scholarly journals Ceftolozane-Tazobactam Pharmacokinetics in a Critically Ill Patient on Continuous Venovenous Hemofiltration

2015 ◽  
Vol 60 (3) ◽  
pp. 1899-1901 ◽  
Author(s):  
Wesley D. Oliver ◽  
Emily L. Heil ◽  
Jeffrey P. Gonzales ◽  
Shailly Mehrotra ◽  
Kathryn Robinett ◽  
...  
Keyword(s):  
Critically Ill ◽  
Multidrug Resistant ◽  
Critically Ill Patient ◽  
Continuous Venovenous Hemofiltration ◽  
Time Curve ◽  
Content Type ◽  
Dosing Interval ◽  
Drug Concentrations ◽  
Extended Infusion ◽  
Susceptibility Breakpoint

Extended-infusion ceftolozane-tazobactam treatment at 1.5 g every 8 h was used to treat multidrug-resistantPseudomonas aeruginosain a critically ill patient on continuous venovenous hemofiltration. Serum drug concentrations were measured at 1, 4, 5, 6, and 8 h after the start of infusion. Prefilter levels of ceftolozane produced a maximum concentration of drug (Cmax) of 38.57 μg/ml, concentration at the end of the dosing interval (Cmin) of 31.63 μg/ml, time toCmax(Tmax) of 4 h, area under the concentration-time curve from 0 to 8 h (AUC0–8) of 284.38 μg · h/ml, and a half-life (t1/2) of 30.7 h. The concentrations were eight times the susceptibility breakpoint for the entire dosing interval.

scholarly journals Pharmacokinetics and Dialytic Clearance of Ceftazidime-Avibactam in a Critically Ill Patient on Continuous Venovenous Hemofiltration

2017 ◽  
Vol 61 (7) ◽  
Author(s):  
Eric Wenzler ◽  
Kristen L. Bunnell ◽  
Susan C. Bleasdale ◽  
Scott Benken ◽  
Larry H. Danziger ◽  
...  
Keyword(s):  
Steady State ◽  
Plasma Concentration ◽  
Critically Ill ◽  
Critically Ill Patient ◽  
Pharmacokinetic Parameters ◽  
Maximum Plasma ◽  
Continuous Venovenous Hemofiltration ◽  
Total Clearance ◽  
Time Curve ◽  
Drug Concentrations

ABSTRACT Ceftazidime-avibactam administered at 1.25 g every 8 h was used to treat multidrug-resistant Pseudomonas aeruginosa bacteremia in a critically ill patient on continuous venovenous hemofiltration (CVVH). Prefiltration plasma drug concentrations of ceftazidime and avibactam were measured at 0, 1, 2, 4, 6, and 8 h along with postfiltration and ultrafiltrate concentrations at h 2 and h 6. Plasma pharmacokinetic parameters of ceftazidime and avibactam, respectively, were as follows: maximum plasma concentration (C max), 61.10 and 14.54 mg/liter; minimum plasma concentration (C min), 31.96 and 8.45 mg/liter; half-life (t 1/2), 6.07 and 6.78 h; apparent volume of distribution at the steady state (V ss), 27.23 and 30.81 liters; total clearance at the steady state (CLss), 2.87 and 2.95 liters/h; area under the concentration-time curve from 0 to 8 h (AUC0–8), 347.87 and 85.69 mg · h/liter. Concentrations of ceftazidime in plasma exceeded the ceftazidime-avibactam MIC (6 mg/liter) throughout the 8-h dosing interval. Mean CVVH extraction ratios for ceftazidime and avibactam were 14.44% and 11.53%, respectively, and mean sieving coefficients were 0.96 and 0.93, respectively. The calculated mean clearance of ceftazidime by CVVH was 1.64 liters/h and for avibactam was 1.59 liters/h, representing 57.1% of the total clearance of ceftazidime and 54.3% of the total clearance of avibactam. Further data that include multiple patients and dialysis modes are needed to verify the optimal ceftazidime-avibactam dosing strategy during critical illness and CVVH.

scholarly journals Colistin Pharmacokinetics in Burn Patients during Continuous Venovenous Hemofiltration

