potent fluoroquinolones

The Science Case for an Extended Spitzer Mission

Although the final observations of the Spitzer Warm Mission are currently scheduled for March 2019, it can continue operations through the end of the decade with no loss of photometric precision. As we will show, there is a strong science case for extending the current Warm Mission to December 2020. Spitzer has already made major impacts in the fields of exoplanets (including microlensing events), characterizing near Earth objects, enhancing our knowledge of nearby stars and brown dwarfs, understanding the properties and structure of our Milky Way galaxy, and deep wide-field extragalactic surveys to study galaxy birth and evolution. By extending Spitzer through 2020, it can continue to make ground-breaking discoveries in those fields, and provide crucial support to the NASA flagship missions JWST and WFIRST, as well as the upcoming TESS mission, and it will complement ground-based observations by LSST and the new large telescopes of the next decade. This scientific program addresses NASA's Science Mission Directive's objectives in astrophysics, which include discovering how the universe works, exploring how it began and evolved, and searching for life on planets around other stars.Comment: 75 pages. See page 3 for Table of Contents and page 4 for Executive Summar

Population pharmacokinetics of fluconazole in critically ill patients receiving continuous venovenous hemodiafiltration - using Monte Carlo Simulations to predict doses for specified pharmacodynamic targets

Fluconazole is a widely used antifungal agent that is extensively reabsorbed in patients with normal renal function. However, its reabsorption can be compromised in patients with acute kidney injury, thereby leading to altered fluconazole clearance and total systemic exposure. Here, we explore the pharmacokinetics of fluconazole in 10 critically ill anuric patients receiving continuous venovenous hemodiafiltration (CVVHDF). We performed Monte Carlo simulations to optimize dosing to appropriate pharmacodynamic endpoints for this population. Pharmacokinetic profiles of initial and steady-state doses of 200 mg intravenous fluconazole twice daily were obtained from plasma and CVVHDF effluent. Nonlinear mixed-effects modeling (NONMEM) was used for data analysis and to perform Monte Carlo simulations. For each dosing regimen, the free drug area under the concentration-time curve (fAUC)/MIC ratio was calculated. The percentage of patients achieving an AUC/MIC ratio greater than 25 was then compared for a range of MIC values. A two-compartment model adequately described the disposition of fluconazole in plasma. The estimate for total fluconazole clearance was 2.67 liters/h and was notably 2.3 times faster than previously reported in healthy volunteers. Of this, fluconazole clearance by the CVVHDF route (CL(CVVHDF)) represented 62% of its total systemic clearance. Furthermore, the predicted efficiency of CL(CVVHDF) decreased to 36.8% when filters were in use >48 h. Monte Carlo simulations demonstrated that a dose of 400 mg twice daily maximizes empirical treatment against fungal organisms with MIC up to 16 mg/liter. This is the first study we are aware of that uses Monte Carlo simulations to inform dosing requirements in patients where tubular reabsorption of fluconazole is probably nonexistent

Consumer involvement in Quality Use of Medicines (QUM) projects – lessons from Australia

BACKGROUND: It is essential that knowledge gained through health services research is collated and made available for evaluation, for policy purposes and to enable collaboration between people working in similar areas (capacity building). The Australian Quality Use of Medicine (QUM) on-line, web-based project database, known as the QUMmap, was designed to meet these needs for a specific sub-section of health services research related to improving the use of medicines. Australia's National Strategy for Quality Use of Medicines identifies the primacy of consumers as a major principle for quality use of medicines, and aims to support consumer led research. The aim of this study was to determine how consumers as a group have been represented in QUM projects in Australia. A secondary aim was to investigate how the projects with consumer involvement fit into Australia's QUM policy framework. METHOD: Using the web-based QUMmap, all projects which claimed consumer involvement were identified and stratified into four categories, projects undertaken by; (a) consumers for consumers, (b) health professionals for consumers, (c) health professionals for health professionals, and (d) other. Projects in the first two categories were then classified according to the policy 'building blocks' considered necessary to achieve QUM. RESULTS: Of the 143 'consumer' projects identified, the majority stated to be 'for consumers' were either actually by health professionals for health professionals (c) or by health professionals for consumers (b) (47% and 40% respectively). Only 12 projects (9%) were directly undertaken by consumers or consumer groups for consumers (a). The majority of the health professionals for consumers (b) projects were directed at the provision of services and interventions, but were not focusing on the education, training or skill development of consumers. CONCLUSION: Health services research relating to QUM is active in Australia and the projects are collated and searchable on the web-based interactive QUMmap. Healthcare professionals appear to be dominating nominally 'consumer focussed' research, with less than half of these projects actively involving the consumers or directly benefiting consumers. The QUMmap provides a valuable tool for policy analysis and for provision of future directions through identification of QUM initiatives

Optimization and evaluation of piperacillin plus tobramycin combination dosage regimens againstfor patients with altered pharmacokineticsthe hollow-fiber infection model and mechanism-based modeling

Augmented renal clearance (ARC) in critically-ill patients can result in suboptimal drug exposures and treatment failure. Combination dosage regimens accounting for ARC have never been optimized and evaluated againstusing the hollow-fiber infection model (HFIM). Using aisolate from a critically-ill patient and static concentration time-kill experiments (SCTK), we studied clinically relevant piperacillin and tobramycin concentrations, alone and in combinations, at two inocula (10and 10CFU/mL) over 72h. We subsequently evaluated the effect of optimized piperacillin (4 g q4h, 0.5h infusion) plus tobramycin (5 mg/kg q24h, 7 mg/kg q24h and 10 mg/kg q48h as 0.5h infusions) regimens on killing and regrowth in the HFIM, simulating a creatinine clearance of 250 mL/min. Mechanism-based modeling was performed in S-ADAPT. In SCTKs, piperacillin plus tobramycin (except combinations with 8 mg/liter tobramycin at low inoculum) achieved synergistic killing (≥2 logthe most active monotherapy at 48h and 72h) and prevented regrowth. Piperacillin monotherapy (4 g q4h) in the HFIM provided 2.4 loginitial killing followed by regrowth at 24h with resistance emergence. Tobramycin monotherapies displayed rapid initial killing (≥5 logat 13h) followed by extensive regrowth. As predicted by mechanism-based modeling, the piperacillin plus tobramycin dosage regimens were synergistic and provided ≥5 logkilling with resistance suppression over 8 days in the HFIM. Optimized piperacillin plus tobramycin regimens provided significant bacterial killing and suppressed resistance emergence. These regimens appear highly promising for effective and early treatment, even in the near-worst case scenario of ARC