Pharmacokinetics and Pharmacodynamics of Antibacterial and Antivirulence Drugs

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 16883

Special Issue Editor


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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:

  1. Pharmacokinetic (PK) and pharmacodynamic (PD) studies of novel antibacterial or anti-virulence compounds.
  2. In vitro characterizations to understand PK/PD relations of novel or established antibacterial or anti-virulence compounds.
  3. In silico PK or PK/PD modeling approaches aiming at translation from early compounds towards the clinic.
  4. Animal PK or PK/PD studies of established antibacterial compounds with implications for current treatment regimens.
  5. PK studies of established antibacterial compounds in special patient populations.
  6. 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

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Keywords

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

Published Papers (7 papers)

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Research

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17 pages, 1308 KiB  
Article
Time-Kill Analysis of Canine Skin Pathogens: A Comparison of Pradofloxacin and Marbofloxacin
by Stefano Azzariti, Andrew Mead, Pierre-Louis Toutain, Ross Bond and Ludovic Pelligand
Antibiotics 2023, 12(10), 1548; https://doi.org/10.3390/antibiotics12101548 - 17 Oct 2023
Viewed by 1247
Abstract
Time-kill curves (TKCs) are more informative compared with the use of minimum inhibitory concentration (MIC) as they allow the capture of bacterial growth and the development of drug killing rates over time, which allows to compute key pharmacodynamic (PD) parameters. Our study aimed, [...] Read more.
Time-kill curves (TKCs) are more informative compared with the use of minimum inhibitory concentration (MIC) as they allow the capture of bacterial growth and the development of drug killing rates over time, which allows to compute key pharmacodynamic (PD) parameters. Our study aimed, using a semi-mechanistic mathematical model, to estimate the best pharmacokinetic/pharmacodynamic (PK/PD) indices (ƒAUC/MIC or %ƒT > MIC) for the prediction of clinical efficacy of veterinary FQs in Staphylococcus pseudintermedius, Staphylococcus aureus, and Escherichia coli collected from canine pyoderma cases with a focus on the comparison between marbofloxacin and pradofloxacin. Eight TCKs for each bacterial species (4 susceptible and 4 resistant) were analysed in duplicate. The best PK/PD index was ƒAUC24h/MIC in both staphylococci and E. coli. For staphylococci, values of 25–40 h were necessary to achieve a bactericidal effect, whereas the calculated values (25–35 h) for E. coli were lower than those predicting a positive clinical outcome (100–120 h) in murine models. Pradofloxacin showed a higher potency (lower EC50) in comparison with marbofloxacin. However, no difference in terms of a maximal possible pharmacological killing rate (Emax) was observed. Taking into account in vivo exposure at the recommended dosage regimen (3 and 2 mg/kg for pradofloxacin and marbofloxacin, respectively), the overall killing rates (Kdrug) computed were also similar in most instances. Full article
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15 pages, 5722 KiB  
Article
Long-Term Use of Amoxicillin Is Associated with Changes in Gene Expression and DNA Methylation in Patients with Low Back Pain and Modic Changes
by 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 2778
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 [...] Read more.
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
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11 pages, 2160 KiB  
Article
Predicting the Area under the Plasma Concentration-Time Curve (AUC) for First Dose Vancomycin Using First-Order Pharmacokinetic Equations
by 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 1933
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 [...] Read more.
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
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13 pages, 2040 KiB  
Article
Pulmonary Pharmacokinetic and Pharmacodynamic Evaluation of Ampicillin/Sulbactam Regimens for Pneumonia Caused by Various Bacteria, including Acinetobacter baumannii
by Tetsushu Onita, Kazuro Ikawa, Noriyuki Ishihara, Hiroki Tamaki, Takahisa Yano, Kohji Naora and Norifumi Morikawa
Antibiotics 2023, 12(2), 303; https://doi.org/10.3390/antibiotics12020303 - 02 Feb 2023
Cited by 1 | Viewed by 2796
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 [...] Read more.
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 (AUC0–3h) ratios for ampicillin and sulbactam were 0.881 and 0.368, respectively. The ampicillin/sulbactam AUC0–3h 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 (CLcr) of 60 mL/min was 2 μg/mL, which covered the MIC90s (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 CLcr 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
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Review