2014 ◽  
Vol 59 (1) ◽  
pp. 46-52 ◽  
Author(s):  
Kevin S. Akers ◽  
Matthew P. Rowan ◽  
Krista L. Niece ◽  
Ian J. Stewart ◽  
Katrin Mende ◽  
...  
Keyword(s):  
Renal Replacement Therapy ◽  
Replacement Therapy ◽  
Bacterial Infections ◽  
Plasma Concentrations ◽  
Multidrug Resistant ◽  
Pharmacokinetic Data ◽  
Continuous Venovenous Hemofiltration ◽  
Burn Patients ◽  
Time Curve ◽  
Content Type

ABSTRACTWhile colistin is considered a last resort for the treatment of multidrug-resistant Gram-negative bacterial infections, there has been an increase in its use due to the increasing prevalence of drug-resistant infections worldwide. The pharmacology of colistin is complex, and pharmacokinetic data are limited, especially in patients requiring renal replacement therapy. As a result, dosing for patients who require renal replacement remains a challenge. Here, we present pharmacokinetic data for colistin from two burn patients (37 and 68 years old) infected with colistin-susceptible isoclonalAcinetobacter baumanniiand receiving continuous venovenous hemofiltration (CVVH). To our knowledge, we are the first to examine data from before and during CVVH (for one patient), allowing analysis of the effect of CVVH on colistin pharmacokinetics. Pharmacokinetic/pharmacodynamic analysis indicated that a dose increase from 1.5 to 2.2 mg/kg of body weight colistin base activity on CVVH was insufficient to satisfy the target parameter of an AUC24/MIC (area under the concentration-time curve over 24 h in the steady state divided by the MIC) of ≥60 at an MIC of ≥1 μg/ml in one patient with residual endogenous renal function. Plasma concentrations of colistin ranged from 0 to 15 μg/ml, with free colistin levels ranging from 0.4 to 2.2 μg/ml. While both patients resolved their clinical infections and survived to discharge, colistin-resistant colonizing isolates resulted from therapy in one patient. The variabilities observed in colistin concentrations and pharmacokinetic characteristics highlight the importance of pharmacokinetic monitoring of antibiotics in patients undergoing renal replacement therapy.

scholarly journals Pharmacokinetics of 2,000 Milligram Ertapenem in Tuberculosis Patients

2018 ◽  
Vol 62 (5) ◽  
Author(s):  
M. A. Zuur ◽  
S. Ghimire ◽  
M. S. Bolhuis ◽  
A. M. A. Wessels ◽  
R. van Altena ◽  
...  
Keyword(s):  
Central Compartment ◽  
Multidrug Resistant ◽  
Volume Of Distribution ◽  
Interindividual Variation ◽  
Infection Model ◽  
Time Curve ◽  
Once Daily ◽  
Content Type ◽  
Drug Concentrations ◽  
Liquid Chromatography Tandem Mass

ABSTRACT Ertapenem is a carbapenem antibiotic with activity against Mycobacterium tuberculosis . Dose simulations in a hollow-fiber infection model showed that 2,000 mg once daily is an appropriate dose to be tested in clinical studies. Before using this dose in a phase II study, the aim of this prospective pharmacokinetic study was to confirm the pharmacokinetics of 2,000 mg once daily in tuberculosis (TB) patients. Twelve TB patients received a single intravenous dose of 2,000 mg ertapenem as a 30-min infusion. Blood samples were collected at 0, 0.5, 1, 2, 3, 4, 8, 12, and 24 h postadministration. Drug concentrations were measured using a validated liquid chromatography-tandem mass spectrometry assay. A large interindividual variation in the pharmacokinetics of ertapenem was observed. The median (interquartile range) area under the plasma concentration-time curve to infinity (AUC 0–∞ ) was 2,032 (1,751 to 2,346) mg · h/liter, the intercompartmental clearance (CL 12 ) was 1.941 (0.979 to 2.817) liters/h, and the volume of distribution in the central compartment ( V 1 ) was 1.514 (1.064 to 2.210) liters. A more than dose-proportional increase in AUC was observed compared to results reported for 1,000 mg ertapenem in multidrug-resistant TB patients. Based on a MIC of 1.0 mg/liter, 11 out of 12 patients would have reached the target value of unbound drug exceeding the MIC over 40% of the time ( f 40% T >MIC). In conclusion, this study shows that 2,000 mg ertapenem once daily in TB patients reached the expected f 40% T >MIC for most of the patients, and exploration in a phase 2 study can be advocated.

