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Antibiotics
Special Issues
Pharmacokinetic and Antibiotic Dosing for Intensive Care Unit Patients
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Pharmacokinetic and Antibiotic Dosing for Intensive Care Unit Patients

A special issue of Antibiotics (ISSN 2079-6382). This special issue belongs to the section "Pharmacokinetics and Pharmacodynamics of Drugs".

Deadline for manuscript submissions: 30 November 2024 | Viewed by 10901

Special Issue Editor

Dr. Yuhki Sato

E-Mail Website
Guest Editor
Department of Pharmaceutical Sciences, Faculty of Pharmacy and Pharmaceutical Sciences, Fukuyama University, Fukuyama-shi, Hiroshima 7290292, Japan
Interests: antibiotics; pharmacokinetics-pharmacodynamics; therapeutic drug monitoring; population pharmacokinetics analysis

Special Issue Information

Dear Colleagues,

Critically ill intensive care patients, particularly those with severe sepsis and septic shock, are at risk of antibiotic failure and secondary infections associated with incorrect antibiotic use. Optimizing antibiotic dosing through prolonged infusions can be beneficial in intensive care populations with altered pharmacokinetics. The use of a drug administration plan and therapeutic drug monitoring (TDM) based on pharmacokinetics (PK) analysis is important for the effective use of antibiotics to treat infections. We focused on antibiotic dosing in intensive care unit (ICU) patients from the viewpoint of PK. PK analysis utilizes the restrictive information that is obtained by a clinic to the maximum, and it allows to provide adequate antibiotic therapy. This Special Issue seeks manuscript submissions that further our understanding of PK and antibiotic dosing in ICU patients.          

Authors are invited to submit manuscripts of original preclinical and clinical research within their area of interest including (but not limited) to the topics highlighted below:

  1. Antibiotic optimization on continuous renal replacement therapy or extracorporeal membrane oxygenation therapy
  2. Population pharmacokinetics analysis of antibiotics
  3. Clinical antibiotic stewardship in the ICU
  4. Antibiotics dosing considering bacterial susceptibility

Dr. Yuhki Sato
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Antibiotics is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • antibiotics
  • pharmacokinetics-pharmacodynamics
  • therapeutic drug monitoring
  • population pharmacokinetics analysis
  • bacterial susceptibility

Published Papers (5 papers)

