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Special Issue "Pharmacokinetics and Pharmacodynamics of Antibacterial and Antivirulence Drugs"

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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 July 2023) | Viewed by 7226

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Special Issue Editor

Dr. Katharina Rox

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Guest Editor

Helmholtz Centre for Infection Research (HZI), Braunschweig, Germany
Interests: pharmacokinetics; pharmacodynamics; PBPK-modeling; antimicrobial resistance; animal models; antibacterials; antivirulence drugs; pathoblockers

Special Issue Information

Dear Colleagues,

In 2017, the WHO published a list of bacteria, including but not limited to the so-called ESKAPE pathogens, for which research of new antibiotics is of critical or high priority as a result of increasing antimicrobial resistance. Currently, less than 50 new antibacterial compounds have been investigated in clinical trials. This highlights that compounds with novel mechanisms of action are desperately needed. To enable translation from bench to bedside, novel compounds must first prove that they reach their target site, and that they are effective under in vitro and in vivo infection conditions. In addition to novel treatment options, more sophisticated treatment regimens of current antibacterial agents can help to lower the risk of rapid emergence of antimicrobial resistance. Therefore, the main goal of this Special Issue is to present contributions of novel approaches to fighting antimicrobial resistance as well as strategies to ameliorate current treatment regimens in human medicine. Some examples are as follows:

Pharmacokinetic (PK) and pharmacodynamic (PD) studies of novel antibacterial or anti-virulence compounds.
In vitro characterizations to understand PK/PD relations of novel or established antibacterial or anti-virulence compounds.
In silico PK or PK/PD modeling approaches aiming at translation from early compounds towards the clinic.
Animal PK or PK/PD studies of established antibacterial compounds with implications for current treatment regimens.
PK studies of established antibacterial compounds in special patient populations.
PK or PK/PD modeling approaches to study effects and/or enhance therapeutic effects in special patient populations.

Dr. Katharina Rox
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

pharmacokinetics
pharmacodynamics
clinical trials
antimicrobial resistance
antibacterials
antivirulence drugs
pathoblockers
antimicrobial use
drug utilization studies
PK/PD modeling
PBPK-modeling

Published Papers (5 papers)

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Research

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Open AccessArticle

Long-Term Use of Amoxicillin Is Associated with Changes in Gene Expression and DNA Methylation in Patients with Low Back Pain and Modic Changes

Maria Dehli Vigeland

Siri Tennebø Flåm

Magnus Dehli Vigeland

Ansgar Espeland

Manuela Zucknick

Monica Wigemyr

Lars Christian Haugli Bråten

Elisabeth Gjefsen

John-Anker Zwart

Kjersti Storheim

Linda Margareth Pedersen

Kaja Selmer

Benedicte Alexandra Lie

Kristina Gervin

and The AIM Study Group

Antibiotics 2023, 12(7), 1217; https://doi.org/10.3390/antibiotics12071217 - 21 Jul 2023

Viewed by 700

Abstract

Long-term antibiotics are prescribed for a variety of medical conditions, recently including low back pain with Modic changes. The molecular impact of such treatment is unknown. We conducted longitudinal transcriptome and epigenome analyses in patients (n = 100) receiving amoxicillin treatment or placebo for 100 days in the Antibiotics in Modic Changes (AIM) study. Gene expression and DNA methylation were investigated at a genome-wide level at screening, after 100 days of treatment, and at one-year follow-up. We identified intra-individual longitudinal changes in gene expression and DNA methylation in patients receiving amoxicillin, while few changes were observed in patients receiving placebo. After 100 days of amoxicillin treatment, 28 genes were significantly differentially expressed, including the downregulation of 19 immunoglobulin genes. At one-year follow-up, the expression levels were still not completely restored. The significant changes in DNA methylation (n = 4548 CpGs) were mainly increased methylation levels between 100 days and one-year follow-up. Hence, the effects on gene expression occurred predominantly during treatment, while the effects on DNA methylation occurred after treatment. In conclusion, unrecognized side effects of long-term amoxicillin treatment were revealed, as alterations were observed in both gene expression and DNA methylation that lasted long after the end of treatment. Full article

