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Personalization of Antimicrobial Dosing in Special Patient Populations: A Mandatory...
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Personalization of Antimicrobial Dosing in Special Patient Populations: A Mandatory Issue in the Era of Precision Medicine

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Clinical Pharmaceutics".

Deadline for manuscript submissions: closed (10 July 2023) | Viewed by 15387

Special Issue Editors

Prof. Dr. Federico Pea

E-Mail Website
Guest Editor
Institute of Clinical Pharmacology and Toxicology, University Teaching Hospital of Udine, P.le SM Misericordia, 3, 33100 Udine, Italy
Interests: chemotherapy (especially on clinical pharmacokinetics and optimization of antimicrobial therapy in critically ill patients); clinical pharmacology; pharmacokinetics; drug interactions; pharmacodynamics
Special Issues, Collections and Topics in MDPI journals
Dr. Pier Giorgio Cojutti

E-Mail Website
Guest Editor
Institute of Clinical Pharmacology and Toxicology, University Teaching Hospital of Udine, P.le SM Misericordia, 3, 33100 Udine, Italy
Interests: pharmacokinetics; pharmacodynamics; therapeutic drug monitoring

Special Issue Information

Dear Colleagues,

In the era of precision medicine, optimizing drug exposure is an essential part of appropriate pharmacotherapy, as it may ultimately affect clinical outcomes. This is especially true for antimicrobials. Facing the current global crisis of antimicrobial resistance and the paucity of innovative drugs on the one hand and the emergence of new special population settings due to social and demographic changes on the other hand, attaining the optimal pharmacokinetic/pharmacodynamic target of efficacy with antimicrobials is becoming more and more challenging in everyday clinical practice.   

The pharmacokinetic profile of antibiotics may be significantly altered by the patient pathophysiological conditions, and the knowledge of the peculiar characteristics of each special patient population is of utmost importance for addressing properly the effectiveness of antimicrobial therapy today.

The critically ill patient represents the archetype of a special patient population in terms of intra- and interindividual pharmacokinetic variability. Drug clearance and volume of distribution may change rapidly and repeatedly over short timeframes in this setting, thus requiring daily monitoring of antimicrobials with frequent dosage adjustments.

Two demographic phenomena are increasing in the 21st century, especially in the developed nations, namely, population aging and obesity. Dosage optimization should not overlook the frequent appearance of organ impairments in the elderly, and is a non-easily addressable issue in obese patients.

Advances in medicine during the last decades have led to the progressive increase of other special patient populations, namely oncohematological patients and transplant patients undergoing long-term immunosuppressive therapy. In the latter populations, different variables may cause augmented renal clearance, and important challenges may raise due to drug–drug interactions with immunosuppressants.

In this Special Issue, some of the most eminent experts in their field will present and discuss the criticalities of optimizing antimicrobial exposure in a specific patient population, with the intent of offering practical indications for dosage optimization to clinicians.         

Prof. Dr. Pea Federico
Dr. Pier Giorgio Cojutti
Guest Editors

Manuscript Submission Information

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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. Pharmaceutics 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

  • PK/PD optimization of antimicrobial therapy
  • special population
  • critically ill patients
  • elderly patients
  • obese patients
  • oncohematological patients
  • transplant patients

Published Papers (5 papers)