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Research

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14 pages, 1006 KiB  
Article
Meropenem Disposition in Neonatal and Pediatric Extracorporeal Membrane Oxygenation and Continuous Renal Replacement Therapy
by Pavla Pokorná, Danica Michaličková, Dick Tibboel and Jonas Berner
Antibiotics 2024, 13(5), 419; https://doi.org/10.3390/antibiotics13050419 - 3 May 2024
Viewed by 401
Abstract
This study aimed to characterize the impact of extracorporeal membrane oxygenation (ECMO) on the pharmacokinetics (PK) of meropenem in neonates and children and to provide recommendations for meropenem dosing in this specific population of patients. Therapeutic drug monitoring (152 meropenem plasma concentrations) data [...] Read more.
This study aimed to characterize the impact of extracorporeal membrane oxygenation (ECMO) on the pharmacokinetics (PK) of meropenem in neonates and children and to provide recommendations for meropenem dosing in this specific population of patients. Therapeutic drug monitoring (152 meropenem plasma concentrations) data from 45 patients (38 received ECMO) with a body weight (BW) of 7.88 (3.62–11.97) kg (median (interquartile range)) and postnatal age of 3 (0–465) days were collected. The population PK analysis was performed using NONMEM V7.3.0. Monte Carlo simulations were performed to assess the probability of target achievement (PTA) for 40% of time the free drug remained above the minimum inhibitory concentration (fT > MIC) and 100% fT > MIC. BW was found to be a significant covariate for the volume of distribution (Vd) and clearance (CL). Additionally, continuous renal replacement therapy (CRRT) was associated with a two-fold increase in Vd. In the final model, the CL and Vd for a typical patient with a median BW of 7.88 kg that was off CRRT were 1.09 L/h (RSE = 8%) and 3.98 L (14%), respectively. ECMO did not affect meropenem PK, while superimposed CRRT significantly increased Vd. We concluded that current dosing regimens provide acceptably high PTA for MIC ≤ 4 mg/L for 40% fT > MIC, but individual dose adjustments are needed for 100% fT > MIC. Full article
(This article belongs to the Special Issue Pharmacokinetic and Antibiotic Dosing for Intensive Care Unit Patients)
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10 pages, 3102 KiB  
Article
No Sequestration of Commonly Used Anti-Infectives in the Extracorporeal Membrane Oxygenation (ECMO) Circuit—An Ex Vivo Study
by Hendrik Booke, Benjamin Friedrichson, Lena Draheim, Thilo Caspar von Groote, Otto Frey, Anka Röhr, Kai Zacharowski and Elisabeth Hannah Adam
Antibiotics 2024, 13(4), 373; https://doi.org/10.3390/antibiotics13040373 - 19 Apr 2024
Viewed by 582
Abstract
Patients undergoing extracorporeal membrane oxygenation (ECMO) often require therapy with anti-infective drugs. The pharmacokinetics of these drugs may be altered during ECMO treatment due to pathophysiological changes in the drug metabolism of the critically ill and/or the ECMO therapy itself. This study investigates [...] Read more.
Patients undergoing extracorporeal membrane oxygenation (ECMO) often require therapy with anti-infective drugs. The pharmacokinetics of these drugs may be altered during ECMO treatment due to pathophysiological changes in the drug metabolism of the critically ill and/or the ECMO therapy itself. This study investigates the latter aspect for commonly used anti-infective drugs in an ex vivo setting. A fully functional ECMO device circulated an albumin–electrolyte solution through the ECMO tubes and oxygenator. The antibiotic agents cefazolin, cefuroxim, cefepime, cefiderocol, linezolid and daptomycin and the antifungal agent anidulafungin were added. Blood samples were taken over a period of four hours and drug concentrations were measured via high-pressure liquid chromatography (HPLC) with UV detection. Subsequently, the study analyzed the time course of anti-infective concentrations. The results showed no significant changes in the concentration of any tested anti-infectives throughout the study period. This ex vivo study demonstrates that the ECMO device itself has no impact on the concentration of commonly used anti-infectives. These findings suggest that ECMO therapy does not contribute to alterations in the concentrations of anti-infective medications in severely ill patients. Full article
(This article belongs to the Special Issue Pharmacokinetic and Antibiotic Dosing for Intensive Care Unit Patients)
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8 pages, 217 KiB  
Article
The Impact of Antibiotics Administration on Mortality for Time in Sepsis and Septic Shock Patients including Possible Reasons for Delayed Administration in Malaysia
by Ann L. Arulappen, Monica Danial, Ling Wei Ng and Jui Chang Teoh
Antibiotics 2022, 11(9), 1202; https://doi.org/10.3390/antibiotics11091202 - 5 Sep 2022
Cited by 3 | Viewed by 1735
Abstract
The 2017 Surviving Sepsis Campaign guidelines endorse a focus on the rapidity of treatment once sepsis has been identified, with a strong recommendation for the administration of antimicrobial drugs within one hour; however, the quality of the supporting evidence is evaluated as moderate. [...] Read more.
The 2017 Surviving Sepsis Campaign guidelines endorse a focus on the rapidity of treatment once sepsis has been identified, with a strong recommendation for the administration of antimicrobial drugs within one hour; however, the quality of the supporting evidence is evaluated as moderate. This study was conducted for six months prospectively at a single center in an intensive care unit (ICU) from March 2020 to August 2020. All the patients, regardless of their age and gender, admitted into ICU who had their first episode of sepsis or septic shock concomitantly started on a broad-spectrum antibiotic given intravenously. For patients who had multiple episodes of sepsis throughout the study period, data from the very first episode of the sepsis were included in this study. Of all the 78 patients, only 38 (48.7%) received the antibiotics prescribed within an hour. The compliance rate as per the Surviving Sepsis Campaign was only 51.3%, which accounted for 40 patients. The overall survival rate was 60.3%. This study revealed that delayed antibiotics administration (more than an hour) significantly affects mortality. Full article
(This article belongs to the Special Issue Pharmacokinetic and Antibiotic Dosing for Intensive Care Unit Patients)
13 pages, 2387 KiB  
Article
Daptomycin Population Pharmacokinetics in Patients Affected by Severe Gram-Positive Infections: An Update
by Giuseppe Balice, Claudio Passino, Maria Grazia Bongiorni, Luca Segreti, Alessandro Russo, Marianna Lastella, Giacomo Luci, Marco Falcone and Antonello Di Paolo
Antibiotics 2022, 11(7), 914; https://doi.org/10.3390/antibiotics11070914 - 7 Jul 2022
Cited by 6 | Viewed by 1597
Abstract
Daptomycin pharmacokinetics may not depend on renal function only and it significantly differs between healthy volunteers and severely ill patients. Herein, we propose a population pharmacokinetics model based on 424 plasma daptomycin concentrations collected from 156 patients affected by severe Gram-positive infections during [...] Read more.
Daptomycin pharmacokinetics may not depend on renal function only and it significantly differs between healthy volunteers and severely ill patients. Herein, we propose a population pharmacokinetics model based on 424 plasma daptomycin concentrations collected from 156 patients affected by severe Gram-positive infections during a routine therapeutic drug monitoring protocol. Model building and validation were performed using NONMEM 7.2 (ICON plc), Xpose4 and Perl-speaks-to-NONMEM. The final pop-PK model was a one-compartment first-order elimination model, with a 2.7% IIV for drug clearance (Cl), influence of creatinine clearance on drug clearance and of sex on distribution volume. After model validation, we simulated 10,000 patients with the Monte-Carlo method to predict the efficacy and tolerability of different daptomycin daily dosages. For the most common 6 mg/kg daily dose, the simulated probability of overcoming the toxic minimum concentration (24.3 mg/L) was 14.8% and the efficacy (expressed as a cumulative fraction of response) against methicillin-resistant S. aureus, S. pneumoniae and E. faecium was 95.77%, 99.99% and 68%, respectively. According to the model-informed precision dosing paradigm, pharmacokinetic models such as ours could help clinicians to perform patient-tailored antimicrobial dosing and maximize the odds of therapy success without neglecting toxicity risks. Full article
(This article belongs to the Special Issue Pharmacokinetic and Antibiotic Dosing for Intensive Care Unit Patients)
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Review

