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Pharmaceutics
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Dose Optimization and Targeting Strategies of Anti-infective Agents
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Dose Optimization and Targeting Strategies of Anti-infective Agents

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Drug Targeting and Design".

Deadline for manuscript submissions: closed (31 May 2023) | Viewed by 25098

Special Issue Editors

Dr. Martin Šíma

E-Mail Website
Guest Editor
Department of Pharmacology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
Interests: pharmacokinetics; therapeutic drug monitoring; pharmacometrics; clinical pharmacology
Prof. Dr. Ondřej Slanař

E-Mail Website
Guest Editor
Department of Pharmacology, First Faculty of Medicine, Charles University and General University Hospital in Prague, 128 00 Prague, Czech Republic
Interests: pharmacokinetics; pharmacogenomics; clinical pharmacology; clinical trials

Special Issue Information

Dear Colleagues,

Most drugs are currently developed, approved and marketed based on their effect in the majority of the population. However, the concept of a single dose of a drug for all patients with the same disease may not lead to the desired results. As a result of inter-individual variability in population, the concentration profile of the drug over time after administration of the same dose to individual patients may vary significantly. The same dose may thus lead to signs of toxicity in some patients, while in others may be ineffective. In addition, for anti-infective agents, low exposure may be accompanied by the development of resistance. In order to achieve maximum therapeutic potential of anti-infective drugs the therapy needs to be targeted and dosage optimized. Therefore, this special issue aims to serve as a platform for sharing the contemporary progress on dose optimization and targeting strategies of antibiotics as well as other anti-infective agents. We cordially invite researchers for submission of original research articles, review articles or commentaries on all aspects of this topic.

 

Dr. Martin Šíma
Prof. Dr. Ondřej Slanař
Guest Editors

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Keywords

  • pharmacokinetics
  • therapeutic drug monitoring
  • antibiotics
  • antimycotics
  • antivirotics
  • interindividual
  • variability
  • personalized pharmacotherapy
  • modeling and simulation

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Published Papers (7 papers)

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Editorial

Jump to: Research, Review

2 pages, 180 KiB  
Editorial
Dose Optimization and Targeting Strategies of Anti-Infective Agents
by Martin Šíma and Ondřej Slanař
Pharmaceutics 2023, 15(7), 1870; https://doi.org/10.3390/pharmaceutics15071870 - 3 Jul 2023
Viewed by 875
Abstract
Most drugs are currently developed, approved and marketed based on their effect on the majority of the population [...] Full article
(This article belongs to the Special Issue Dose Optimization and Targeting Strategies of Anti-infective Agents)

