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Optimizing Antibiotic Treatment: Pharmacokinetics and Clinical Trials

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

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 26808

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Dr. Philipp Simon

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Guest Editor

Department of Anaesthesiology and Intensive Care Medicine, University of Leipzig Medical Centre, Leipzig, Germany
Interests: critical care; infections; sepsis; obesity; antibiotics; microdialysis; anesthesia; mechanical ventilation; electric impedance tomography
Special Issues, Collections and Topics in MDPI journals

Dr. David P. Nicolau

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Guest Editor

Center for Anti-Infective Research & Development Hartford Hospital, 80 Seymour Street, Hartford, CT 06102, USA
Interests: clinical pharmacokinetics; pharmacodynamics; development of antimicrobial utilization methodologies focusing on animal models of infection; healthy volunteer studies; clinical studies as tools for success

Special Issue Information

Dear Colleagues,

For the success of an anti-infective therapy as well as the prevention of resistance development, the correct dosage is decisive, in addition to the choice of antibiotic and the duration of therapy. The pharmacological concept of therapy with antibiotics is based on the fact that a sufficient and adequate antibacterial effect is achieved at the site of the bacterial infection. Distribution as a pharmacokinetic process depends on the pharmacological properties of the substances but also on physiological conditions.

Various factors, such as liver or kidney insufficiency as well as obesity, influence the pharmacokinetics of antibiotics to different degrees and often make dose adjustment necessary. Especially in intensive care medicine for the treatment of severe, life-threatening infections, this poses ever new challenges for physicians.

Against this background, well-founded pharmacokinetic information in different patient groups with different influencing factors is essential to ensure adequate antibiotic therapy. This also makes it necessary to determine concentrations in the target tissue. In addition, different dosage regimens such as prolonged and continuous application are of great interest in order to ensure effective antibiotic therapy.

In this Special Issue on “Optimizing Antibiotic Treatment: Pharmacokinetics and Clinical Trials”, the progress made in optimizing antibiotic therapy from a pharmacokinetic perspective and the effects in different clinical areas will be published. The issue welcomes different types of submission, such as original research papers, short communications, reviews, case reports, and perspectives.

Dr. Philipp Simon
Dr. David P. Nicolau
Guest Editors

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.

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Keywords

Pharmacokinetic/pharmacodynamic
Renal insufficiency
Renal replacement therapy
Interactions
Dosing
Therapeutic drug monitoring
Antibiotic resistance
Empiric therapy
Obesity
Sepsis
Critical care
Microdialysis

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Published Papers (8 papers)

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Research

9 pages, 662 KiB

Open AccessArticle

Concomitant Treatment with Voriconazole and Flucloxacillin: A Combination to Avoid

by Ruth Van Daele, Joost Wauters, Pieter De Cock, Franky Buyle, John Leys, Pieter Van Brantegem, Matthias Gijsen, Pieter Annaert, Yves Debaveye, Katrien Lagrou, Willy E. Peetermans, Roger J. Brüggemann and Isabel Spriet

Antibiotics 2021, 10(9), 1112; https://doi.org/10.3390/antibiotics10091112 - 15 Sep 2021

Cited by 9 | Viewed by 2578

Abstract

Background: Voriconazole is an antifungal drug used as one of the first-line treatments for invasive aspergillosis. This drug is extensively metabolized, predominantly via cytochrome P450 enzymes. An interaction between flucloxacillin and voriconazole, leading to subtherapeutic voriconazole concentrations, has previously been reported. We aimed to demonstrate that flucloxacillin independently influences voriconazole exposure. Methods: Patients from three Belgian hospitals, treated with a combination of voriconazole and flucloxacillin, were included in this retrospective study. Voriconazole concentrations were collected both in a timeframe with and without flucloxacillin co-treatment. Multivariate analyses were performed to study the independent effect of flucloxacillin treatment on voriconazole exposure and the possible influence of the flucloxacillin dose. Results: Thirty-three patients were included in this study and 145 trough concentrations (51 with, and 94 without concomitant flucloxacillin treatment) were analyzed. The median (IQR) voriconazole trough concentration sampled during flucloxacillin co-treatment was 0.5 (0–1.8) mg/L, whereas samples without flucloxacillin co-treatment had a median (IQR) voriconazole trough concentration of 3.5 (1.7–5.1) mg/L (p = 0.002), while receiving similar voriconazole doses. Subtherapeutic concentrations (<1 mg/L) were observed in 69% and 7% of the samples with flucloxacillin co-treatment versus samples without flucloxacillin co-treatment, respectively. Conclusion: This study shows that flucloxacillin co-treatment independently decreases voriconazole exposure. Caution is needed when these two drugs are administered simultaneously. Full article