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17 pages, 1304 KiB  
Review
Update on Therapeutic Drug Monitoring of Beta-Lactam Antibiotics in Critically Ill Patients—A Narrative Review
by Jan Stašek, Filip Keller, Veronika Kočí, Jozef Klučka, Eva Klabusayová, Ondřej Wiewiorka, Zuzana Strašilová, Miroslava Beňovská, Markéta Škardová and Jan Maláska
Antibiotics 2023, 12(3), 568; https://doi.org/10.3390/antibiotics12030568 - 13 Mar 2023
Cited by 6 | Viewed by 5753
Abstract
Beta-lactam antibiotics remain one of the most preferred groups of antibiotics in critical care due to their excellent safety profiles and their activity against a wide spectrum of pathogens. The cornerstone of appropriate therapy with beta-lactams is to achieve an adequate plasmatic concentration [...] Read more.
Beta-lactam antibiotics remain one of the most preferred groups of antibiotics in critical care due to their excellent safety profiles and their activity against a wide spectrum of pathogens. The cornerstone of appropriate therapy with beta-lactams is to achieve an adequate plasmatic concentration of a given antibiotic, which is derived primarily from the minimum inhibitory concentration (MIC) of the specific pathogen. In a critically ill patient, the plasmatic levels of drugs could be affected by many significant changes in the patient’s physiology, such as hypoalbuminemia, endothelial dysfunction with the leakage of intravascular fluid into interstitial space and acute kidney injury. Predicting antibiotic concentration from models based on non-critically ill populations may be misleading. Therapeutic drug monitoring (TDM) has been shown to be effective in achieving adequate concentrations of many drugs, including beta-lactam antibiotics. Reliable methods, such as high-performance liquid chromatography, provide the accurate testing of a wide range of beta-lactam antibiotics. Long turnaround times remain the main drawback limiting their widespread use, although progress has been made recently in the implementation of different novel methods of antibiotic testing. However, whether the TDM approach can effectively improve clinically relevant patient outcomes must be proved in future clinical trials. Full article
(This article belongs to the Special Issue Pharmacokinetic and Antibiotic Dosing for Intensive Care Unit Patients)
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Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

