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Antibiotics
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Clinical Pharmacokinetics and Dose Optimization of Anti-infectives in Critical Care
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Clinical Pharmacokinetics and Dose Optimization of Anti-infectives in Critical Care

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 (15 November 2023) | Viewed by 21499

Special Issue Editors

Dr. Daniel Richter

E-Mail Website
Guest Editor
Department of Anaesthesiology, Heidelberg University Hospital, 69120 Heidelberg, Germany
Interests: individualized dosing & therapeutic drug monitoring, pharmacokinetics/-dynamics of antimicrobials; infections in intensive care (bacterial, viral & fungal); sepsis & septic shock
Prof. Dr. Thorsten Brenner

E-Mail Website
Guest Editor
Department of Anesthesiology and Intensive Care Medicine, University Hospital Essen, University Duisburg Essen, Hufelandstr. 55, 45147 Essen, Germany
Interests: innate immune response to sepsis; septic coagulopathy; pathogen diagnosis in sepsis

Special Issue Information

Dear Colleagues,

The scientific work of the last decade has led to a drastic change in both the understanding and the use of anti-infective substances in critically ill patients. A central factor was the realization that pathophysiological changes in the course of intensive care treatment lead to profound alterations in the pharmacokinetic (PK) properties of many anti-infective substances. Accordingly, clinical data have repeatedly demonstrated that standard bolus applications of fixed doses jeopardize treatment success in critically ill patients, most likely due to significant variations in the serum concentrations of the anti-infective drug (while most of these data relate to antibiotics, the latter effects occur in other anti-infective substances, too). These findings made clinicians abandon the “one-size-fits-all” dogma and stressed the need for a pharmacokinetic (PK)/pharmacodynamic (PD)-centered dose optimization of anti-infective drugs. Dose optimization measures encompass a modern administration regimen for appropriate substances (i.e., extended infusions for carbapenems and b-lactams), the use of individually calculated doses with respect to the clinical scenario (sepsis, septic shock) and attention to organ dysfunction (i.e., acute kidney injury, renal replacement therapy). The goals of PK/PD and dose optimization are to assure optimal exposure of pathogens and drugs in any given clinical scenario and to minimize insufficiently low or toxic concentrations at the same time. Therapeutic drug monitoring (TDM) is still routinely utilized to determine (mostly) serum concentrations of the drug and deduct individual doses according to the TDM result. The sole use of TDM for optimized drug dosing harbors the risk of significant variations in serum concentrations, especially after treatment initiation. Given the limitations of TDM (costs, availability, time-to-reporting of results), PK simulations/dose approximation algorithms and the facilitation of artificial intelligence (AI) to determine individual doses a priori are promising tools that might, in fact, reduce the need for continuous TDM measures. A combination of TDM, PK simulations and extended infusion (depending on the substance) might be a promising approach to increase treatment efficacy in the future.

This Special Issue of Antibiotics aims to publish manuscripts that highlight the importance of clinical pharmacokinetics and dose optimization in critically ill patients. We understand that a great share of the topic refers to antibiotic treatment. However, manuscripts discussing PK/PD and dose-optimisation in antifungals or even antivirals are appreciated as well. Since Antibiotics understands itself as being a part of scientific progress, we explicitly encourage a critical discussion of the topic.

Dr. Daniel Richter
Prof. Dr. Thorsten Brenner
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.

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 (PK)
  • pharmacodynamics (PD)
  • anti-infective drugs
  • dose optimization
  • therapeutic drug monitoring (TDM)
  • dose approximation
  • critical care

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Published Papers (8 papers)