scholarly journals Enteral Administration of Twice-Daily Dolutegravir and Rilpivirine as a Part of a Triple-Therapy Regimen in a Critically Ill Patient with HIV

2017 ◽  
Vol 16 (2) ◽  
pp. 117-119 ◽  
Author(s):  
Sarah Lynn Turley ◽  
Patricia Pecora Fulco
Keyword(s):  
Critically Ill ◽  
Multidrug Resistant ◽  
Critically Ill Patient ◽  
Therapeutic Drug ◽  
Pharmacokinetic Data ◽  
Virologic Suppression ◽  
Orogastric Tube ◽  
Therapy Regimen ◽  
Drug Concentrations ◽  
Enteral Administration

The administration of antiretroviral therapy (ART) in intubated critically ill patients may be challenging. Limited pharmacokinetic data exist characterizing the effects of crushed ART with subsequent enteral administration on antiretroviral drug concentrations or the clinical impact on HIV virologic suppression. We report a case of a 27-year-old HIV-positive male with presumed multidrug-resistant HIV and a diagnosis of lymphoma who required enteral ART administration after intensive care unit admission. Crushed twice-daily dolutegravir (separated from enteral nutrition by 2 hours) and rilpivirine (concurrently with a bolus feed) were administered via an orogastric tube. Therapeutic drug monitoring for both dolutegravir and rilpivirine demonstrated antiretroviral absorption via the enteral route (both values slightly below the therapeutic laboratory reference range) with continued virologic suppression.

scholarly journals Pharmacodynamics of Daptomycin against Enterococcus faecium and Enterococcus faecalis in the Murine Thigh Infection Model

2018 ◽  
Vol 62 (10) ◽  
Author(s):  
James M. Kidd ◽  
Kamilia Abdelraouf ◽  
Tomefa E. Asempa ◽  
Romney M. Humphries ◽  
David P. Nicolau
Keyword(s):  
Enterococcus Faecalis ◽  
Enterococcus Faecium ◽  
Hill Equation ◽  
Infection Model ◽  
Free Drug Concentration ◽  
Time Curve ◽  
Content Type ◽  
Concentration Time ◽  
The Hill ◽  
Susceptibility Breakpoint

ABSTRACT The Clinical and Laboratory Standards Institute (CLSI) daptomycin MIC susceptibility breakpoint for the treatment of enterococcal infections is ≤4 μg/ml. However, patients receiving daptomycin for the treatment of infections caused by enterococci with MICs of ≤4 μg/ml may experience treatment failures. We assessed the pharmacodynamics of daptomycin against enterococci in a neutropenic murine thigh infection model and determined the exposures necessary for bacteriostasis and a 1-log10-CFU reduction of Enterococcus faecalis and Enterococcus faecium. We further characterized daptomycin efficacy at clinically achievable exposures. Six E. faecium and 6 E. faecalis isolates (daptomycin MICs, 0.5 to 32 μg/ml) were studied. Daptomycin was administered at various doses over 24 h to achieve area under the free drug concentration-time curve-to-MIC ratios (fAUC0–24/MIC) ranging from 1 to 148. Daptomycin regimens that simulate mean human exposures following doses of 6, 8, and 10 mg/kg of body weight/day were also studied. Efficacy was assessed by the differences in the number of log10 CFU per thigh at 24 h. The Hill equation was used to estimate the fAUC0–24/MIC required to achieve bacteriostasis and a 1-log10-CFU reduction. For E. faecium, a 1-log10-CFU reduction required an fAUC0–24/MIC of 12.9 (R2 = 0.71). For E. faecalis, a 1-log10-CFU reduction was not achieved, while the fAUC0–24/MIC required for stasis was 7.2 (R2 = 0.8). With a human-simulated regimen of 6 mg/kg/day, a 1-log10-CFU reduction was observed in 3/3 E. faecium isolates with MICs of <4 μg/ml and 0/3 E. faecium isolates with MICs of ≥4 μg/ml; however, a 1-log10-CFU reduction was not achieved for any of the 6 E. faecalis isolates. These results, alongside clinical data, prompt a reevaluation of the current breakpoint.

