scholarly journals Pharmacodynamic Optimization for Treatment of Invasive Candida auris Infection

2017 ◽  
Vol 61 (8) ◽  
Author(s):  
Alexander J. Lepak ◽  
Miao Zhao ◽  
Elizabeth L. Berkow ◽  
Shawn R. Lockhart ◽  
David R. Andes
Keyword(s):  
Animal Model ◽  
Steady State ◽  
Invasive Candidiasis ◽  
Maximum Concentration ◽  
Multidrug Resistant ◽  
Total Drug ◽  
Candida Auris ◽  
Time Curve ◽  
Content Type ◽  
Concentration Time

ABSTRACT Candida auris is an emerging multidrug-resistant threat. The pharmacodynamics of three antifungal classes against nine C. auris strains was explored using a murine invasive candidiasis model. The total drug median pharmacodynamic (PD) target associated with net stasis was a fluconazole AUC/MIC (the area under the concentration-time curve over 24 h in the steady state divided by the MIC) of 26, an amphotericin B C max/MIC (maximum concentration of drug in serum divided by the MIC) of 0.9, and a micafungin AUC/MIC of 54. The micafungin PD targets for C. auris were ≥20-fold lower than those of other Candida species in this animal model. Clinically relevant micafungin exposures produced the most killing among the three classes.

scholarly journals Pharmacodynamic Evaluation of Rezafungin (CD101) against Candida auris in the Neutropenic Mouse Invasive Candidiasis Model

2018 ◽  
Vol 62 (11) ◽  
Author(s):  
Alexander J. Lepak ◽  
Miao Zhao ◽  
David R. Andes
Keyword(s):  
Invasive Candidiasis ◽  
Free Drug ◽  
Candida Auris ◽  
Time Curve ◽  
Content Type ◽  
Susceptibility Data ◽  
Concentration Time ◽  
Target Exposure ◽  
Human Dose

ABSTRACT Rezafungin (CD101) is a novel echinocandin under development for once-weekly intravenous (i.v.) dosing. We evaluated the pharmacodynamics (PD) of rezafungin against 4 Candida auris strains, using the neutropenic mouse invasive candidiasis model. The area under the concentration-time curve (AUC)/MIC was a robust predictor of efficacy (R2 = 0.76). The stasis free-drug 24-h AUC/MIC target exposure for the group was 1.88, whereas the 1-log-kill free-drug 24-h AUC/MIC target exposure was 5.77. These values are very similar to those in previous rezafungin PD studies with other Candida spp. Based on recent surveillance susceptibility data, AUC/MIC targets are likely to be exceeded for >90% of C. auris isolates with the previously studied human dose of 400 mg administered i.v. once weekly.

scholarly journals Evaluating the Relationship between Vancomycin Trough Concentration and 24-Hour Area under the Concentration-Time Curve in Neonates

2018 ◽  
Vol 62 (4) ◽  
pp. e01647-17 ◽  
Author(s):  
Sheng-Hsuan Tseng ◽  
Chuan Poh Lim ◽  
Qi Chen ◽  
Cheng Cai Tang ◽  
Sing Teang Kong ◽  
...  
Keyword(s):  
Steady State ◽  
Trough Concentration ◽  
Therapeutic Drug ◽  
Population Pharmacokinetic ◽  
Time Curve ◽  
Content Type ◽  
Concentration Time ◽  
Vancomycin Trough ◽  
Trough Concentrations ◽  
The Relationship