Research

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16 pages, 1935 KiB  
Article
Meropenem PK/PD Variability and Renal Function: “We Go Together”
by Jacopo Angelini, Simone Giuliano, Sarah Flammini, Alberto Pagotto, Francesco Lo Re, Carlo Tascini and Massimo Baraldo
Pharmaceutics 2023, 15(9), 2238; https://doi.org/10.3390/pharmaceutics15092238 - 30 Aug 2023
Cited by 2 | Viewed by 1478
Abstract
Background: Meropenem is a carbapenem antibiotic widely employed for serious bacterial infections. Therapeutic drug monitoring (TDM) is a strategy to optimize dosing, especially in critically ill patients. This study aims to show how TDM influences the management of meropenem in a real-life setting, [...] Read more.
Background: Meropenem is a carbapenem antibiotic widely employed for serious bacterial infections. Therapeutic drug monitoring (TDM) is a strategy to optimize dosing, especially in critically ill patients. This study aims to show how TDM influences the management of meropenem in a real-life setting, not limited to intensive care units. Methods: From December 2021 to February 2022, we retrospectively analyzed 195 meropenem serum concentrations (Css). We characterized patients according to meropenem exposure, focusing on the renal function impact. Results: A total of 36% (n = 51) of the overall observed patients (n = 144) were in the therapeutic range (8–16 mg/L), whereas 64% (n = 93) required a meropenem dose modification (37 patients (26%) underexposed; 53 (38%) overexposed). We found a strong relationship between renal function and meropenem concentrations (correlation coefficient = −0.7; p-value < 0.001). We observed different dose-normalized meropenem exposure (Css/D) among renal-impaired (severe and moderate), normal, and hyperfiltrating patients, with a median (interquartile range) of 13.1 (10.9–20.2), 7.9 (6.1–9.5), 3.8 (2.6–6.0), and 2.4 (1.6–2.7), respectively (p-value < 0.001). Conclusions: Meropenem TDM in clinical practice allows modification of dosing in patients inadequately exposed to meropenem to maximize antibiotic efficacy and minimize the risk of antibiotic resistance, especially in renal alterations despite standard dose adaptations. Full article
(This article belongs to the Special Issue Dose Optimization and Targeting Strategies of Anti-infective Agents)
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16 pages, 2058 KiB  
Article
Intraperitoneally Administered Vancomycin in Patients with Peritoneal Dialysis-Associated Peritonitis: Population Pharmacokinetics and Dosing Implications
by Jan Miroslav Hartinger, Danica Michaličková, Eliška Dvořáčková, Karolína Hronová, Elke H. J. Krekels, Barbora Szonowská, Vladimíra Bednářová, Hana Benáková, Gabriela Kroneislová, Jan Závora, Vladimír Tesař and Ondřej Slanař
Pharmaceutics 2023, 15(5), 1394; https://doi.org/10.3390/pharmaceutics15051394 - 2 May 2023
Cited by 2 | Viewed by 5927
Abstract
Peritonitis is a limiting complication of peritoneal dialysis, which is treated by intraperitoneal administration of antibiotics. Various dosing strategies are recommended for intraperitoneally administered vancomycin, which leads to large differences in intraperitoneal vancomycin exposure. Based on data from therapeutic drug monitoring, we developed [...] Read more.
Peritonitis is a limiting complication of peritoneal dialysis, which is treated by intraperitoneal administration of antibiotics. Various dosing strategies are recommended for intraperitoneally administered vancomycin, which leads to large differences in intraperitoneal vancomycin exposure. Based on data from therapeutic drug monitoring, we developed the first-ever population pharmacokinetic model for intraperitoneally administered vancomycin to evaluate intraperitoneal and plasma exposure after dosing schedules recommended by the International Society for Peritoneal Dialysis. According to our model, currently recommended dosing schedules lead to possible underdosing of a large proportion of patients. To prevent this, we suggest avoiding intermittent intraperitoneal vancomycin administration, and for the continuous dosing regimen, we suggest a loading dose of 20 mg/kg followed by maintenance doses of 50 mg/L in each dwell to improve the intraperitoneal exposure. Vancomycin plasma level measurement on the fifth day of treatment with subsequent dose adjustment would prevent it from reaching toxic levels in the few patients who are susceptible to overdose. Full article
(This article belongs to the Special Issue Dose Optimization and Targeting Strategies of Anti-infective Agents)
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17 pages, 1043 KiB  
Article
Pharmacokinetic/Pharmacodynamic Evaluation of Aztreonam/Amoxicillin/Clavulanate Combination against New Delhi Metallo-β-Lactamase and Serine-β-Lactamase Co-Producing Escherichia coli and Klebsiella pneumoniae
by Jiayuan Zhang, Mengyuan Wu, Shuo Diao, Shixing Zhu, Chu Song, Jiali Yue, Frederico S. Martins, Peijuan Zhu, Zhihua Lv, Yuanqi Zhu, Mingming Yu and Sherwin K. B. Sy
Pharmaceutics 2023, 15(1), 251; https://doi.org/10.3390/pharmaceutics15010251 - 11 Jan 2023
Cited by 6 | Viewed by 2520
Abstract
This study aimed to examine specific niches and usage for the aztreonam/amoxicillin/clavulanate combination and to use population pharmacokinetic simulations of clinical dosing regimens to predict the impact of this combination on restricting mutant selection. The in vitro susceptibility of 19 New-Delhi metallo-β-lactamase (NDM)-producing [...] Read more.
This study aimed to examine specific niches and usage for the aztreonam/amoxicillin/clavulanate combination and to use population pharmacokinetic simulations of clinical dosing regimens to predict the impact of this combination on restricting mutant selection. The in vitro susceptibility of 19 New-Delhi metallo-β-lactamase (NDM)-producing clinical isolates to amoxicillin/clavulanate and aztreonam alone and in co-administration was determined based on the minimum inhibitory concentration (MIC) and mutant prevention concentration (MPC). The fractions of a 24-h duration that the free drug concentration was within the mutant selection window (fTMSW) and above the MPC (fT>MPC) in both plasma and epithelial lining fluid were determined from simulations of 10,000 subject profiles based on regimens by renal function categories. This combination reduced the MIC of aztreonam and amoxicillin/clavulanate to values below their clinical breakpoint in 7/9 K. pneumoniae and 8/9 E. coli, depending on the β-lactamase genes detected in the isolate. In the majority of the tested isolates, the combination resulted in fT>MPC > 90% and fTMSW < 10% for both aztreonam and amoxicillin/clavulanate. Clinical dosing regimens of aztreonam and amoxicillin/clavulanate were sufficient to provide mutant restriction coverage for MPC and MIC ≤ 4 mg/L. This combination has limited coverage against NDM- and extended-spectrum β-lactamase co-producing E. coli and K. pneumoniae and is not effective against isolates carrying plasmid-mediated AmpC and KPC-2. This study offers a potential scope and limitations as to where the aztreonam/amoxicillin/clavulanate combination may succeed or fail. Full article