Lacosamide Pharmacokinetics in a Critically Ill Patient Receiving Continuous Venovenous Hemofiltration

2017 ◽  
Vol 38 (2) ◽  
pp. e17-e21 ◽  
Author(s):  
Miguel J. Franquiz ◽  
Shamir N. Kalaria ◽  
Michael J. Armahizer ◽  
Mathangi Gopalakrishnan ◽  
Paul J. McCarthy ◽  
...  
Keyword(s):  
Critically Ill ◽  
Critically Ill Patient ◽  
Continuous Venovenous Hemofiltration

scholarly journals Clinical Pharmacodynamic Index Identification for Micafungin in Esophageal Candidiasis: Dosing Strategy Optimization

2013 ◽  
Vol 57 (11) ◽  
pp. 5714-5716 ◽  
Author(s):  
David R. Andes ◽  
Daniel K. Reynolds ◽  
Scott A. Van Wart ◽  
Alexander J. Lepak ◽  
Laura L. Kovanda ◽  
...  
Keyword(s):  
Dose Level ◽  
Randomized Trials ◽  
Clinical Investigation ◽  
Time Curve ◽  
Content Type ◽  
Dosing Interval ◽  
Concentration Time ◽  
Dosing Regimens ◽  
Dosing Strategy ◽  
Current Report

ABSTRACTEchinocandins exhibit concentration-dependent effects onCandidaspecies, and preclinical studies support the administration of large, infrequent doses. The current report examines the pharmacokinetics/pharmacodynamics of two multicenter, randomized trials of micafungin dosing regimens that differed in both dose level and dosing interval. Analysis demonstrates the clinical relevance of the dose level and area under the concentration-time curve (AUC). Better, although not statistically significant (P= 0.056), outcomes were seen with higher maximum concentrations of drug in serum (Cmax) and large, infrequent doses. The results support further clinical investigation of novel micafungin dosing regimens with large doses but less than daily administration. (These studies have been registered at ClinicalTrials.gov under registration no. NCT00666185 and NCT00665639.)

scholarly journals Pharmacokinetics and Pharmacodynamics of Imipenem during Continuous Renal Replacement Therapy in Critically Ill Patients

2005 ◽  
Vol 49 (6) ◽  
pp. 2421-2428 ◽  
Author(s):  
Douglas N. Fish ◽  
Isaac Teitelbaum ◽  
Edward Abraham
Keyword(s):  
High Performance ◽  
Continuous Venovenous Hemofiltration ◽  
Systemic Clearance ◽  
Pharmacokinetics And Pharmacodynamics ◽  
Drug Infusion ◽  
Dosing Interval ◽  
Adult Intensive Care Unit ◽  
Drug Concentrations ◽  
Elimination Half ◽  
Higher Doses

ABSTRACT The pharmacokinetics of imipenem were studied in adult intensive care unit (ICU) patients during continuous venovenous hemofiltration (CVVH; n = 6 patients) or hemodiafiltration (CVVHDF; n = 6 patients). Patients (mean ± standard deviation age, 50.9 ± 15.9 years; weight, 98.5 ± 15.9 kg) received imipenem at 0.5 g every 8 to 12 h (total daily doses of 1 to 1.5 g/day) by intravenous infusion over 30 min. Pre- and postmembrane blood (plasma) and corresponding ultrafiltrate or dialysate samples were collected 1, 2, 4, and 8 or 12 h (depending on dosing interval) after completion of the drug infusion. Drug concentrations were measured using validated high-performance liquid chromatography methods. Mean systemic clearance (CL S ) and elimination half-life (t 1/2) of imipenem were 145 ± 18 ml/min and 2.7 ± 1.3 h during CVVH versus 178 ± 18 ml/min and 2.6 ± 1.6 h during CVVHDF, respectively. Imipenem clearance was substantially increased during both CVVH and CVVHDF, with membrane clearance representing 25% and 32% of CL S , respectively. The results of this study indicate that CVVH and CVVHDF contribute to imipenem clearance to a greater degree than previously reported. Imipenem doses of 1.0 g/day appear to achieve concentrations adequate to treat most common gram-negative pathogens (MIC up to 2 μg/ml) during CVVH or CVVHDF, but doses of 2.0 g/day or more may be required to adequately treat and prevent resistance in pathogens with higher MICs (MIC = 4 to 8 μg/ml). Higher doses should only be used after consideration of potential central nervous system toxicities or other risks of therapy in these severely ill patients.