(This article belongs to the Special Issue Pharmacokinetics and Pharmacodynamics of Antibacterial and Antivirulence Drugs)

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Open AccessArticle

Predicting the Area under the Plasma Concentration-Time Curve (AUC) for First Dose Vancomycin Using First-Order Pharmacokinetic Equations

Kritsaporn Sujjavorakul

Wasan Katip

Stephen J. Kerr

Noppadol Wacharachaisurapol

and

Thanyawee Puthanakit

Antibiotics 2023, 12(4), 630; https://doi.org/10.3390/antibiotics12040630 - 23 Mar 2023

Viewed by 1171

Abstract

To treat critically ill patients, early achievement of the target area under the plasma concentration-time curve/minimum inhibitory concentration (AUC/MIC) in the first 24 h is recommended. However, accurately calculating the AUC before steady state is an obstacle to this goal. A first-order pharmacokinetic equation to calculate vancomycin AUC after a first dose of vancomycin has never been studied. We sought to estimate AUC using two first-order pharmacokinetic equations, with different paired concentration time points, and to compare these to the actual first dose vancomycin AUC calculated by the linear-log trapezoid rule as a reference. The equations were validated using two independent intensive first dose vancomycin concentration time data sets, one from 10 adults and another from 14 children with severe infection. The equation with compensation for the alpha distribution phase using a first vancomycin serum concentration from 60 to 90 min and the second concentration from 240 to 300 min after the completed infusion showed good agreement and low bias of calculated AUC, with mean differences <5% and Lin’s correlation coefficient >0.96. Moreover, it gave an excellent correlation with Pearson’s r > 0.96. Estimating the first dose vancomycin AUC calculated using this first-order pharmacokinetic equation is both reliable and reproducible in clinical practice settings. Full article

(This article belongs to the Special Issue Pharmacokinetics and Pharmacodynamics of Antibacterial and Antivirulence Drugs)

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Open AccessArticle

Pulmonary Pharmacokinetic and Pharmacodynamic Evaluation of Ampicillin/Sulbactam Regimens for Pneumonia Caused by Various Bacteria, including Acinetobacter baumannii

and

Antibiotics 2023, 12(2), 303; https://doi.org/10.3390/antibiotics12020303 - 02 Feb 2023

Viewed by 1745

Abstract

This study aimed to assess the dosing regimens of ampicillin/sulbactam for pneumonia based on pulmonary pharmacokinetic (PK)/pharmacodynamic (PD) target attainment. Using the literature data, we developed pulmonary PK models and estimated the probabilities of attaining PK/PD targets in lung tissue. Against bacteria other than A. baumannii (the general treatment), the PK/PD target was set as both 50% time above the minimum inhibitory concentration (T > MIC) for ampicillin and 50% T > 0.5 MIC for sulbactam. For the A. baumannii treatment, the PK/PD target was set as 60% T > MIC for sulbactam. The pulmonary PK/PD breakpoint was defined as the highest minimum inhibitory concentration (MIC) at which the target attainment probability in the lung tissue was ≥90%. The lung tissue/serum area under the drug concentration–time curve from 0 to 3 h (AUC_0–3h) ratios for ampicillin and sulbactam were 0.881 and 0.368, respectively. The ampicillin/sulbactam AUC_0–3h ratio in the lung tissue was 3.89. For the general treatment, the pulmonary PK/PD breakpoint for ampicillin/sulbactam at 3 g four times daily in typical patients with creatinine clearance (CL_cr) of 60 mL/min was 2 μg/mL, which covered the MIC_90s (the MICs that inhibited the growth of 90% of the strains) of most gram-positive and gram-negative bacteria. For the A. baumannii treatment, the pulmonary PK/PD breakpoint for ampicillin/sulbactam at 9 g 4-h infusion three times daily (27 g/day) in patients with a CL_cr of 60 mL/min was 4 μg/mL, which covered the MIC₉₀ of A. baumannii. A PK/PD evaluation for pneumonia should be performed in the lung tissue (the target site) rather than in the blood because sulbactam concentrations are lower in lung tissue. These findings should facilitate the selection of ampicillin/sulbactam regimens for pneumonia caused by various bacteria, including A. baumannii. Full article

