Pharmacodynamics of Voriconazole for Invasive Pulmonary Scedosporiosis

ABSTRACT Scedosporium apiospermum is a medically important fungal pathogen that causes a wide range of infections in humans. There are relatively few antifungal agents that are active against Scedosporium spp. Little is known about the pharmacodynamics of voriconazole against Scedosporium. Both static and dynamic in vitro models of invasive scedosporiosis were developed. Monoclonal antibodies that target a soluble cell wall antigen secreted by Scedosporium apiospermum were used to describe the pharmacodynamics of voriconazole. Mathematical pharmacokinetic-pharmacodynamic models were fitted to the data to estimate the drug exposure required to suppress the release of fungal antigen. The experimental results were bridged to humans using Monte Carlo simulation. All 3 strains of S. apiospermum tested invaded through the cellular bilayer of the in vitro models and liberated antigen. There was a concentration-dependent decline in the amount of antigen, with near maximal antifungal activity against all 3 strains being achieved with voriconazole at 10 mg/liter. Similarly, there was a drug exposure-dependent decline in the amount of circulating antigen in the dynamic model and complete suppression of antigen, with an area under the concentration-time curve (AUC) of approximately 80 mg · h/liter. A regression of the AUC/MIC versus the area under the antigen-time curve showed that a near maximal effect was obtained with an AUC/MIC of approximately 100. Monte Carlo simulation suggested that only isolates with an MIC of 0.5 mg/liter enabled pharmacodynamic targets to be achieved with a standard regimen of voriconazole. Isolates with higher MICs may need drug exposure targets higher than those currently recommended for other fungi.

Download Full-text

Apotransferrin in Combination with Ciprofloxacin Slows Bacterial Replication, Prevents Resistance Amplification, and Increases Antimicrobial Regimen Effect

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00112-19 ◽

2019 ◽

Vol 63 (5) ◽

Cited By ~ 2

Author(s):

Paul G. Ambrose ◽

Brian D. VanScoy ◽

Brian M. Luna ◽

Jun Yan ◽

Amber Ulhaq ◽

...

Keyword(s):

Antimicrobial Agents ◽

Bactericidal Effect ◽

Bacterial Density ◽

Infection Model ◽

Time Curve ◽

Content Type ◽

Wide Range ◽

Bacterial Replication ◽

The Impact

ABSTRACT There has been renewed interest in combining traditional small-molecule antimicrobial agents with nontraditional therapies to potentiate antimicrobial effects. Apotransferrin, which decreases iron availability to microbes, is one such approach. We conducted a 48-h one-compartment in vitro infection model to explore the impact of apotransferrin on the bactericidal activity of ciprofloxacin. The challenge panel included four Klebsiella pneumoniae isolates with ciprofloxacin MIC values ranging from 0.08 to 32 mg/liter. Each challenge isolate was subjected to an ineffective ciprofloxacin monotherapy exposure (free-drug area under the concentration-time curve over 24 h divided by the MIC [AUC/MIC ratio] ranging from 0.19 to 96.6) with and without apotransferrin. As expected, the no-treatment and apotransferrin control arms showed unaltered prototypical logarithmic bacterial growth. We identified relationships between exposure and change in bacterial density for ciprofloxacin alone (R2 = 0.64) and ciprofloxacin in combination with apotransferrin (R2 = 0.84). Addition of apotransferrin to ciprofloxacin enabled a remarkable reduction in bacterial density across a wide range of ciprofloxacin exposures. For instance, at a ciprofloxacin AUC/MIC ratio of 20, ciprofloxacin monotherapy resulted in nearly 2 log10 CFU increase in bacterial density, while the combination of apotransferrin and ciprofloxacin resulted in 2 log10 CFU reduction in bacterial density. Furthermore, addition of apotransferrin significantly reduced the emergence of ciprofloxacin-resistant subpopulations compared to monotherapy. These data demonstrate that decreasing the rate of bacterial replication with apotransferrin in combination with antimicrobial therapy represents an opportunity to increase the magnitude of the bactericidal effect and to suppress the growth rate of drug-resistant subpopulations.