(This article belongs to the Special Issue Optimizing Antibiotic Treatment: Pharmacokinetics and Clinical Trials)

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11 pages, 1147 KiB

Open AccessArticle

The Role of Non-Enzymatic Degradation of Meropenem—Insights from the Bottle to the Body

by Uwe Liebchen, Sophie Rakete, Michael Vogeser, Florian M. Arend, Christina Kinast, Christina Scharf, Michael Zoller, Ulf Schönermarck and Michael Paal

Antibiotics 2021, 10(6), 715; https://doi.org/10.3390/antibiotics10060715 - 14 Jun 2021

Cited by 3 | Viewed by 3263

Abstract

Several studies have addressed the poor stability of meropenem in aqueous solutions, though not considering the main degradation product, the open-ring metabolite (ORM) form. In the present work, we elucidate the metabolic fate of meropenem and ORM from continuous infusion to the human bloodstream. We performed in vitro infusate stability tests at ambient temperature with 2% meropenem reconstituted in 0.9% normal saline, and body temperature warmed buffered human serum with 2, 10, and 50 mg/L meropenem, covering the therapeutic range. We also examined meropenem and ORM levels over several days in six critically ill patients receiving continuous infusions. Meropenem exhibited a constant degradation rate of 0.006/h and 0.025/h in normal saline at 22 °C and serum at 37 °C, respectively. Given that 2% meropenem remains stable for 17.5 h in normal saline (≥90% of the initial concentration), we recommend replacement of the infusate every 12 h. Our patients showed inter-individually highly variable, but intra-individually constant molar ORM/(meropenem + ORM) ratios of 0.21–0.52. Applying a population pharmacokinetic approach using the degradation rate in serum, spontaneous degradation accounted for only 6% of the total clearance. Full article

(This article belongs to the Special Issue Optimizing Antibiotic Treatment: Pharmacokinetics and Clinical Trials)

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14 pages, 16695 KiB

Open AccessArticle

Novel Pharmacokinetic/Pharmacodynamic Parameters Quantify the Exposure–Effect Relationship of Levofloxacin against Fluoroquinolone-Resistant Escherichia coli

by Johanna Seeger, Sebastian Guenther, Katharina Schaufler, Stefan E. Heiden, Robin Michelet and Charlotte Kloft

Antibiotics 2021, 10(6), 615; https://doi.org/10.3390/antibiotics10060615 - 21 May 2021

Cited by 7 | Viewed by 2934

Abstract

Minimal inhibitory concentration-based pharmacokinetic/pharmacodynamic (PK/PD) indices are commonly applied to antibiotic dosing optimisation, but their informative value is limited, as they do not account for bacterial growth dynamics over time. We aimed to comprehensively characterise the exposure–effect relationship of levofloxacin against Escherichia coli and quantify strain-specific characteristics applying novel PK/PD parameters. In vitro infection model experiments were leveraged to explore the exposure–effect relationship of three clinical Escherichia coli isolates, harbouring different genomic fluoroquinolone resistance mechanisms, under constant levofloxacin concentrations or human concentration–time profiles (≤76 h). As an exposure metric, the ‘cumulative area under the levofloxacin–concentration time curve’ was determined. The antibiotic effect was assessed as the ‘cumulative area between the growth control and the bacterial-killing and -regrowth curve’. PK/PD modelling was applied to characterise the exposure–effect relationship and derive novel PK/PD parameters. A sigmoidal E_max model with an inhibition term best characterised the exposure–effect relationship and allowed for discrimination between two isolates sharing the same MIC value. Strain- and exposure-pattern-dependent differences were captured by the PK/PD parameters and elucidated the contribution of phenotypic adaptation to bacterial regrowth. The novel exposure and effect metrics and derived PK/PD parameters allowed for comprehensive characterisation of the isolates and could be applied to overcome the limitations of the MIC in clinical antibiotic dosing decisions, drug research and preclinical development. Full article