scholarly journals Simultaneous Infection with Enterobacteriaceae and Pseudomonas aeruginosa Harboring Multiple Carbapenemases in a Returning Traveler Colonized with Candida auris

2019 ◽  
Vol 64 (2) ◽  
Author(s):  
Ayesha Khan ◽  
William C. Shropshire ◽  
Blake Hanson ◽  
An Q. Dinh ◽  
Audrey Wanger ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Susceptibility Testing ◽  
Multidrug Resistant ◽  
Critically Ill Patient ◽  
Whole Genome ◽  
Candida Auris ◽  
Content Type ◽  
Simultaneous Infection ◽  
Polymicrobial Infections ◽  
Selection Of

ABSTRACT We report our clinical experience treating a critically ill patient with polymicrobial infections due to multidrug-resistant Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa in a 56-year-old woman who received health care in India and was also colonized by Candida auris. A precision medicine approach using whole-genome sequencing revealed a multiplicity of mobile elements associated with NDM-1, NDM-5, and OXA-181 and, supplemented with susceptibility testing, guided the selection of rational antimicrobial therapy.

scholarly journals Effect of the β-Lactamase Inhibitor Vaborbactam Combined with Meropenem against Serine Carbapenemase-Producing Enterobacteriaceae

2016 ◽  
Vol 60 (9) ◽  
pp. 5454-5458 ◽  
Author(s):  
Mariana Castanheira ◽  
Paul R. Rhomberg ◽  
Robert K. Flamm ◽  
Ronald N. Jones
Keyword(s):  
Multidrug Resistant ◽  
Inhibitor Concentration ◽  
Efflux System ◽  
Content Type ◽  
Fixed Concentration ◽  
Serious Infections ◽  
Elevated Expression ◽  
Further Development ◽  
Susceptibility Breakpoint ◽  
Lactamase Inhibitor

ABSTRACTKlebsiella pneumoniaecarbapenemase (KPC)-producing isolates have become increasingly prevalent worldwide, and these organisms are often multidrug resistant, limiting the therapeutic options available for treating infections. We evaluated the activity of meropenem combined with the serine β-lactamase inhibitor vaborbactam (formerly RPX7009) against 315 serine carbapenemase-producingEnterobacteriaceae(CPE) isolates by use of checkerboard-designed panels to assess the optimal inhibitor concentration (range tested, 0.5 to 32 μg/ml). Overall, meropenem alone (MIC50and MIC90, 16 and >64 μg/ml, respectively) inhibited only 2.2% of the isolates at ≤1 μg/ml (the CLSI susceptibility breakpoint) and 7.3% of the isolates at ≤2 μg/ml (the EUCAST breakpoint). Vaborbactam restored meropenem activity for 72.7 to 98.1% of CPE isolates at ≤2 μg/ml, and maximum potentiation was achieved with fixed concentrations of ≥8 μg/ml of the inhibitor (≥96.5% of isolates were inhibited at ≤2 μg/ml of meropenem-vaborbactam). Meropenem-vaborbactam with a fixed concentration of 8 μg/ml of the inhibitor (MIC50, ≤0.06 μg/ml for all organisms) inhibited 93.7% of the CPE isolates displaying elevated meropenem MICs at ≤1 μg/ml. Meropenem-vaborbactam MICs were elevated for isolates producing metallo-β-lactamases (MIC, 16 to >64 μg/ml) or displaying decreased expression of OmpK37 and/or elevated expression of the AcrAB-TolC efflux system (MIC, 16 μg/ml). Vaborbactam showed no antibacterial activity alone (all MICs, >64 μg/ml). Meropenem-vaborbactam appears to be a good candidate for further development and it could increase the options for treatment of serious infections caused by carbapenemase-producing pathogens.

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