ABSTRACT Bacterial sepsis is a major cause of morbidity and mortality in neonates, especially those involving methicillin-resistant Staphylococcus aureus (MRSA). Guidelines by the Infectious Diseases Society of America recommend the vancomycin 24-h area under the concentration-time curve to MIC ratio (AUC24/MIC) of >400 as the best predictor of successful treatment against MRSA infections when the MIC is ≤1 mg/liter. The relationship between steady-state vancomycin trough concentrations and AUC24 values (mg·h/liter) has not been studied in an Asian neonatal population. We conducted a retrospective chart review in Singapore hospitals and collected patient characteristics and therapeutic drug monitoring data from neonates on vancomycin therapy over a 5-year period. A one-compartment population pharmacokinetic model was built from the collected data, internally validated, and then used to assess the relationship between steady-state trough concentrations and AUC24. A Monte Carlo simulation sensitivity analysis was also conducted. A total of 76 neonates with 429 vancomycin concentrations were included for analysis. Median (interquartile range) was 30 weeks (28 to 36 weeks) for postmenstrual age (PMA) and 1,043 g (811 to 1,919 g) for weight at the initiation of treatment. Vancomycin clearance was predicted by weight, PMA, and serum creatinine. For MRSA isolates with a vancomycin MIC of ≤1, our major finding was that the minimum steady-state trough concentration range predictive of achieving an AUC24/MIC of >400 was 8 to 8.9 mg/liter. Steady-state troughs within 15 to 20 mg/liter are unlikely to be necessary to achieve an AUC24/MIC of >400, whereas troughs within 10 to 14.9 mg/liter may be more appropriate.

scholarly journals Intra- and Extracellular Activities of Trimethoprim-Sulfamethoxazole against Susceptible and Multidrug-Resistant Mycobacterium tuberculosis

2014 ◽  
Vol 58 (12) ◽  
pp. 7557-7559 ◽  
Author(s):  
L. Davies Forsman ◽  
T. Schön ◽  
U. S. H. Simonsson ◽  
J. Bruchfeld ◽  
M. Larsson ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Treatment Option ◽  
Multidrug Resistant ◽  
Drug Resistant ◽  
Potential Treatment ◽  
Time Curve ◽  
Content Type ◽  
Extensively Drug Resistant ◽  
Concentration Time ◽  
Strain H37rv

ABSTRACTWe investigated the activity of trimethoprim-sulfamethoxazole (SXT) againstMycobacterium tuberculosis, the pathogen that causes tuberculosis (TB). The MIC distribution of SXT was 0.125/2.4 to 2/38 mg/liter for the 100 isolates tested, including multi- and extensively drug-resistant isolates (MDR/XDR-TB), whereas the intracellular MIC90of sulfamethoxazole (SMX) for the pansusceptible strain H37Rv was 76 mg/liter. In an exploratory analysis using a ratio of the unbound area under the concentration-time curve from 0 to 24 h over MIC (fAUC0–24/MIC) using ≥25 as a potential target, the cumulative fraction response was ≥90% at doses of ≥2,400 mg of SMX. SXT is a potential treatment option for MDR/XDR-TB.

scholarly journals Pharmacokinetic-Pharmacodynamic Characterization of Omadacycline against Haemophilus influenzae Using a One-Compartment In Vitro Infection Model

2020 ◽  
Vol 64 (6) ◽  
Author(s):  
Brian D. VanScoy ◽  
Elizabeth A. Lakota ◽  
Haley Conde ◽  
Jennifer McCauley ◽  
Lawrence Friedrich ◽  
...  
Keyword(s):  
Haemophilus Influenzae ◽  
Antimicrobial Agents ◽  
Nonlinear Least Squares ◽  
Infection Model ◽  
Least Squares Regression ◽  
Total Drug ◽  
Time Curve ◽  
Content Type ◽  
Concentration Time

ABSTRACT Omadacycline is a novel aminomethylcycline with activity against Gram-positive and -negative organisms, including Haemophilus influenzae, which is one of the leading causes of community-acquired bacterial pneumonia (CABP). The evaluation of antimicrobial agents against H. influenzae using standard murine infection models is challenging due to the low pathogenicity of this species in mice. Therefore, 24-h dose-ranging studies using a one-compartment in vitro infection model were undertaken with the goal of characterizing the magnitude of the ratio of the area under the concentration-time curve (AUC) to the MIC (AUC/MIC ratio) associated with efficacy for a panel of five H. influenzae isolates. These five isolates, for which MIC values were 1 or 2 mg/liter, were exposed to omadacycline total-drug epithelial lining fluid (ELF) concentration-time profiles based on those observed in healthy volunteers following intravenous omadacycline administration. Relationships between change in log10 CFU/ml from baseline at 24 h and the total-drug ELF AUC/MIC ratios for each isolate and for the isolates pooled were evaluated using Hill-type models and nonlinear least-squares regression. As evidenced by the high coefficients of determination (r2) of 0.88 to 0.98, total-drug ELF AUC/MIC ratio described the data well for each isolate and the isolates pooled. The median total-drug ELF AUC/MIC ratios associated with net bacterial stasis and 1- and 2-log10 CFU/ml reductions from baseline at 24 h were 6.91, 8.91, and 11.1, respectively. These data were useful to support the omadacycline dosing regimens selected for the treatment of patients with CABP, as well as susceptibility breakpoints for H. influenzae.