(This article belongs to the Special Issue Optimizing Antibiotic Treatment: Pharmacokinetics and Clinical Trials)

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12 pages, 977 KiB

Open AccessArticle

Pharmacokinetic/Pharmacodynamic Target Attainment Based on Measured versus Predicted Unbound Ceftriaxone Concentrations in Critically Ill Patients with Pneumonia: An Observational Cohort Study

by Matthias Gijsen, Erwin Dreesen, Ruth Van Daele, Pieter Annaert, Yves Debaveye, Joost Wauters and Isabel Spriet

Antibiotics 2021, 10(5), 557; https://doi.org/10.3390/antibiotics10050557 - 11 May 2021

Cited by 13 | Viewed by 3539

Abstract

The impact of ceftriaxone pharmacokinetic alterations on protein binding and PK/PD target attainment still remains unclear. We evaluated pharmacokinetic/pharmacodynamic (PK/PD) target attainment of unbound ceftriaxone in critically ill patients with severe community-acquired pneumonia (CAP). Besides, we evaluated the accuracy of predicted vs. measured unbound ceftriaxone concentrations, and its impact on PK/PD target attainment. A prospective observational cohort study was carried out in adult patients admitted to the intensive care unit with severe CAP. Ceftriaxone 2 g q24h intermittent infusion was administered to all patients. Successful PK/PD target attainment was defined as unbound trough concentrations above 1 or 4 mg/L throughout the whole dosing interval. Acceptable overall PK/PD target attainment was defined as successful target attainment in ≥90% of all dosing intervals. Measured unbound ceftriaxone concentrations (CEFu) were compared to unbound concentrations predicted from various protein binding models. Thirty-one patients were included. The 1 mg/L and 4 mg/L targets were reached in 26/32 (81%) and 15/32 (47%) trough samples, respectively. Increased renal function was associated with the failure to attain both PK/PD targets. Unbound ceftriaxone concentrations predicted by the protein binding model developed in the present study showed acceptable bias and precision and had no major impact on PK/PD target attainment. We showed suboptimal (i.e., <90%) unbound ceftriaxone PK/PD target attainment when using a standard 2 g q24h dosing regimen in critically ill patients with severe CAP. Renal function was the major driver for the failure to attain the predefined targets, in accordance with results found in general and septic ICU patients. Interestingly, CEFu was reliably predicted from CEFt without major impact on clinical decisions regarding PK/PD target attainment. This suggests that, when carefully selecting a protein binding model, CEFu does not need to be measured. As a result, the turn-around time and cost for ceftriaxone quantification can be substantially reduced. Full article

(This article belongs to the Special Issue Optimizing Antibiotic Treatment: Pharmacokinetics and Clinical Trials)

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12 pages, 351 KiB

Open AccessArticle

Pharmacokinetics and Pharmacodynamics of Cefepime in Adults with Hematological Malignancies and Febrile Neutropenia after Chemotherapy

by José C. Álvarez, Sonia I. Cuervo, Edelberto Silva, Jorge A. Díaz, Lorena L. Jiménez, Daniel S. Parra, Julio C. Gómez, Ricardo Sánchez and Jorge A. Cortés

Antibiotics 2021, 10(5), 504; https://doi.org/10.3390/antibiotics10050504 - 29 Apr 2021