Title: Meropenem disposition in neonatal and pediatric extracorporeal membrane oxygenation: a retrospective study
Authors: Pavla Pokorná (1,2,4), Danica Michaličková (1), Dick Tibboel (2,5) Jonas Berner (2,3,4),
Affiliation: Affiliations: 1. Institute of Pharmacology, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic 2. Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic 3. Department of Physiology and Pharmacology, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden 4. Pediatric Perioperative medicine and intensive care, Astrid Lindgren Children´s Hospital, Karolinska University Hospital, Stockholm, Sweden 5. Department of Paediatric Surgery, Erasmus Medical Center Sophia Children’s Hospital, Rotterdam, The Netherlands
Abstract: Introduction: Meropenem is a broad-spectrum antibiotic commonly used to treat serious infections in the pediatric population treated with extracorporeal membrane oxygenation (ECMO). It is known that ECMO may affect the drug's pharmacokinetics (PK) by altering the drug's clearance (CL), volume of distribution (Vd). There are limited data on ECMO influence on PK of meropenem in neonates and children undergoing ECMO. Therefore, the aim of this study was to describe PK of meropenem in critically ill neonates and children undergoing ECMO. Methodology: Data from therapeutic drug monitoring (TDM) were available from 45 critically ill patients (median (interquartile range, IQR), body weight (BW): 7.88 (3.62 – 11.97) kg; postnatal age (PNA) at start of therapy: 3 (0 – 465)) days) treated with meropenem. In total 38 patients received veno-venous (VV) or veno-arterial (VA) ECMO. There were 152 available plasma concentrations ranging from 0.68 to 75 mg/L, of whom 94 were collected during ECMO treatment. Population PK analysis was performed using NONMEM V7.4.0. The following covariates were tested: maturation variables: BW, PNA; disease status: laboratory values, including serum creatinine, serum urea, serum albumin, total bilirubin, blood pH, aspartate transaminase, and alanine transaminase; concomitant therapy: use of diuretics, inotropes, as well as use of continuous renal replacement therapy (CRRT); ECMO variables: on/off ECMO, duration of ECMO treatment, ECMO flow rate and speed. Monte Carlo dosing simulations were performed using Simulx (Lixoft, France) for short-term infusion (0.5, and 3 h) of 20mg/kg and 40 mg/kg of meropenem every 8 h (q8h) and continuous regimen of 60 and 120 mg/kg/day for patients with a typical individual with BW of 7.88 on and off CRRT during 7 days. Probability of target attainment (PTA) was assessed for 40% and 100% fT% > MIC for MIC= 1, 2, 4, 8, 16, 32 mg/L. Results: Observed meropenem plasma concentrations were best described by a one-compartment model with log-normally distributed intra-individual variability (IIV) on CL and Vd. A proportional residual error model provided the best description of residual variability. BW was found to be a significant covariate for Vd and CL; adding CRRT as a binary covariate (i.e., on/off) on Vd resulted in a statistically significant improvement of the model fit. In the final model, CL and Vd for a typical patient of the median BW of 7.88 kg that was off CRRT were 1.09 L/hr (RSE = 8%)) and 3.98 L (14%), respectively. CRRT was found to increase Vd approximately 2 times. According to simulations, none of the regimens achieved PTA for 100% fT% > MIC for any MIC, whereas PTA for 40% fT% > MIC was achieved for MICs up to 4 mg/L. Conclusion: ECMO does not affect the PK of meropenem in the neonatal and pediatric cohort, but CRRT use increases Vd. BW is a significant covariate for CL and Vd. Further larger studies should confirm these results.

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