Download Full-text

Characterization and Quantitation of the Pharmacodynamics of Fluconazole in a Neutropenic Murine Disseminated Candidiasis Infection Model

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.43.9.2116 ◽

1999 ◽

Vol 43 (9) ◽

pp. 2116-2120 ◽

Cited By ~ 149

Author(s):

D. Andes ◽

M. van Ogtrop

Keyword(s):

Time Course ◽

Infection Model ◽

Maximal Effect ◽

Time Curve ◽

In Vitro Susceptibility ◽

Disseminated Candidiasis ◽

Wide Range ◽

Dosing Intervals ◽

Dose Dependent

ABSTRACT We determined the pharmacodynamic parameter and the magnitude of that parameter that was predictive of the efficacy of fluconazole in the treatment of disseminated candidiasis. We used a neutropenic murine model of disseminated Candida albicans infection to characterize the time course of activity of fluconazole. Quantitation of colony counts in kidneys after 24 h of therapy with a wide range of doses and three dosing intervals was used to determine the dose required to achieve 50% of the maximal effect (ED50). The ED50 was similar for each of the dosing intervals studied, supporting the area under the concentration-time curve (AUC) MIC ratio as the parameter that predicts the efficacy of fluconazole. Similar studies were performed with C. albicans strains for which fluconazole MICs are in the susceptible-dose-dependent range (MICs, 16 to 32 mg/liter). We found that the magnitude of the AUC/MIC ratio required to reach the ED50 was similar for all three organisms studied, ranging from 12 to 25. When the pharmacokinetics of fluconazole in humans are considered, these AUC/MIC ratios would support in vitro susceptibility breakpoints of 8 mg/liter for dosages of 200 mg/day and susceptibility breakpoints of 16 to 32 mg/liter for dosages of 400 to 800 mg/day.

Download Full-text

Pharmacokinetics of Miltefosine in Children and Adults with Cutaneous Leishmaniasis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02198-16 ◽

2016 ◽

Vol 61 (3) ◽

Cited By ~ 18

Author(s):

María del Mar Castro ◽

Maria Adelaida Gomez ◽

Anke E. Kip ◽

Alexandra Cossio ◽

Eduardo Ortiz ◽

...

Keyword(s):

Cutaneous Leishmaniasis ◽

Drug Exposure ◽

Mononuclear Cells ◽

Open Label ◽

Time Curve ◽

Peripheral Blood Mononuclear ◽

Content Type ◽

Liquid Chromatography Tandem Mass ◽

Intracellular Compartments

ABSTRACT An open-label pharmacokinetics (PK) clinical trial was conducted to comparatively assess the PK and explore the pharmacodynamics (PD) of miltefosine in children and adults with cutaneous leishmaniasis (CL) in Colombia. Sixty patients, 30 children aged 2 to 12 years and 30 adults aged 18 to 60 years, were enrolled. Participants received miltefosine (Impavido) at a nominal dose of 2.5 mg/kg/day for 28 days. Miltefosine concentrations were measured in plasma and peripheral blood mononuclear cells by liquid chromatography-tandem mass spectrometry of samples obtained during treatment and up to 6 months following completion of treatment, when therapeutic outcome was determined. Fifty-two patients were cured, 5 pediatric patients failed treatment, and 3 participants were lost to follow-up. Leishmania (Viannia) panamensis predominated among the strains isolated (42/46; 91%). Noncompartmental analysis demonstrated that plasma and intracellular miltefosine concentrations were, overall, lower in children than in adults. Exposure to miltefosine, estimated by area under the concentration-time curve and maximum concentration, was significantly lower in children in both the central and intracellular compartments (P < 0.01). Leishmania persistence was detected in 43% of study participants at the end of treatment and in 27% at 90 days after initiation of treatment. Clinical response was not dependent on parasite elimination. In vitro miltefosine susceptibility was similar for Leishmania strains from adults and children. Our results document PK differences for miltefosine in children and adults with cutaneous leishmaniasis that affect drug exposure and could influence the outcome of treatment, and they provide bases for optimizing therapeutic regimens for CL in pediatric populations. (This study has been registered at ClinicalTrials.gov under identifier NCT01462500.)

Download Full-text

Pharmacokinetics-Pharmacodynamics of a Novel β-Lactamase Inhibitor, CB-618, in Combination with Meropenem in anIn VitroInfection Model

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02943-15 ◽

2016 ◽

Vol 60 (7) ◽

pp. 3891-3896 ◽

Cited By ~ 8

Author(s):

Brian D. VanScoy ◽

Michael Trang ◽

Jennifer McCauley ◽

Haley Conde ◽

Sujata M. Bhavnani ◽

...

