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12 pages, 2524 KiB

Open AccessArticle

A Quantitative Examination and Comparison of the Ability of Australian Gentamicin Dosing Guidelines to Achieve Target Therapeutic Concentrations in Neonates

by Luke E. Grzeskowiak, Sheree Wynne and Michael J. Stark

Antibiotics 2025, 14(1), 48; https://doi.org/10.3390/antibiotics14010048 - 8 Jan 2025

Viewed by 740

Abstract

Background: Effective gentamicin dosing is crucial to the survival of neonates with suspected sepsis but requires a careful balance between attaining both effective peak and safe trough concentrations. We aimed to systematically compare existing gentamicin dosing guidelines for neonates in Australia to determine [...] Read more.

Background: Effective gentamicin dosing is crucial to the survival of neonates with suspected sepsis but requires a careful balance between attaining both effective peak and safe trough concentrations. We aimed to systematically compare existing gentamicin dosing guidelines for neonates in Australia to determine the extent to which they reach therapeutic targets. Methods: Simulations of a single gentamicin dose to a virtual representative neonatal population according to each Australian guideline were performed using population pharmacokinetic modelling. We determined the proportion of neonates who would achieve peak gentamicin concentrations of ≥5 or ≥10 mg/L and trough concentrations of ≤1 or ≤2 mg/L. We calculated the probability of target attainment (PTA) according to gestation at birth (22 to 40 weeks) and postnatal age (1–7, 8–14, 15–21, 22–28 days). Results: Five unique dosing guidelines were identified. Guidelines varied considerably with respect to dose (4.5 to 7 mg/kg), dosing interval (24 to 48 h), and characteristics used to individualise dosing regimens (e.g., gestation at birth and postnatal age). Guidelines were satisfactory in routinely achieving effective peak concentrations ≥ 5 mg/L, but PTAs for effective peak concentrations ≥ 10 mg/L varied considerably from 5% to 100% based on dose, gestation, and postnatal age. PTAs for trough concentrations ≤ 1 mg/L ranged from 0% to 100%, being lowest among extremely preterm infants. Conclusions: Current Australian gentamicin guidelines demonstrate significant variability in their ability to achieve defined therapeutic targets, necessitating efforts to improve standardisation of dosing recommendations. Further research to define optimal pharmacodynamic targets in neonates with respect to clinical outcomes are also urgently warranted. Full article

(This article belongs to the Special Issue Pharmacokinetic and Antibiotic Dosing for Intensive Care Unit Patients)

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12 pages, 1316 KiB

Open AccessArticle

Therapeutic Monitoring of Vancomycin Implemented by Eremomycin ELISA

by Inna A. Galvidis, Yury A. Surovoy, Vitaly R. Sharipov, Pavel D. Sobolev and Maksim A. Burkin

Antibiotics 2024, 13(12), 1133; https://doi.org/10.3390/antibiotics13121133 - 25 Nov 2024

Viewed by 1096

Abstract

Background/Objectives: Due to a narrow therapeutic window, side-effects, toxicities, and individual pharmacokinetics (PK) variability, WHO classifies vancomycin (VCM) as a “watch antibiotic” whose use should be monitored to improve clinical effectiveness. Availability and ease of use have made the immunoassay technique the basic [...] Read more.

Background/Objectives: Due to a narrow therapeutic window, side-effects, toxicities, and individual pharmacokinetics (PK) variability, WHO classifies vancomycin (VCM) as a “watch antibiotic” whose use should be monitored to improve clinical effectiveness. Availability and ease of use have made the immunoassay technique the basic tool for the therapeutic drug monitoring (TDM) of VCM concentrations. Methods: The present study describes the development of a TDM tool for VCM based on anti-eremomycin (ERM) antibody enzyme-linked immunosorbent assay (ELISA). Results: The optimized assay format based on coating a BSA-VCM conjugate allowed for the equal recognition of both VCM and ERM (100 and 104%) and was not influenced by concomitant antibiotics. Among the sample pretreatments studied, acetonitrile deproteinization was preferred to effectively remove the most likely matrix interferences and to provide 75–96% VCM recovery in the range of 3–30 mg/L, ensuring reliable determination of the key PK parameter, Ctrough. Higher peak concentrations were measured in more diluted samples. Several inflammatory indices, biochemical markers, and key proteins significantly different from normal in critically ill patients were investigated as assay interferers and were found not to interfere with VCM analysis. Serum samples (n = 108) from patients (n = 4) with extensive burn injuries treated with combined antibiotic therapy were analyzed for VCM using the developed assay and confirmed by LC-MS/MS, demonstrating good agreement. Conclusions: The approach used shows that the same analytical instrument is suitable for measuring structurally related analytes and is fully adequate for their therapeutic monitoring. Suboptimal exposure based on Ctrough values obtained with standard dosing regimens supports the use of TDM in these patients. Full article

(This article belongs to the Special Issue Pharmacokinetic and Antibiotic Dosing for Intensive Care Unit Patients)

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9 pages, 1618 KiB

Open AccessArticle

Loading Dose of Ceftazidime Needs to Be Increased in Critically Ill Patients: A Retrospective Study to Evaluate Recommended Loading Dose with Pharmacokinetic Modelling

by Manon Launay, Edouard Ollier, Benjamin Kably, Félicien Le Louedec, Guillaume Thiery, Julien Lanoiselée and Sophie Perinel-Ragey

Antibiotics 2024, 13(8), 756; https://doi.org/10.3390/antibiotics13080756 - 11 Aug 2024

Viewed by 1247

Abstract

To rapidly achieve ceftazidime target concentrations, a 2 g loading dose (LD) is recommended before continuous infusion, but its adequacy in critically ill patients, given their unique pharmacokinetics, needs investigation. This study included patients from six ICUs in Saint-Etienne and Paris, France, who [...] Read more.

To rapidly achieve ceftazidime target concentrations, a 2 g loading dose (LD) is recommended before continuous infusion, but its adequacy in critically ill patients, given their unique pharmacokinetics, needs investigation. This study included patients from six ICUs in Saint-Etienne and Paris, France, who received continuous ceftazidime infusion with plasma concentration measurements. Using MONOLIX and R, a pharmacokinetic (PK) model was developed, and the literature on ICU patient PK models was reviewed. Simulations calculated the LD needed to reach a 60 mg/L target concentration and assessed ceftazidime exposure for various regimens. Among 86 patients with 223 samples, ceftazidime PK was best described by a one-compartment model with glomerular filtration rate explaining clearance variability. Typical clearance and volume of distribution were 4.45 L/h and 88 L, respectively. The literature median volume of distribution was 37.2 L. Simulations indicated that an LD higher than 2 g was needed to achieve 60 mg/L in 80% of patients, with a median LD of 4.9 g. Our model showed a 4 g LD followed by 6 g/day infusion reached effective concentrations within 1 h, while a 2 g LD caused an 18 h delay in achieving target steady state. Full article

(This article belongs to the Special Issue Pharmacokinetic and Antibiotic Dosing for Intensive Care Unit Patients)

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14 pages, 1006 KiB

Open AccessFeature PaperArticle

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

Cited by 1 | Viewed by 1760

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

Open AccessArticle

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

Cited by 3 | Viewed by 1838

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

Open AccessArticle

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 5 | Viewed by 2905

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

Open AccessArticle

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 7 | Viewed by 2441

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

Open AccessReview

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 16 | Viewed by 8930

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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