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Research

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14 pages, 1902 KiB  
Article
Software- and TDM-Guided Dosing of Meropenem Promises High Rates of Target Attainment in Critically Ill Patients
by Ute Chiriac, Daniel Richter, Otto R. Frey, Anka C. Röhr, Sophia Helbig, Stefan Hagel, Uwe Liebchen, Markus A. Weigand and Alexander Brinkmann
Antibiotics 2023, 12(7), 1112; https://doi.org/10.3390/antibiotics12071112 - 27 Jun 2023
Cited by 2 | Viewed by 2056
Abstract
Various studies have reported insufficient beta-lactam concentrations in critically ill patients. The optimal dosing strategy for beta-lactams in critically ill patients, particularly in septic patients, is an ongoing matter of discussion. This retrospective study aimed to evaluate the success of software-guided empiric meropenem [...] Read more.
Various studies have reported insufficient beta-lactam concentrations in critically ill patients. The optimal dosing strategy for beta-lactams in critically ill patients, particularly in septic patients, is an ongoing matter of discussion. This retrospective study aimed to evaluate the success of software-guided empiric meropenem dosing (CADDy, Calculator to Approximate Drug-Dosing in Dialysis) with subsequent routine meropenem measurements and expert clinical pharmacological interpretations. Adequate therapeutic drug exposure was defined as concentrations of 8–16 mg/L, whereas concentrations of 16–24 mg/L were defined as moderately high and concentrations >24 mg/L as potentially harmful. A total of 91 patients received meropenem as a continuous infusion (229 serum concentrations), of whom 60% achieved 8–16 mg/L, 23% achieved 16–24 mg/L, and 10% achieved unnecessarily high and potentially harmful meropenem concentrations >24 mg/L in the first 48 h using the dosing software. No patient showed concentrations <2 mg/L using the dosing software in the first 48 h. With a subsequent TDM-guided dose adjustment, therapeutic drug exposure was significantly (p ≤ 0.05) enhanced to 70%. No patient had meropenem concentrations >24 mg/L with TDM-guided dose adjustments. The combined use of dosing software and consecutive TDM promised a high rate of adequate therapeutic drug exposures of meropenem in patients with sepsis and septic shock. Full article
(This article belongs to the Special Issue Clinical Pharmacokinetics and Dose Optimization of Anti-infectives in Critical Care)
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11 pages, 609 KiB  
Article
Voriconazole Pharmacokinetics in Critically Ill Patients and Extracorporeal Membrane Oxygenation Support: A Retrospective Comparative Case-Control Study
by Mar Ronda, Josep Manuel Llop-Talaveron, MariPaz Fuset, Elisabet Leiva, Evelyn Shaw, Victor Daniel Gumucio-Sanguino, Yolanda Diez, Helena Colom, Raul Rigo-Bonnin, Mireia Puig-Asensio, Jordi Carratalà and Ariadna Padullés
Antibiotics 2023, 12(7), 1100; https://doi.org/10.3390/antibiotics12071100 - 25 Jun 2023
Cited by 6 | Viewed by 1754
Abstract
Voriconazole, an antifungal agent, displays high intra- and inter-individual variability. The predictive pharmacokinetic (PK) index requires a minimum plasma concentration (Cmin) in patient serum of between 1–5.5 mg/L. It is common to encounter fungal infections in patients undergoing extracorporeal membrane oxygenation [...] Read more.
Voriconazole, an antifungal agent, displays high intra- and inter-individual variability. The predictive pharmacokinetic (PK) index requires a minimum plasma concentration (Cmin) in patient serum of between 1–5.5 mg/L. It is common to encounter fungal infections in patients undergoing extracorporeal membrane oxygenation (ECMO) support, and data regarding voriconazole PK changes during ECMO are scarce. Our study compared voriconazole PKs in patients with and without ECMO support in a retrospective cohort of critically-ill patients. Fifteen patients with 26 voriconazole Cmin determinations in the non-ECMO group and nine patients with 27 voriconazole Cmin determinations in the ECMO group were recruited. The ECMO group had lower Cmin (0.38 ± 2.98 vs. 3.62 ± 3.88, p < 0.001) and higher infratherapeutic Cmin values (16 vs. 1, p < 0.001) than the non-ECMO group. Multivariate analysis identified ECMO support (−0.668, CI95 −0.978–−0.358) and plasma albumin levels (−0.023, CI95 −0.046–−0.001) as risk factors for low Cmin values. When comparing pre- and post-therapeutic drug optimisation samples from the ECMO group, the dose required to achieve therapeutic Cmin was 6.44 mg/kg twice a day. Therapeutic drug optimisation is essential to improve target attainment. Full article
(This article belongs to the Special Issue Clinical Pharmacokinetics and Dose Optimization of Anti-infectives in Critical Care)
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12 pages, 2017 KiB  
Article