scholarly journals Comparative Pharmacodynamics of Posaconazole in Neutropenic Murine Models of Invasive Pulmonary Aspergillosis and Mucormycosis

2014 ◽  
Vol 58 (11) ◽  
pp. 6767-6772 ◽  
Author(s):  
Russell E. Lewis ◽  
Nathaniel D. Albert ◽  
Dimitrios P. Kontoyiannis
Keyword(s):  
Rhizopus Oryzae ◽  
Invasive Pulmonary Aspergillosis ◽  
High Dose ◽  
Murine Models ◽  
Total Drug ◽  
Pulmonary Aspergillosis ◽  
Time Curve ◽  
Content Type ◽  
Pulmonary Mucormycosis ◽  
Concentration Time

ABSTRACTWe used two established neutropenic murine models of pulmonary aspergillosis and mucormycosis to explore the association between the posaconazole area under the concentration-time curve (AUC)-to-MIC ratio (AUC/MIC) and treatment outcome. Posaconazole serum pharmacokinetics were verified in infected mice to ensure that the studied doses reflected human exposures with the oral suspension, delayed-release tablet, and intravenous formulations of posaconazole. Sinopulmonary infections were then induced in groups of neutropenic mice withAspergillus fumigatusstrain 293 (posaconazole MIC, 0.5 mg/liter) orRhizopus oryzaestrain 969 (posaconazole MIC, 2 mg/liter) and treated with escalating daily dosages of oral posaconazole, which was designed to achieve AUCs ranging from 1.10 to 392 mg · h/liter. After 5 days of treatment, lung fungal burden was analyzed by quantitative real-time PCR. The relationships of the total drug AUC/MIC and the treatment response were similar in both models, with 90% effective concentrations (EC90s) corresponding to an AUC/MIC threshold of 76 (95% confidence interval [CI], 46 to 102) for strain 293 versus 87 (95% CI, 66 to 101) for strain 969. Using a provisional AUC/MIC target of >100, these exposures correlated with minimum serum posaconazole concentrations (Cmins) of 1.25 mg/liter for strain 293 and 4.0 mg/liter for strain 969. The addition of deferasirox, but not liposomal amphotericin or caspofungin, improved the activity of a suboptimal posaconazole regimen (AUC/MIC, 33) in animals with pulmonary mucormycosis. However, no combination was as effective as the high-dose posaconazole monotherapy regimen (AUC/MIC, 184). Our analysis suggests that posaconazole pharmacodynamics are similar forA. fumigatusandR. oryzaewhen indexed to pathogen MICs.

scholarly journals Pharmacokinetic-Pharmacodynamic Target Attainment Analyses To Support Dose Selection for ME1100, an Arbekacin Inhalation Solution

2020 ◽  
Vol 64 (10) ◽  
Author(s):  
Sujata M. Bhavnani ◽  
Jeffrey P. Hammel ◽  
Elizabeth A. Lakota ◽  
M. Courtney Safir ◽  
Brian D. VanScoy ◽  
...  
Keyword(s):  
Compartment Model ◽  
Simulated Patients ◽  
Population Pharmacokinetic ◽  
Total Drug ◽  
Target Attainment ◽  
Time Curve ◽  
Content Type ◽  
Concentration Time