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Research

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10 pages, 445 KiB  
Article
Clinical Efficacy and Nephrotoxicity of the Loading Dose Colistin for the Treatment of Carbapenem-Resistant Acinetobacter baumannii in Critically Ill Patients
by Wasan Katip, Suriyon Uitrakul and Peninnah Oberdorfer
Pharmaceutics 2022, 14(1), 31; https://doi.org/10.3390/pharmaceutics14010031 - 24 Dec 2021
Cited by 35 | Viewed by 2989
Abstract
Carbapenem-resistant Acinetobacter baumannii (CRAB) is one of the most common causes of nosocomial infections in critically ill patients. Colistin methanesulfonate (CMS), an inactive prodrug, has been considered as a last-resort treatment for CRAB infection in critically ill patients. The objective of this study [...] Read more.
Carbapenem-resistant Acinetobacter baumannii (CRAB) is one of the most common causes of nosocomial infections in critically ill patients. Colistin methanesulfonate (CMS), an inactive prodrug, has been considered as a last-resort treatment for CRAB infection in critically ill patients. The objective of this study was to assess 30-day survival and nephrotoxicity in critically ill patients who received non-loading dose (LD) versus LD of CMS for CRAB infection treatment. Between 2012 and 2017, this retrospective cohort analysis was performed at Chiang Mai University Hospital (CMUH), focusing on critically ill patients with CRAB infection who received either non-LD or LD of CMS. A total of 383 patients met the criteria for inclusion. At the 30th day of treatment, the survival rate of patients in the LD CMS group was 1.70 times (adjusted HR) of those in the non-LD group (95% CI = 1.17–2.50, p = 0.006). Clinical response was significantly higher in the LD CMS group than non-LD CMS group (aHR, 1.35, 95% CI, 1.01–1.82, p = 0.046). In addition, a microbiological response—eradication of pre-treatment isolated pathogens in post-treatment cultures—in patients with LD CMS was 1.57 times that of patients with non-LD CMS (95% CI, 1.15–2.15, p = 0.004). Additionally, there was a significant difference in nephrotoxicity between LD CMS and non-LD CMS (aHR, 1.57, 95% CI, 1.14–2.17, p = 0.006). Based on these results, LD CMS should be used to increase the opportunity of patients to achieve favourable outcomes. However, LD CMS was found associated with an increase in nephrotoxicity, so renal function should be closely monitored when LD colistin was administered. Full article
(This article belongs to the Special Issue Personalization of Antimicrobial Dosing in Special Patient Populations: A Mandatory Issue in the Era of Precision Medicine)
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15 pages, 2079 KiB  
Article
Similar Piperacillin/Tazobactam Target Attainment in Obese versus Nonobese Patients despite Differences in Interstitial Tissue Fluid Pharmacokinetics
by David Busse, Philipp Simon, David Petroff, Christoph Dorn, Lisa Schmitt, Davide Bindellini, Alexander Kratzer, Arne Dietrich, Markus Zeitlinger, Wilhelm Huisinga, Robin Michelet, Hermann Wrigge and Charlotte Kloft
Pharmaceutics 2021, 13(9), 1380; https://doi.org/10.3390/pharmaceutics13091380 - 31 Aug 2021
Cited by 4 | Viewed by 2688
Abstract
Precision dosing of piperacillin/tazobactam in obese patients is compromised by sparse information on target-site exposure. We aimed to evaluate the appropriateness of current and alternative piperacillin/tazobactam dosages in obese and nonobese patients. Based on a prospective, controlled clinical trial in 30 surgery patients [...] Read more.
Precision dosing of piperacillin/tazobactam in obese patients is compromised by sparse information on target-site exposure. We aimed to evaluate the appropriateness of current and alternative piperacillin/tazobactam dosages in obese and nonobese patients. Based on a prospective, controlled clinical trial in 30 surgery patients (15 obese/15 nonobese; 0.5-h infusion of 4 g/0.5 g piperacillin/tazobactam), piperacillin pharmacokinetics were characterized in plasma and at target-site (interstitial fluid of subcutaneous adipose tissue) via population analysis. Thereafter, multiple 3–4-times daily piperacillin/tazobactam short-term/prolonged (recommended by EUCAST) and continuous infusions were evaluated by simulation. Adequacy of therapy was assessed by probability of pharmacokinetic/pharmacodynamic target-attainment (PTA ≥ 90%) based on time unbound piperacillin concentrations exceed the minimum inhibitory concentration (MIC) during 24 h (%fT>MIC). Lower piperacillin target-site maximum concentrations in obese versus nonobese patients were explained by the impact of lean (approximately two thirds) and fat body mass (approximately one third) on volume of distribution. Simulated steady-state concentrations were 1.43-times, 95%CI = (1.27; 1.61), higher in plasma versus target-site, supporting targets of %fT>2×MIC instead of %fT>4×MIC during continuous infusion to avoid target-site concentrations constantly below MIC. In all obesity and renally impairment/hyperfiltration stages, at MIC = 16 mg/L, adequate PTA required prolonged (thrice-daily 4 g/0.5 g over 3.0 h at %fT>MIC = 50) or continuous infusions (24 g/3 g over 24 h following loading dose at %fT>MIC = 98) of piperacillin/tazobactam. Full article
(This article belongs to the Special Issue Personalization of Antimicrobial Dosing in Special Patient Populations: A Mandatory Issue in the Era of Precision Medicine)
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9 pages, 615 KiB  
Article
Clinical Efficacy and Nephrotoxicity of Colistin Alone versus Colistin Plus Vancomycin in Critically Ill Patients Infected with Carbapenem-Resistant Acinetobacter baumannii: A Propensity Score-Matched Analysis
by Wasan Katip and Peninnah Oberdorfer
Pharmaceutics 2021, 13(2), 162; https://doi.org/10.3390/pharmaceutics13020162 - 26 Jan 2021
Cited by 32 | Viewed by 2094
Abstract
Acinetobacter baumannii has emerged as a significant concern worldwide. The mortality rate of carbapenem-resistant A. baumannii (CRAB) is increasing, especially in the intensive care unit (ICU). Thus, the objective of this study is to compare the efficacy and safety of colistin plus vancomycin [...] Read more.
Acinetobacter baumannii has emerged as a significant concern worldwide. The mortality rate of carbapenem-resistant A. baumannii (CRAB) is increasing, especially in the intensive care unit (ICU). Thus, the objective of this study is to compare the efficacy and safety of colistin plus vancomycin for the treatment of critically ill patients with CRAB in Chiang Mai University Hospital. We conducted a retrospective cohort study of critically ill patients in the ICU with CRAB infection who received colistin alone or colistin-vancomycin combination therapy at Chiang Mai University Hospital. A total of 365 critically ill patients met the inclusion criteria. The results in this study showed that after propensity score matching, colistin plus vancomycin showed no significant differences in the 30-day mortality compared to colistin alone. Likewise, for colistin plus vancomycin, compared with colistin therapy alone, there were no significant differences in the clinical response, microbiological response and nephrotoxicity. In conclusion, colistin plus vancomycin was no significant differences in 30-day mortality, clinical response, microbiological response compared to colistin alone for infections due to CRAB. The nephrotoxicity rates were similar for both groups, so colistin combination with vancomycin was not necessary for the management of infection caused by CRAB. Full article
(This article belongs to the Special Issue Personalization of Antimicrobial Dosing in Special Patient Populations: A Mandatory Issue in the Era of Precision Medicine)
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11 pages, 1544 KiB  
Article
Population Pharmacokinetics of Continuous-Infusion Meropenem in Febrile Neutropenic Patients with Hematologic Malignancies: Dosing Strategies for Optimizing Empirical Treatment against Enterobacterales and P. aeruginosa
by Pier Giorgio Cojutti, Anna Candoni, Davide Lazzarotto, Carla Filì, Maria Zannier, Renato Fanin and Federico Pea
Pharmaceutics 2020, 12(9), 785; https://doi.org/10.3390/pharmaceutics12090785 - 19 Aug 2020
Cited by 7 | Viewed by 2469
Abstract
A population pharmacokinetic analysis of continuous infusion (CI) meropenem was conducted in a prospective cohort of febrile neutropenic (FN) patients with hematologic malignancies. A non-parametric approach with Pmetrics was used for pharmacokinetic analysis and covariate evaluation. Monte Carlo simulations were performed for identifying [...] Read more.
A population pharmacokinetic analysis of continuous infusion (CI) meropenem was conducted in a prospective cohort of febrile neutropenic (FN) patients with hematologic malignancies. A non-parametric approach with Pmetrics was used for pharmacokinetic analysis and covariate evaluation. Monte Carlo simulations were performed for identifying the most appropriate dosages for empirical treatment against common Enterobacterales and P. aeruginosa. The probability of target attainment (PTA) of steady-state meropenem concentration (Css)-to-minimum inhibitory concentration (MIC) ratio (Css/MIC) ≥1 and ≥4 at the European Committee on Antimicrobial Susceptibility Testing (EUCAST) clinical breakpoint of 2 mg/L were calculated. Cumulative fraction of response (CFR) against Enterobacterales and P. aeruginosa were assessed as well. PTAs and CFRs ≥ 90% were considered optimal. A total of 61 patients with 178 meropenem Css were included. Creatinine clearance (CLCR) was the only covariate associated with meropenem clearance. Monte Carlo simulations showed that dosages of meropenem ranging between 1 g q8h and 1.25 g q6h by CI may grant optimal PTAs of Css/MIC ≥4 at the EUCAST clinical breakpoint. Optimal CFRs may be granted with these dosages against the Enterobacterales at Css/MIC ≥ 4 and against P. aeruginosa at Css/MIC ≥ 1. When dealing against P. aeruginosa at Css/MIC ≥ 4, only a dosage of 1.5 g q6h by CI may grant quasi-optimal CFR (around 80–87%). In conclusion, our findings suggest that dosages of meropenem ranging between 1 g q8h and 1.25 g q6h by CI may maximize empirical treatment against Enterobacterales and P. aeruginosa among FN patients with hematologic malignancies having different degree of renal function. Full article
(This article belongs to the Special Issue Personalization of Antimicrobial Dosing in Special Patient Populations: A Mandatory Issue in the Era of Precision Medicine)
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Review