Comparing the Synergistic and Antagonistic Interactions of Ciprofloxacin and Levofloxacin Combined with Rifampin against Drug-Resistant Staphylococcus aureus: A Time–Kill Assay
by Yu Ri Kang, Doo Ryeon Chung, Jae-Hoon Ko, Kyungmin Huh, Sun Young Cho, Cheol-In Kang and Kyong Ran Peck
Antibiotics 2023, 12(4), 711; https://doi.org/10.3390/antibiotics12040711 - 6 Apr 2023
Cited by 3 | Viewed by 2693
Abstract
Background: Treatment of device-related infections by drug-resistant Staphylococcus aureus can be challenging, and combination therapy has been proposed as a potential solution. We compared the effectiveness of levofloxacin–rifampin and ciprofloxacin–rifampin combinations in killing methicillin-resistant S. aureus (MRSA) using a time–kill assay. Methods: We [...] Read more.
Background: Treatment of device-related infections by drug-resistant Staphylococcus aureus can be challenging, and combination therapy has been proposed as a potential solution. We compared the effectiveness of levofloxacin–rifampin and ciprofloxacin–rifampin combinations in killing methicillin-resistant S. aureus (MRSA) using a time–kill assay. Methods: We randomly selected 15 vancomycin-susceptible S. aureus (VSSA) strains, 3 vancomycin-intermediate S. aureus (VISA) strains, and 12 heterogeneous VISA (hVISA) strains from the Asian Bacterial Bank. Time–kill experiments were performed in duplicate for each isolate. Viable bacterial counts were determined at 0 h, 4 h, 8 h, and 24 h for the ciprofloxacin– and levofloxacin–rifampin combinations at 1× MIC and 0.5× MIC. We compared synergistic and antagonistic interactions between the two combinations. Results: The viable bacterial count significantly decreased after 24 h of exposure to ciprofloxacin–rifampin and levofloxacin–rifampin combinations, with synergy observed more frequently in isolates exposed to ciprofloxacin–rifampin (43.3%) than levofloxacin–rifampin (20.0%) (p = 0.0082). The synergistic interactions of both combinations were more frequently observed in resistant strains with high MICs of ciprofloxacin (≥16 mg/L) and levofloxacin (≥8 mg/L). Levofloxacin tended to exhibit more frequent antagonistic interactions with rifampin than ciprofloxacin, although there was no statistical difference in antagonism between the two combinations. Conclusions: Our study demonstrated that ciprofloxacin exhibits superior synergistic activity against MRSA strains, including VISA/hVISA, when combined with rifampin compared with levofloxacin. High MICs of fluoroquinolones were found to predict synergism. Our results suggest that ciprofloxacin may be a more effective choice than levofloxacin for combination therapy with rifampin in the treatment of MRSA infections. Full article
(This article belongs to the Special Issue Clinical Pharmacokinetics and Dose Optimization of Anti-infectives in Critical Care)
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12 pages, 1649 KiB  
Article
Population Pharmacokinetic Study of Benzylpenicillin in Critically Unwell Adults
by Reya V. Shah, Karin Kipper, Emma H. Baker, Charlotte I. S. Barker, Isobel Oldfield, Barbara J. Philips, Atholl Johnston, Jeffrey Lipman, Andrew Rhodes, Marina Basarab, Mike Sharland, Sarraa Almahdi, Rachel M. Wake, Joseph F. Standing and Dagan O. Lonsdale
Antibiotics 2023, 12(4), 643; https://doi.org/10.3390/antibiotics12040643 - 24 Mar 2023
Cited by 1 | Viewed by 2742
Abstract
Pharmacokinetics are highly variable in critical illness, and suboptimal antibiotic exposure is associated with treatment failure. Benzylpenicillin is a commonly used beta-lactam antibiotic, and pharmacokinetic data of its use in critically ill adults are lacking. We performed a pharmacokinetic study of critically unwell [...] Read more.
Pharmacokinetics are highly variable in critical illness, and suboptimal antibiotic exposure is associated with treatment failure. Benzylpenicillin is a commonly used beta-lactam antibiotic, and pharmacokinetic data of its use in critically ill adults are lacking. We performed a pharmacokinetic study of critically unwell patients receiving benzylpenicillin, using data from the ABDose study. Population pharmacokinetic modelling was undertaken using NONMEM version 7.5, and simulations using the final model were undertaken to optimize the pharmacokinetic profile. We included 77 samples from 12 participants. A two-compartment structural model provided the best fit, with allometric weight scaling for all parameters and a creatinine covariate effect on clearance. Simulations (n = 10,000) demonstrated that 25% of simulated patients receiving 2.4 g 4-hourly failed to achieve a conservative target of 50% of the dosing interval with free drug above the clinical breakpoint MIC (2 mg/L). Simulations demonstrated that target attainment was improved with continuous or extended dosing. To our knowledge, this study represents the first full population PK analysis of benzylpenicillin in critically ill adults. Full article