ABSTRACT ME1100 (arbekacin inhalation solution) is an inhaled aminoglycoside that is being developed to treat patients with hospital-acquired and ventilator-associated bacterial pneumonia (HABP and VABP, respectively). Pharmacokinetic-pharmacodynamic (PK-PD) target attainment analyses were undertaken to evaluate ME1100 regimens for the treatment of patients with HABP/VABP. The data used included a population pharmacokinetic (PPK) 4-compartment model with 1st-order elimination, nonclinical PK-PD targets from one-compartment in vitro and/or in vivo infection models, and in vitro surveillance data. Using the PPK model, total-drug epithelial lining fluid (ELF) concentration-time profiles were generated for simulated patients with varying creatinine clearance (CLcr) (ml/min/1.73 m2) values. Percent probabilities of PK-PD target attainment by MIC were determined based on the ratio of total-drug ELF area under the concentration-time curve (AUC) to MIC (AUC/MIC ratio) targets associated with 1- and 2-log10 CFU reductions from baseline for Klebsiella pneumoniae, Pseudomonas aeruginosa, and Staphylococcus aureus. Percent probabilities of PK­PD target attainment based on PK-PD targets for a 1-log10 CFU reduction from baseline at MIC values above the MIC90 value for K. pneumoniae (8 μg/ml), P. aeruginosa (4 μg/ml), and S. aureus (0.5 μg/ml) were ≥99.8% for ME1100 600 mg twice daily (BID) in simulated patients with CLcr values >80 to ≤120 ml/min/1.73 m2. ME1100 600 mg BID, 450 mg BID, and 600 mg once daily in simulated patients with CLcr values >50 to ≤80, >30 to ≤50, and 0 to ≤30 ml/min/1.73 m2, respectively, provided arbekacin exposures that best matched those for 600 mg BID in simulated patients with normal renal function. These data provide support for ME1100 as a treatment for patients with HABP/VABP.

scholarly journals Mutant Prevention Concentration-Based Pharmacokinetic/Pharmacodynamic Indices as Dosing Targets for Suppressing the Enrichment of Levofloxacin-Resistant Subpopulations of Staphylococcus aureus

2011 ◽  
Vol 55 (5) ◽  
pp. 2409-2412 ◽  
Author(s):  
Beibei Liang ◽  
Nan Bai ◽  
Yun Cai ◽  
Rui Wang ◽  
Karl Drlica ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Hollow Fiber ◽  
Maximum Concentration ◽  
Resistant Mutant ◽  
Kappa Coefficient ◽  
Bacterial Isolates ◽  
Time Curve ◽  
Content Type ◽  
Concentration Time ◽  
Mutant Prevention Concentration

ABSTRACTMIC- and mutant prevention concentration (MPC)-based pharmacokinetic/pharmacodynamic (PK/PD) indices were compared for suitability as attainment targets for restricting amplification of levofloxacin-resistant mutant subpopulations. When threeStaphylococcus aureusstrains were examined with a hollow-fiber PK/PD model, area under the concentration-time curve over 24 h (AUC24)/MPC values of >25 and maximum concentration of drug in serum (Cmax)/MPC values of >2.2 predicted resistance outcome among different isolates with an interisolate kappa coefficient of 1. MIC-based mutant-restrictive PK/PD values varied >8-fold and exhibited only a moderate interisolate agreement (kappa coefficient of 0.5). Thus, MPC-based PK/PD indices are more suitable than MIC-based indices for predicting mutant-restricting fluoroquinolone doses when multiple bacterial isolates are considered.

scholarly journals Effects of Food and Omeprazole on a Novel Formulation of Super Bioavailability Itraconazole in Healthy Subjects

2018 ◽  
Vol 62 (12) ◽  
Author(s):  
Julian Lindsay ◽  
Stuart Mudge ◽  
George R. Thompson
Keyword(s):  
Steady State ◽  
Maximum Concentration ◽  
Healthy Adults ◽  
Plasma Exposure ◽  
Open Label ◽  
Time Curve ◽  
Dosing Interval ◽  
Fasted State ◽  
Concentration Time ◽  
Bioavailability Study