Keyword(s):

Antimicrobial Agents ◽

Dose Fractionation ◽

Infection Model ◽

Time Curve ◽

Content Type ◽

Concentration Time ◽

Wide Range ◽

Dosing Regimens ◽

Lactamase Inhibitor

ABSTRACTThe usefulness of β-lactam antimicrobial agents is threatened as never before by β-lactamase-producing bacteria. For this reason, there has been renewed interest in the development of broad-spectrum β-lactamase inhibitors. Herein we describe the results of dose fractionation and dose-ranging studies carried out using a one-compartmentin vitroinfection model to determine the exposure measure for CB-618, a novel β-lactamase inhibitor, most predictive of the efficacy when given in combination with meropenem. The challenge panel includedEnterobacteriaceaeclinical isolates, which collectively produced a wide range of β-lactamase enzymes (KPC-2, KPC-3, FOX-5, OXA-48, SHV-11, SHV-27, and TEM-1). Human concentration-time profiles were simulated for each drug, and samples were collected for drug concentration and bacterial density determinations. Using data from dose fractionation studies and a challengeKlebsiella pneumoniaeisolate (CB-618-potentiated meropenem MIC = 1 mg/liter), relationships between change from baseline in log10CFU/ml at 24 h and each of CB-618 area under the concentration-time curve over 24 h (AUC0–24), maximum concentration (Cmax), and percentage of the dosing interval that CB-618 concentrations remained above a given threshold were evaluated in combination with meropenem at 2 g every 8 h (q8h). The exposure measures most closely associated with CB-618 efficacy in combination with meropenem were the CB-618 AUC0–24(r2= 0.835) andCmax(r2= 0.826). Using the CB-618 AUC0–24indexed to the CB-618-potentiated meropenem MIC value, the relationship between change from baseline in log10CFU/ml at 24 h and CB-618 AUC0–24/MIC ratio in combination with meropenem was evaluated using the pooled data from five challenge isolates; the CB-618 AUC0–24/MIC ratio associated with net bacterial stasis and the 1- and 2-log10CFU/ml reductions from baseline at 24 h were 27.3, 86.1, and 444.8, respectively. These data provide a pharmacokinetics-pharmacodynamics (PK-PD) basis for evaluating potential CB-618 dosing regimens in combination with meropenem in future studies.

Download Full-text

Pharmacodynamics of Cefepime Combined with the Novel Extended-Spectrum-β-Lactamase (ESBL) Inhibitor Enmetazobactam for Murine Pneumonia Caused by ESBL-Producing Klebsiella pneumoniae

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00180-20 ◽

2020 ◽

Vol 64 (6) ◽

Cited By ~ 3

Author(s):

Adam Johnson ◽

Laura McEntee ◽

Nicola Farrington ◽

Ruwanthi Kolamunnage-Dona ◽

Samantha Franzoni ◽

...

Keyword(s):

Klebsiella Pneumoniae ◽

Drug Exposure ◽

Antimicrobial Effect ◽

Therapeutic Options ◽

Dose Fractionation ◽

Maximal Effect ◽

The Novel ◽

Time Curve ◽

Content Type ◽

Extended Spectrum

ABSTRACT Klebsiella pneumoniae strains that produce extended-spectrum beta lactamases (ESBLs) are a persistent public health threat. There are relatively few therapeutic options, and there is undue reliance on carbapenems. Alternative therapeutic options are urgently required. A combination of cefepime and the novel beta lactamase inhibitor enmetazobactam is being developed for the treatment of serious infections caused by ESBL-producing organisms. The pharmacokinetics-pharmacodynamics (PK-PD) of cefepime-enmetazobactam against ESBL-producing K. pneumoniae was studied in a neutropenic murine pneumonia model. Dose-ranging studies were performed. Dose fractionation studies were performed to define the relevant PD index for the inhibitor. The partitioning of cefepime and enmetazobactam into the lung was determined by comparing the area under the concentration-time curve (AUC) in plasma and epithelial lining fluid. The magnitude of drug exposure for cefepime-enmetazobactam required for logarithmic killing in the lung was defined using 3 ESBL-producing strains. Cefepime, given as 100 mg/kg of body weight every 8 h intravenously (q8h i.v.), had minimal antimicrobial effect. When this background regimen of cefepime was combined with enmetazobactam, a half-maximal effect was induced with enmetazobactam at 4.71 mg/kg q8h i.v. The dose fractionation study suggested both fT > threshold and fAUC:MIC are relevant PD indices. The AUCELF:AUCplasma ratio for cefepime and enmetazobactam was 73.4% and 61.5%, respectively. A ≥2-log kill in the lung was achieved with a plasma and ELF cefepime fT > MIC of ≥20% and enmetazobactam fT > 2 mg/liter of ≥20% of the dosing interval. These data and analyses provide the underpinning evidence for the combined use of cefepime and enmetazobactam for nosocomial pneumonia.