(This article belongs to the Special Issue Clinical Pharmacokinetics and Dose Optimization of Anti-infectives in Critical Care)
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11 pages, 857 KiB  
Article
Vancomycin Sequestration in ST Filters: An In Vitro Study
by Frédéric J. Baud, Pascal Houzé, Jean-Herlé Raphalen, Pascal Philippe and Lionel Lamhaut
Antibiotics 2023, 12(3), 620; https://doi.org/10.3390/antibiotics12030620 - 21 Mar 2023
Cited by 1 | Viewed by 1410
Abstract
Background. Sequestration of vancomycin in ST® filters used in continuous renal therapy is a pending question. Direct vancomycin-ST® interaction was assessed using the in vitro NeckEpur® technology. Method. ST150® filter and Prismaflex dialyzer, Baxter-Gambro, were used. Two modes were [...] Read more.
Background. Sequestration of vancomycin in ST® filters used in continuous renal therapy is a pending question. Direct vancomycin-ST® interaction was assessed using the in vitro NeckEpur® technology. Method. ST150® filter and Prismaflex dialyzer, Baxter-Gambro, were used. Two modes were assessed in duplicate: (i) continuous diafiltration (CDF): 4 L/h, (ii) continuous dialysis (CD): 2.5 L/h post-filtration. Results. The mean initial vancomycin concentration in the central compartment (CC) was 51.4 +/− 5.0 mg/L. The mean percentage eliminated from the CC over 6 h was 91 +/− 4%. The mean clearances from the CC by CDF and CD were 2.8 and 1.9 L/h, respectively. The mean clearances assessed using cumulative effluents were 4.4 and 2.2 L/h, respectively. The mean percentages of the initial dose eliminated in the effluents from the CC by CDF and CD were 114 and 108% with no detectable sequestration of vancomycin in both modes of elimination. Discussion. Significant sequestration adds a clearance to that provided by CDF and CD. The study provides multiple evidence from the CC, the filter, and the effluents of the lack of an increase in total clearance in comparison with the flow rates without significant sequestration in the ST® filter comparing cumulative effluents to the initial dose in the CC. Conclusions. There is no evidence ST® filters directly sequestrate vancomycin. Full article
(This article belongs to the Special Issue Clinical Pharmacokinetics and Dose Optimization of Anti-infectives in Critical Care)
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10 pages, 269 KiB  
Article
Pharmacokinetic of Cefiderocol in Critically Ill Patients Receiving Renal Replacement Therapy: A Case Series
by Simone Mornese Pinna, Silvia Corcione, Amedeo De Nicolò, Giorgia Montrucchio, Silvia Scabini, Davide Vita, Ilaria De Benedetto, Tommaso Lupia, Jacopo Mula, Giovanni Di Perri, Antonio D’Avolio and Francesco Giuseppe De Rosa
Antibiotics 2022, 11(12), 1830; https://doi.org/10.3390/antibiotics11121830 - 16 Dec 2022
Cited by 6 | Viewed by 4060
Abstract
Background: Cefiderocol is a novel parenteral siderophore cephalosporin, demonstrating enhanced activity against multidrug-resistant (MDR) Gram-negative bacteria and difficult-to-treat Acinetobacter baumannii (DTR-AB). Plasma-free trough concentration (fCtrough) over the minimum inhibitory concentration (MIC) was reported as the best pharmacokinetic parameter to [...] Read more.
Background: Cefiderocol is a novel parenteral siderophore cephalosporin, demonstrating enhanced activity against multidrug-resistant (MDR) Gram-negative bacteria and difficult-to-treat Acinetobacter baumannii (DTR-AB). Plasma-free trough concentration (fCtrough) over the minimum inhibitory concentration (MIC) was reported as the best pharmacokinetic parameter to describe the microbiological efficacy of cefiderocol. Materials and methods: We retrospectively described the pharmacokinetic and pharmacodynamic profile of three critically ill patients admitted to the intensive care unit, receiving cefiderocol under compassionate use to treat severe DTR-AB infections while undergoing continuous venovenous haemofiltration. Cefiderocol was administrated at a dosage of 2 g every 8 h infused over 3 h. Therapeutic drug monitoring (TDM) was assessed at the steady state. Cthrough was evaluated by assuming a plasma protein binding of 58.0%. The fCmin/MIC was calculated assuming a cefiderocol MIC equal to the PK-PD breakpoint of susceptibility ≤ 2. The association between the PK/PD parameters and microbiological outcome was assessed. Results: fCtrough/MIC were >12 in 2 patients and 2.9 in the 1 who rapidly recovered from renal failure. Microbiological cure occurred in 3/3 of patients. None of the 3 patients died within 30 days. Conclusions: A cefiderocol dosage of 2 g q8 h in critically ill patients with AKI undergoing CVVH may bring about a very high plasma concentration, corresponding to essentially 100% free time over the MIC for DTR-AB. Full article
(This article belongs to the Special Issue Clinical Pharmacokinetics and Dose Optimization of Anti-infectives in Critical Care)