(This article belongs to the Special Issue Pharmacokinetics and Pharmacodynamics of Antibacterial and Antivirulence Drugs)

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Review

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Open AccessReview

Clinical Experience with Off-Label Intrathecal Administration of Selected Antibiotics in Adults: An Overview with Pharmacometric Considerations

Anouk E. Muller

Peter van Vliet

and

Birgit C. P. Koch

Antibiotics 2023, 12(8), 1291; https://doi.org/10.3390/antibiotics12081291 - 05 Aug 2023

Viewed by 2074

Abstract

Drain-associated intracerebral infections are life-threatening emergencies. Their treatment is challenging due to the limited penetration of antibiotics to the site of infection, resulting in potentially inadequate exposure. The emergence of multidrug-resistant pathogens might force the use of off-label intrathecal (IT) doses of antibiotics. We reviewed the literature on general aspects determining intrathecal dosing regimen, using pharmacometric knowledge. We summarised clinical experience with IT doses of antibiotics that are usually not used intrathecally, as well as the outcome of the cases and concentrations reached in the cerebrospinal fluid (CSF). Factors determining the IT regimen are the size of the ventricle system and the CSF drainage volume. With regard to pharmacometrics, pharmacokinetic/pharmacodynamic indices are likely similar to those in non-cerebral infections. The following number (N) of cases were described: benzylpenicillin (>50), ampicillin (1), ceftazidime (2), cephaloridine (56), ceftriaxone (1), cefotiam (1), meropenem (57), linezolid (1), tigecycline (15), rifampicin (3), levofloxacin (2), chloramphenicol (3) and daptomycin (8). Many side effects were reported for benzylpenicillin in the 1940–50s, but for the other antibiotics, when administered correctly, all side effects were minor and reversible. These data might help when choosing an IT dosing regimen in case there is no alternative option due to antimicrobial resistance. Full article

(This article belongs to the Special Issue Pharmacokinetics and Pharmacodynamics of Antibacterial and Antivirulence Drugs)

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Open AccessReview

All Roads Lead to Rome: Enhancing the Probability of Target Attainment with Different Pharmacokinetic/Pharmacodynamic Modelling Approaches

Kashaf Khalid

and

Katharina Rox

Antibiotics 2023, 12(4), 690; https://doi.org/10.3390/antibiotics12040690 - 01 Apr 2023

Viewed by 992

Abstract

In light of rising antimicrobial resistance and a decreasing number of antibiotics with novel modes of action, it is of utmost importance to accelerate development of novel treatment options. One aspect of acceleration is to understand pharmacokinetics (PK) and pharmacodynamics (PD) of drugs and to assess the probability of target attainment (PTA). Several in vitro and in vivo methods are deployed to determine these parameters, such as time-kill-curves, hollow-fiber infection models or animal models. However, to date the use of in silico methods to predict PK/PD and PTA is increasing. Since there is not just one way to perform the in silico analysis, we embarked on reviewing for which indications and how PK and PK/PD models as well as PTA analysis has been used to contribute to the understanding of the PK and PD of a drug. Therefore, we examined four recent examples in more detail, namely ceftazidime-avibactam, omadacycline, gepotidacin and zoliflodacin as well as cefiderocol. Whereas the first two compound classes mainly relied on the ‘classical’ development path and PK/PD was only deployed after approval, cefiderocol highly profited from in silico techniques that led to its approval. Finally, this review shall highlight current developments and possibilities to accelerate drug development, especially for anti-infectives. Full article

(This article belongs to the Special Issue Pharmacokinetics and Pharmacodynamics of Antibacterial and Antivirulence Drugs)

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