Cited by 9 | Viewed by 2999

Abstract

Patients with chemotherapy-induced febrile neutropenia (CIFN) may have changes in the pharmacokinetics (PK) compared to patients without malignancies or neutropenia. Those changes in antibiotic PK could lead to negative outcomes for patients if the therapy is not adequately adjusted to this. In this, open-label, non-randomized, prospective, observational, and descriptive study, a PK model of cefepime was developed for patients with hematological neoplasms and post-chemotherapy febrile neutropenia. This study was conducted at a cancer referral center, and study participants were receiving 2 g IV doses of cefepime every 8 h as 30-min infusions. Cefepime PK was well described by a two compartment model with a clearance dependent on a serum creatinine level. Using Monte Carlo simulations, it was shown that continuous infusions of 6g q24h could have a good achievement of PK/PD targets for MIC levels below the resistance cut-off point of Enterobacteriaceae. According to the simulations, it is unnecessary to increase the daily dose of cefepime (above 6 g daily) to increase the probability of target attainment (PTA). Cumulative fraction of response (CFR) using interment dosing was suboptimal for empirical therapy regimens against K. pneumoniae and P. aeruginosa, and continuous infusions could be used in this setting to maximize exposure. Patients with high serum creatinine levels were more likely to achieve predefined PK/PD targets than patients with low levels. Full article

(This article belongs to the Special Issue Optimizing Antibiotic Treatment: Pharmacokinetics and Clinical Trials)

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13 pages, 1645 KiB

Open AccessArticle

Meropenem Stability in Human Plasma at −20 °C: Detailed Assessment of Degradation

by Matthias Gijsen, Benjamin Filtjens, Pieter Annaert, Yeghig Armoudjian, Yves Debaveye, Joost Wauters, Peter Slaets and Isabel Spriet

Antibiotics 2021, 10(4), 449; https://doi.org/10.3390/antibiotics10040449 - 16 Apr 2021

Cited by 9 | Viewed by 3506

Abstract

There are concerns about the stability of meropenem in plasma samples, even when frozen at −20 °C. Previous smaller studies suggested significant degradation of meropenem at −20 °C after 3–20 days. However, in several recent clinical studies, meropenem plasma samples were still stored at −20 °C, or the storage temperature and/or time were not mentioned in the paper. The aim of this study was to describe and model meropenem degradation in human plasma at −20 °C over 1 year. Stability of meropenem in human plasma at −20 °C was investigated at seven concentrations (0.44, 4.38, 17.5, 35.1, 52.6, 70.1, and 87.6 mg/L) representative for the range of relevant concentrations encountered in clinical practice. For each concentration, samples were stored for 0, 7, 14, 21, 28, 42, 56, 70, 84, 112, 140, 168, 196, 224, 252, 280, 308, 336, and 364 days at −20 °C before being transferred to −80 °C until analysis. Degradation was modeled using polynomial regression analysis and artificial neural network (ANN). Meropenem showed significant degradation over time in human plasma when stored at −20 °C. Degradation was present over the whole concentration range and increased with higher concentrations until a concentration of 35.1 mg/L. Both models showed accurate prediction of meropenem degradation. In conclusion, this study provides detailed insights into the concentration-dependent degradation of meropenem in human plasma stored at −20 °C over 1 year. Meropenem in human plasma is shown to be stable at least up to approximately 80 days when stored at −20 °C. The polynomial model allows calculating original meropenem concentrations in samples stored for a known period of time at −20 °C. Full article

(This article belongs to the Special Issue Optimizing Antibiotic Treatment: Pharmacokinetics and Clinical Trials)

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11 pages, 713 KiB

Open AccessArticle

Pharmacokinetics and Safety of Rifamycin SV after Single and Multiple Doses of MMX^® Modified Release Tablets in Healthy Male and Female Volunteers

by Andrea Francesco Daniele Di Stefano, Milko Massimiliano Radicioni, Angelo Vaccani, Alessandro Mazzetti, Luigi Maria Longo and Luigi Moro

Antibiotics 2021, 10(2), 167; https://doi.org/10.3390/antibiotics10020167 - 6 Feb 2021