ABSTRACT To address the limited bioavailability and intolerance of the conventional itraconazole (ITZ) formulations, a new formulation labeled super bioavailability (SUBA) itraconazole has been developed; however, the specific effects of food and gastric pH are unknown. This study evaluated the pharmacokinetic profile of SUBA itraconazole under fasting and fed conditions, as well as with the concomitant administration of a proton pump inhibitor. First, the effect of food was assessed in an open-label, randomized, crossover bioavailability study of 65-mg SUBA itraconazole capsules (2 65-mg capsules twice a day) in healthy adults (n = 20) under fasting and fed conditions to steady-state levels. Second, an open-label, two-treatment, fixed-sequence comparative bioavailability study in healthy adults (n = 28) under fasted conditions compared the pharmacokinetics of a single oral dose of SUBA itraconazole capsules (2 65-mg capsules/day) with and without coadministration of daily omeprazole delayed-release capsules (1 40-mg capsule/day) under steady-state conditions. In the fed and fasted states, SUBA itraconazole demonstrated similar concentrations at the end of the dosing interval, with modestly lower total and peak ITZ exposure being shown when it was administered under fed conditions than when it was administered in the fasted state, with fed state/fasted state ratios of 78.09% (90% confidence interval [CI], 74.49 to 81.86%) for the area under the concentration-time curve over the dosing interval (14,183.2 versus 18,479.8 ng · h/ml), 73.05% (90% CI, 69.01 to 77.33%) for the maximum concentration at steady state (1,519.1 versus 2,085.2 ng/ml), and 91.53% (90% CI, 86.41 to 96.96%) for the trough concentration (1,071.5 versus 1,218.5 ng/ml) being found. When dosed concomitantly with omeprazole, there was a 22% increase in the total plasma exposure of ITZ, as measured by the area under the concentration-time curve from time zero to infinity (P = 0.0069), and a 31% increase in the peak plasma exposure of ITZ, as measured by the maximum concentration (P = 0.0083).

scholarly journals Amikacin Optimal Exposure Targets in the Hollow-Fiber System Model of Tuberculosis

2016 ◽  
Vol 60 (10) ◽  
pp. 5922-5927 ◽  
Author(s):  
Shashikant Srivastava ◽  
Chawanga Modongo ◽  
Chandima W. Siyambalapitiyage Dona ◽  
Jotam G. Pasipanodya ◽  
Devyani Deshpande ◽  
...  
Keyword(s):  
Hollow Fiber ◽  
Bactericidal Effect ◽  
Multidrug Resistant ◽  
System Model ◽  
Intermittent Therapy ◽  
Fiber System ◽  
Time Curve ◽  
Content Type ◽  
Concentration Time ◽  
Mdr Tb

ABSTRACTAminoglycosides such as amikacin are currently used for the treatment of multidrug-resistant tuberculosis (MDR-TB). However, formal pharmacokinetic/pharmacodynamic (PK/PD) studies to identify amikacin exposures and dosing schedules that optimizeMycobacterium tuberculosiskilling have not been performed. It is believed that aminoglycosides do not work well under acidic conditions, which, if true, would mean poor sterilizing activity against semidormant bacilli at low pH. We performed time-kill studies to compare the bactericidal effect of amikacin in log-phase-growth bacilli with the sterilizing effect in semidormant bacilli at pH 5.8 in broth. In log-phaseM. tuberculosisat normal pH versus semidormantM. tuberculosisat pH 5.8, the maximal kill (Emax) estimate and 95% confidence interval (CI) were 5.39 (95% CI, 4.91 to 5.63) versus 4.88 (CI, 4.46 to 5.22) log10CFU/ml, while the concentration mediating 50% ofEmax(EC50) was 1.0 (CI, 0. 0.86 to 1.12) versus 0.60 (CI, 0.50 to 0.66) times the MIC, respectively. Thus, the optimal exposures and kill rates identified for log-phaseM. tuberculosiswill be optimal even for semidormant bacilli. Next, we performed exposure-response and dose-scheduling studies in the hollow-fiber system model of tuberculosis using log-phaseM. tuberculosis. We recapitulated the amikacin concentration-time profiles observed in lungs of patients treated over 28 days. The PK/PD index linked toM. tuberculosiskill was the peak concentration (Cmax)-to-MIC ratio (r2> 0.99), closely followed by the area under the concentration-time curve from 0 to 24 h (AUC0–24)-to-MIC ratio (r2= 0.98). The EC90was aCmax/MIC ratio of 10.13 (95% CI, 7.73 to 12.48). The EC90is the dosing target for intermittent therapy that optimizes cure in TB programs for MDR-TB patients.

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