(This article belongs to the Special Issue Dose Optimization and Targeting Strategies of Anti-infective Agents)
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11 pages, 1942 KiB  
Article
Factors Affecting the Metabolic Conversion of Ciprofloxacin and Exposure to Its Main Active Metabolites in Critically Ill Patients: Population Pharmacokinetic Analysis of Desethylene Ciprofloxacin
by Martin Šíma, Daniel Bobek, Petra Cihlářová, Pavel Ryšánek, Jaroslava Roušarová, Jan Beroušek, Martin Kuchař, Tomáš Vymazal and Ondřej Slanař
Pharmaceutics 2022, 14(8), 1627; https://doi.org/10.3390/pharmaceutics14081627 - 4 Aug 2022
Cited by 3 | Viewed by 2359
Abstract
The objective of this prospective study was to examine the exposure to the main active metabolites of ciprofloxacin in critically ill patients and to examine the factors (demographic, laboratory and genetic) that could potentially affect the drug metabolic conversion of ciprofloxacin. The secondary [...] Read more.
The objective of this prospective study was to examine the exposure to the main active metabolites of ciprofloxacin in critically ill patients and to examine the factors (demographic, laboratory and genetic) that could potentially affect the drug metabolic conversion of ciprofloxacin. The secondary aim was to develop a population pharmacokinetic model for the metabolite showing the most associations with the abovementioned factors. A total of 29 patients were treated with intravenous infusion of ciprofloxacin and enrolled on this trial. Blood samples for pharmacokinetic analysis were taken at 1, 4, and 11.5 h following the completion of the infusion. Sex, age, body weight, height, serum creatinine and bilirubin levels, and creatinine clearance (CLCR) were recorded, and polymorphisms rs2032582 and rs1045642 in the ABCB1 gene, rs4148977 in the SLCO1A2 gene and rs762551 in the CYP1A2 gene were analyzed. A three-stage parent drug–metabolite population pharmacokinetic model was developed. Median (IQR) metabolite/parent ratios of the desethylene ciprofloxacin, formyl ciprofloxacin and oxociprofloxacin were 5.86 (4.09–9.87)%, 4.08 (3.38–6.92)% and 5.91 (3.42–13.65)%, respectively. The desethylene ciprofloxacin metabolic ratio was positively associated with height (r2 = 0.2277, p = 0.0089) and CLCR (r2 = 0.2023, p = 0.0144) and negatively associated with age (r2 = 0.2227, p = 0.0112). Males had a significantly higher oxociprofloxacin metabolic ratio than females (9.14 vs 3.42%, p = 0.0043). In the desethylene ciprofloxacin population PK model, the volume of distribution decreased with age, the parent drug-metabolite transfer rate constant increased with CLCR, and the metabolite elimination rate constant decreased with age and is increased in CYP1A2 rs762551 variant allele carriers. We therefore hypothesized that the CYP1A2 inhibition by ciprofloxacin is mediated by its metabolite desethylene ciprofloxacin. Full article
(This article belongs to the Special Issue Dose Optimization and Targeting Strategies of Anti-infective Agents)
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11 pages, 473 KiB  
Article
Effectiveness and Nephrotoxicity of Loading Dose Colistin–Meropenem versus Loading Dose Colistin–Imipenem in the Treatment of Carbapenem-Resistant Acinetobacter baumannii Infection
by Wasan Katip, Peninnah Oberdorfer and Nongyao Kasatpibal
Pharmaceutics 2022, 14(6), 1266; https://doi.org/10.3390/pharmaceutics14061266 - 14 Jun 2022
Cited by 28 | Viewed by 2518
Abstract
Carbapenem-resistant Acinetobacter baumannii (CRAB) is becoming more widely recognized as a serious cause of nosocomial infections, and colistin has been reintroduced in recent years for the treatment of CRAB infection. Combinations of colistin and meropenem or imipenem have been found to be [...] Read more.
Carbapenem-resistant Acinetobacter baumannii (CRAB) is becoming more widely recognized as a serious cause of nosocomial infections, and colistin has been reintroduced in recent years for the treatment of CRAB infection. Combinations of colistin and meropenem or imipenem have been found to be effective against CRAB isolates, whereas clinical investigations have not definitively demonstrated the theoretical benefits of colistin combined therapy in patients with CRAB infections. The objective of this study was to compare the primary outcome (30-day survival rate) and secondary outcomes (clinical response, microbiological response and nephrotoxicity) between patients who received loading dose (LD) colistin–meropenem and LD colistin–imipenem for the treatment of CRAB infection. A retrospective cohort analysis was performed at Chiang Mai University Hospital in patients with CRAB infection who received LD colistin–meropenem or LD colistin–imipenem between 2011 and 2017, and 379 patients fulfilled the requirements for the inclusion criteria. The results of this study showed that patients who received LD colistin–imipenem had a lower 30-day survival rate (adjusted HR = 0.57, 95% CI: 0.37–0.90; p = 0.015) and a lower clinical response (aHR = 0.56, 95% CI: 0.35–0.90; p = 0.017) compared with those who received LD colistin–meropenem. The microbiological response in patients with LD colistin–imipenem was 0.52 times (aHR) lower than that in those who received colistin–meropenem (95% CI: 0.34–0.81; p = 0.004); however, there was no significant difference in nephrotoxicity (aHR = 1.03, 95% CI: 0.67–1.57; p = 0.897) between the two combination regimens. In conclusion, when comparing the combination of LD colistin with imipenem or meropenem, the combination of LD colistin and meropenem provides a better survival rate for treating CRAB. Thus, we suggest that combinations of LD colistin and meropenem should be considered when treating CRAB infections. Full article
(This article belongs to the Special Issue Dose Optimization and Targeting Strategies of Anti-infective Agents)
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Review