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25 pages, 1230 KiB  
Review
Clinical Experience with Off-Label Intrathecal Administration of Selected Antibiotics in Adults: An Overview with Pharmacometric Considerations
by 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
Cited by 2 | Viewed by 4317
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. [...] Read more.
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
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16 pages, 346 KiB  
Review
All Roads Lead to Rome: Enhancing the Probability of Target Attainment with Different Pharmacokinetic/Pharmacodynamic Modelling Approaches
by Kashaf Khalid and Katharina Rox
Antibiotics 2023, 12(4), 690; https://doi.org/10.3390/antibiotics12040690 - 01 Apr 2023
Cited by 2 | Viewed by 1646
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 [...] Read more.
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

Other

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14 pages, 619 KiB  
Systematic Review
The Clinical Efficacy of Multidose Oritavancin: A Systematic Review
by Giammarco Baiardi, Michela Cameran Caviglia, Fabio Piras, Fabio Sacco, Roberta Prinapori, Maria Luisa Cristina, Francesca Mattioli, Marina Sartini and Emanuele Pontali
Antibiotics 2023, 12(10), 1498; https://doi.org/10.3390/antibiotics12101498 - 29 Sep 2023
Cited by 2 | Viewed by 1364
Abstract
Oritavancin (ORI) is a semisynthetic lipoglycopeptide approved as a single 1200 mg dose intravenous infusion for the treatment of acute bacterial skin and skin structure infections (ABSSSIs) caused by Gram-positive organisms in adults. The pharmacokinetic/pharmacodynamic (PK/PD) linear kinetic profile and long terminal half-life [...] Read more.
Oritavancin (ORI) is a semisynthetic lipoglycopeptide approved as a single 1200 mg dose intravenous infusion for the treatment of acute bacterial skin and skin structure infections (ABSSSIs) caused by Gram-positive organisms in adults. The pharmacokinetic/pharmacodynamic (PK/PD) linear kinetic profile and long terminal half-life (~393 h) of ORI make it therapeutically attractive for the treatment of other Gram-positive infections for which prolonged therapy is needed. Multidose regimens are adopted in real-world clinical practice with promising results, but aggregated efficacy data are still lacking. A comprehensive search on PubMed/Medline, Scopus, Cochrane and Google Scholar databases was performed to include papers published up to the end of January 2023. All articles on ORI multiple doses usage, including case reports, with quantitative data and relevant clinical information were included. Two reviewers independently assessed papers against the inclusion/exclusion criteria and for methodological quality. Differences in opinion were adjudicated by a third party. From 1751 potentially relevant papers identified by this search, a total of 16 studies met the inclusion criteria and were processed further in the final data analysis. We extracted data concerning clinical response, bacteriologic response, mortality and adverse events (AEs). From the 16 included papers, 301 cases of treatment with multidose ORIs were identified. Multidose regimens comprised an initial ORI dose of 1200 mg followed by 1200 mg or 800 mg subsequent doses with a varying total number and frequency of reinfusions. The most often treated infections and isolates were osteomyelitis (148; 54.4%), ABSSSI (35; 12.9%) and cellulitis (14; 5.1%); and MRSA (121), MSSA (66), CoNS (17), E. faecalis (13) and E. faecium (12), respectively. Clinical cure and improvement by multidose ORI regimens were observed in 85% (231/272) and 8% (22/272) patients, respectively. Multidose ORI was safe and well tolerated; the most frequent AEs were infusion-related reactions and hypoglycemia. A multidose ORI regimen may be beneficial in treating other Gram-positive infections besides ABSSSIs, with a good safety profile. Further studies are warranted to ascertain the superiority of one multidose ORI scheme or posology over the other. Full article
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