Download Full-text

In VitroPharmacokinetic/Pharmacodynamic Modeling of Voriconazole Activity against Aspergillus Species in a NewIn VitroDynamic Model

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00549-12 ◽

2012 ◽

Vol 56 (10) ◽

pp. 5321-5327 ◽

Cited By ~ 15

Author(s):

R. Al-Saigh ◽

A. Elefanti ◽

A. Velegraki ◽

L. Zerva ◽

J. Meletiadis

Keyword(s):

Drug Exposure ◽

Maximum Activity ◽

Pharmacodynamic Modeling ◽

Therapeutic Drug ◽

Human Pharmacokinetics ◽

Target Attainment ◽

Time Curve ◽

Standard Dosage ◽

Content Type

ABSTRACTThe pharmacodynamics (PD) of voriconazole activity againstAspergillusspp. were studied using a newin vitrodynamic model simulating voriconazole human pharmacokinetics (PK), and the PK-PD data were bridged with human drug exposure to assess the percent target (near-maximum activity) attainment of different voriconazole dosages. ThreeAspergillusclinical isolates (1A. fumigatus, 1A. flavus, and 1A. terreusisolate) with CLSI MICs of 0.5 mg/liter were tested in anin vitromodel simulating voriconazole PK in human plasma withCmaxvalues of 7, 3.5, and 1.75 mg/liter and at1/2of 6 h. The area under the galactomannan index-time curve (AUCGI) was used as the PD parameter.In vitroPK-PD data were bridged with population human PK of voriconazole exposure, and the percent target attainment was calculated. Thein vitroPK-PD relationship offAUC0-24-AUCGIfollowed a sigmoid pattern (globalR2= 0.97), with near-maximum activities (10% fungal growth) observed at anfAUC0-24(95% confidence interval [CI]) of 18.9 (14.4 to 23.1) mg · h/liter againstA. fumigatus, 26.6 (21.1 to 32.9) mg · h/liter againstA. flavus, and 36.2 (27.8 to 45.7) mg · h/liter againstA. terreus(F test;P< 0.0001). Target attainment for 3, 4, and 5 mg/kg-of-body-weight voriconazole dosages was 24% (11 to 45%), 80% (32 to 97%), and 93% (86 to 97%) forA. fumigatus, 12% (5 to 26%), 63% (17 to 93%), and 86% (73 to 94%) forA. flavus, and 4% (2 to 11%), 36% (6 to 83%), and 68% (47 to 83%) forA. terreus. Based on thein vitroexposure-effect relationships, a standard dosage of voriconazole may be adequate for most patients withA. fumigatusbut notA. flavusandA. terreusinfections, for which a higher drug exposure may be required. This could be achieved using a higher voriconazole dosage, thus highlighting the usefulness of therapeutic drug monitoring in patients receiving a standard dosage.

Download Full-text

Penetration of Vancomycin into Epithelial Lining Fluid in Healthy Volunteers

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00712-11 ◽

2011 ◽

Vol 55 (12) ◽

pp. 5507-5511 ◽

Cited By ~ 37

Author(s):

Thomas P. Lodise ◽

George L. Drusano ◽

Jill M. Butterfield ◽

Joshua Scoville ◽

Mark Gotfried ◽

...