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21 pages, 1347 KiB  
Review
Optimizing Antiviral Dosing for HSV and CMV Treatment in Immunocompromised Patients
by Daan W. Huntjens, Jacob A. Dijkstra, Lisanne N. Verwiel, Mirjam Slijkhuis, Paul Elbers, Matthijs R. A. Welkers, Agnes I. Veldkamp, Marianne A. Kuijvenhoven, David C. de Leeuw, Heshu Abdullah-Koolmees, Maria T. Kuipers and Imke H. Bartelink
Pharmaceutics 2023, 15(1), 163; https://doi.org/10.3390/pharmaceutics15010163 - 3 Jan 2023
Cited by 14 | Viewed by 8100
Abstract
Herpes simplex virus (HSV) and cytomegalovirus (CMV) are DNA viruses that are common among humans. Severely immunocompromised patients are at increased risk of developing HSV or CMV disease due to a weakened immune system. Antiviral therapy can be challenging because these drugs have [...] Read more.
Herpes simplex virus (HSV) and cytomegalovirus (CMV) are DNA viruses that are common among humans. Severely immunocompromised patients are at increased risk of developing HSV or CMV disease due to a weakened immune system. Antiviral therapy can be challenging because these drugs have a narrow therapeutic window and show significant pharmacokinetic variability. Above that, immunocompromised patients have various comorbidities like impaired renal function and are exposed to polypharmacy. This scoping review discusses the current pharmacokinetic (PK) and pharmacodynamic (PD) knowledge of antiviral drugs for HSV and CMV treatment in immunocompromised patients. HSV and CMV treatment guidelines are discussed, and multiple treatment interventions are proposed: early detection of drug resistance; optimization of dose to target concentration by therapeutic drug monitoring (TDM) of nucleoside analogs; the introduction of new antiviral drugs; alternation between compounds with different toxicity profiles; and combinations of synergistic antiviral drugs. This research will also serve as guidance for future research, which should focus on prospective evaluation of the benefit of each of these interventions in randomized controlled trials. Full article
(This article belongs to the Special Issue Dose Optimization and Targeting Strategies of Anti-infective Agents)
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