Review

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14 pages, 309 KiB  
Review
The Influence of Extracorporeal Membrane Oxygenation on Antibiotic Pharmacokinetics
by Gregory J. Peitz and Daryl J. Murry
Antibiotics 2023, 12(3), 500; https://doi.org/10.3390/antibiotics12030500 - 2 Mar 2023
Cited by 2 | Viewed by 2502
Abstract
Extracorporeal membrane oxygenation (ECMO) is becoming increasingly utilized to support critically ill patients who experience life-threatening cardiac or pulmonary compromise. The provision of this intervention poses challenges related to its complications and the optimization of medication therapy. ECMO’s mechanical circulatory support is facilitated [...] Read more.
Extracorporeal membrane oxygenation (ECMO) is becoming increasingly utilized to support critically ill patients who experience life-threatening cardiac or pulmonary compromise. The provision of this intervention poses challenges related to its complications and the optimization of medication therapy. ECMO’s mechanical circulatory support is facilitated via various devices and equipment that have been shown to sequester lipophilic- and protein-bound medications, including anti-infectives. Since infectious outcomes are dependent on achieving specific anti-infectives’ pharmacodynamic targets, the understanding of these medications’ pharmacokinetic parameters in the setting of ECMO is important to clinicians. This narrative, non-systematic review evaluated the findings of the most recent and robust pharmacokinetic analyses for commonly utilized anti-infectives in the setting of ECMO. The data from available literature indicates that anti-infective pharmacokinetic parameters are similar to those observed in other non-ECMO critically ill populations, but considerable variability in the findings was observed between patients, thus prompting further evaluation of therapeutic drug monitoring in this complex population. Full article
(This article belongs to the Special Issue Clinical Pharmacokinetics and Dose Optimization of Anti-infectives in Critical Care)
14 pages, 338 KiB  
Review
Antimicrobial Pharmacokinetics and Pharmacodynamics in Critical Care: Adjusting the Dose in Extracorporeal Circulation and to Prevent the Genesis of Multiresistant Bacteria
by Jesus Ruiz-Ramos, Laura Gras-Martín and Paula Ramírez
Antibiotics 2023, 12(3), 475; https://doi.org/10.3390/antibiotics12030475 - 27 Feb 2023
Cited by 5 | Viewed by 3162
Abstract
Critically ill patients suffering from severe infections are prone to pathophysiological pharmacokinetic changes that are frequently associated with inadequate antibiotic serum concentrations. Minimum inhibitory concentrations (MICs) of the causative pathogens tend to be higher in intensive care units. Both pharmacokinetic changes and high [...] Read more.
Critically ill patients suffering from severe infections are prone to pathophysiological pharmacokinetic changes that are frequently associated with inadequate antibiotic serum concentrations. Minimum inhibitory concentrations (MICs) of the causative pathogens tend to be higher in intensive care units. Both pharmacokinetic changes and high antibiotic resistance likely jeopardize the efficacy of treatment. The use of extracorporeal circulation devices to support hemodynamic, respiratory, or renal failure enables pharmacokinetic changes and makes it even more difficult to achieve an adequate antibiotic dose. Besides a clinical response, antibiotic pharmacokinetic optimization is important to reduce the selection of strains resistant to common antibiotics. In this review, we summarize the present knowledge regarding pharmacokinetic changes in critically ill patients and we discuss the effects of extra-corporeal devices on antibiotic treatment together with potential solutions. Full article
(This article belongs to the Special Issue Clinical Pharmacokinetics and Dose Optimization of Anti-infectives in Critical Care)
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