Keyword(s):

Monte Carlo Simulation ◽

Monte Carlo ◽

Healthy Volunteers ◽

Compartment Model ◽

Epithelial Lining ◽

Time Curve ◽

Epithelial Lining Fluid ◽

Content Type ◽

Concentration Time ◽

Few Data

ABSTRACTAlthough vancomycin is often regarded as an agent that concentrates poorly in the lower respiratory tract, as determined from concentrations in epithelial lining fluid (ELF), few data are available. This study sought to determine the profile of vancomycin exposure in the ELF relative to plasma. Population modeling and Monte Carlo simulation were employed to estimate the penetration of vancomycin into ELF. Plasma and ELF pharmacokinetic (PK) data were obtained from 10 healthy volunteers. Concentration-time profiles in plasma and ELF were simultaneously modeled using a three-compartment model with zero-order infusion and first-order elimination and transfer using the big nonparametric adaptive grid (BigNPAG) program. Monte Carlo simulation with 9,999 subjects was performed to calculate the ELF/plasma penetration ratios by estimating the area under the concentration-time curve (AUC) in ELF (AUCELF) and plasma (AUCplasma) after a single simulated 1,000-mg dose. The mean (standard deviation) AUCELF/AUCplasmapenetration ratio was 0.675 (0.677), and the 25th, 50th, and 75th percentile penetration ratios were 0.265, 0.474, and 0.842, respectively. Our results indicate that vancomycin penetrates ELF at approximately 50% of plasma levels. To properly judge the adequacy of current doses and schedules employed in practice, future studies are needed to delineate the PK/PD (pharmacodynamics) target for vancomycin in ELF. If the PK/PD target in ELF is found to be consistent with the currently proposed target of an AUC/MIC of ≥400, suboptimal probability of target attainment would be expected when vancomycin is utilized for pneumonias due to MRSA (methicillin-resistantStaphylococcus aureus) with MICs in excess of 1 mg/liter.

Download Full-text

Pharmacokinetics-Pharmacodynamics of Pyrazinamide in a Novel In Vitro Model of Tuberculosis for Sterilizing Effect: a Paradigm for Faster Assessment of New Antituberculosis Drugs

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01681-08 ◽

2009 ◽

Vol 53 (8) ◽

pp. 3197-3204 ◽

Cited By ~ 126

Author(s):

Tawanda Gumbo ◽

Chandima S. W. Siyambalapitiyage Dona ◽

Claudia Meek ◽

Richard Leff

Keyword(s):

Monte Carlo ◽

Monte Carlo Simulations ◽

Pharmacokinetic Parameters ◽

Maximal Effect ◽

Time Curve ◽

Time Profiles ◽

Concentration Time ◽

Antituberculosis Therapy ◽

Vitro Model

ABSTRACT There are currently renewed efforts to develop drugs that could shorten the duration of antituberculosis therapy. This is best achieved by optimizing the sterilizing effect. However, the current pathway for the development of new molecules with the potential to have a sterilizing effect is inefficient. We designed an in vitro pharmacokinetic-pharmacodynamic model in which Mycobacterium tuberculosis replicating slowly at pH 5.8 was exposed to pyrazinamide by use of the concentration-time profiles encountered in patients. The sterilizing effect rates and the time to the emergence of drug resistance were examined. Daily pyrazinamide dosing for 28 days accurately achieved (i) the pyrazinamide pharmacokinetic parameters, (ii) the lack of early bactericidal activity, (iii) a sterilizing effect rate of 0.10 log10 CFU/ml per day starting on day 6 of therapy, and (iv) a time to the emergence of resistance of the from 2 to 3 weeks of monotherapy encountered in patients with tuberculosis. Next, dose-scheduling studies were performed. The sterilizing effect was linked to the pyrazinamide ratio of the area under the concentration-time curve from 0 to 24 h (AUC0-24) to the MIC (r 2 = 0.80 to 0.90), with 90% of the maximal effect being achieved by an AUC0-24/MIC of 209.08. Resistance suppression was associated with the percentage of time that the concentration persisted above the MIC (r 2 = 0.73 to 0.91). Monte Carlo simulations of 10,000 patients demonstrated that the currently recommended pyrazinamide doses (15 to 30 mg/kg of body weight/day) achieved the AUC0-24/MIC of 209.08 in the epithelial lining fluid of only 15.1 to 53.3% of patients. Doses of >60 mg/kg per day performed better. Our vitro model for the sterilizing effect, together with Monte Carlo simulations, can be used for the faster identification of the clinical doses that are needed to achieve a sterilizing effect and that can then be studied in clinical trials.

Download Full-text