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22 pages, 1760 KiB  
Review
What Are the Current Approaches to Optimising Antimicrobial Dosing in the Intensive Care Unit?
by Ming G. Chai, Menino O. Cotta, Mohd H. Abdul-Aziz and Jason A. Roberts
Pharmaceutics 2020, 12(7), 638; https://doi.org/10.3390/pharmaceutics12070638 - 07 Jul 2020
Cited by 33 | Viewed by 3800
Abstract
Antimicrobial dosing in the intensive care unit (ICU) can be problematic due to various challenges including unique physiological changes observed in critically ill patients and the presence of pathogens with reduced susceptibility. These challenges result in reduced likelihood of standard antimicrobial dosing regimens [...] Read more.
Antimicrobial dosing in the intensive care unit (ICU) can be problematic due to various challenges including unique physiological changes observed in critically ill patients and the presence of pathogens with reduced susceptibility. These challenges result in reduced likelihood of standard antimicrobial dosing regimens achieving target exposures associated with optimal patient outcomes. Therefore, the aim of this review is to explore the various methods for optimisation of antimicrobial dosing in ICU patients. Dosing nomograms developed from pharmacokinetic/statistical models and therapeutic drug monitoring are commonly used. However, recent advances in mathematical and statistical modelling have resulted in the development of novel dosing software that utilise Bayesian forecasting and/or artificial intelligence. These programs utilise therapeutic drug monitoring results to further personalise antimicrobial therapy based on each patient’s clinical characteristics. Studies quantifying the clinical and cost benefits associated with dosing software are required before widespread use as a point-of-care system can be justified. Full article
(This article belongs to the Special Issue Personalization of Antimicrobial Dosing in Special Patient Populations: A Mandatory Issue in the Era of Precision Medicine)
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