Cited by 2 | Viewed by 2738

Abstract

The primary objective of this single- and multiple-dose pharmacokinetic study was the investigation of rifamycin SV’s pharmacokinetic profile in plasma and urine. All the 18 enrolled healthy men and post-menopausal women received modified release tablets containing 600 mg of the oral non-absorbable antibiotic, rifamycin SV, according to a multiple dose regimen: one tablet three times a day (daily intake: 1800 mg) for 14 consecutive days. Blood sampling and urine collection were performed up to 24 h post-dose after the first dose on Days 1 and 7. On average, on Day 1, C_max,0–24 was 5.79 ± 4.24 ng/mL and was attained in a median time of 9 h. On Day 7, all the subjects had quantifiable levels of rifamycin SV in plasma at each sampling time. After a peak concentration attained 2 h post-dose (mean ± SD concentration: 10.94 ± 16.41 ng/mL), rifamycin SV decreased in plasma to levels similar to those of Day 1. The amounts of rifamycin SV excreted in urine paralleled the plasma concentration at the corresponding times. On Day 1, the total amount excreted in urine was 0.0013%, and was 0.0029% on Day 7. The study results confirmed those of the previous Phase I study: the systemic absorption of rifamycin SV was also proved negligible after 7 days of the 600 mg t.i.d. dose regimen of the newly formulated tablets, currently under development for the treatment of several small and large intestinal pathologies, including diarrhea-predominant irritable bowel syndrome, hepatic encephalopathy, and others. Registered at ClinicalTrials.gov with the identifier NCT02969252, last updated on 26JAN18. Full article

(This article belongs to the Special Issue Optimizing Antibiotic Treatment: Pharmacokinetics and Clinical Trials)

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11 pages, 832 KiB

Open AccessArticle

Meropenem Plasma and Interstitial Soft Tissue Concentrations in Obese and Nonobese Patients—A Controlled Clinical Trial

by Philipp Simon, David Petroff, David Busse, Jana Heyne, Felix Girrbach, Arne Dietrich, Alexander Kratzer, Markus Zeitlinger, Charlotte Kloft, Frieder Kees, Hermann Wrigge and Christoph Dorn

Antibiotics 2020, 9(12), 931; https://doi.org/10.3390/antibiotics9120931 - 21 Dec 2020

Cited by 15 | Viewed by 4122

Abstract

Background: This controlled clinical study aimed to investigate the impact of obesity on plasma and tissue pharmacokinetics of meropenem. Methods: Obese (body mass index (BMI) ≥ 35 kg/m²) and age-/sex-matched nonobese (18.5 kg/m² ≥ BMI ≤ 30 kg/m²) surgical patients received a short-term infusion of 1000-mg meropenem. Concentrations were determined via high performance liquid chromatography-ultraviolet (HPLC-UV) in the plasma and microdialysate from the interstitial fluid (ISF) of subcutaneous tissue up to eight h after dosing. An analysis was performed in the plasma and ISF by noncompartmental methods. Results: The maximum plasma concentrations in 15 obese (BMI 49 ± 11 kg/m²) and 15 nonobese (BMI 24 ± 2 kg/m²) patients were 54.0 vs. 63.9 mg/L (95% CI for difference: −18.3 to −3.5). The volume of distribution was 22.4 vs. 17.6 L, (2.6–9.1), but the clearance was comparable (12.5 vs. 11.1 L/h, −1.4 to 3.1), leading to a longer half-life (1.52 vs. 1.31 h, 0.05–0.37) and fairly similar area under the curve (AUC)_8h (78.7 vs. 89.2 mg*h/L, −21.4 to 8.6). In the ISF, the maximum concentrations differed significantly (12.6 vs. 18.6 L, −16.8 to −0.8) but not the AUC_8h (28.5 vs. 42.0 mg*h/L, −33.9 to 5.4). Time above the MIC (T > MIC) in the plasma and ISF did not differ significantly for MICs of 0.25–8 mg/L. Conclusions: In morbidly obese patients, meropenem has lower maximum concentrations and higher volumes of distribution. However, due to the slightly longer half-life, obesity has no influence on the T > MIC, so dose adjustments for obesity seem unnecessary. Full article

(This article belongs to the Special Issue Optimizing Antibiotic Treatment: Pharmacokinetics and Clinical Trials)

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