A Themed Issue in Honor of Professor Hartmut Derendorf —Outstanding Contributions in the Fields of Quantitative Clinical Pharmacology

A special issue of Antibiotics (ISSN 2079-6382).

Deadline for manuscript submissions: closed (30 September 2022) | Viewed by 27197

Special Issue Editors

Pharmacologie Cellulaire et Moléculaire, Louvain Drug Research Institute, Université Catholique de Louvain, Avenue Mounier 73 B1.73.05, 1200 Brussels, Belgium
Interests: new antibiotics; pharmacokinetics and pharmacodynamics; intracellular infection; efflux transporters
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Sebastian Wicha
E-Mail Website
Guest Editor
Department of Clinical Pharmacy, Institute of Pharmacy, University of Hamburg, Hamburg, Germany
Interests: development of mathematical models to describe biological systems to ultimately improve drug development and drug therapy
Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria
Interests: antimicrobial agents with focus on pharmacokinetics; PK/PD; protein binding; cellular transporters; pharmacogenetics; elucidation of the impact of genetic variants; various pathophysiological states on pharmacokinetics and pharmacodynamics; drug-drug interactions; therapeutic drug monitoring (TDM)
Prof. Dr. Paul M. Tulkens
E-Mail Website
Guest Editor
Pharmacologie Cellulaire et Moléculaire, Louvain Drug Research Institute, Université Catholique de Louvain, Avenue Mounier 73 B1.73.05, 1200 Brussels, Belgium
Interests: pathophysiology of lysosomes; endocytosis and of the interactions of drugs and chemicals with membranbes and subcellular organelles; antibiotic toxicity (molecular, cellular and clinical aspects); chemotherapy of intracellular infection; antibiotic efflux pumps and transporters; pharmacodynamics and pharmacokinetics of anti-infective drugs (in vitro models and clinical trials); discovery and development of new antibiotics; promotion of proper antibiotic usage (trough guidelines and public actions); implementation of clinical pharmacy in Belgium

Special Issue Information

Dear Colleagues,

Hartmut Derendorf, University of Gainesville, Florida, US, was a renowned expert in pharmacokinetics and pharmacodynamics, with a specific interest in antibiotics. As such, he is considered one of the “fathers” of modern pharmacokinetics and pharmacometrics. He was the deeply appreciated mentor of 70 graduate students and 40 postdoctoral fellows and published over 500 papers during his career. He gave more than 900 presentations at national or international meetings to promote the use of these disciplines in order to optimize antibiotic dosing for each individual patient. He was an active member of many scientific societies (including ISAP (International Society for Anti-infective Pharmacology) and EPASG (ESCMID PK/PD of Anti-Infectives Study Group)), aiming at improving knowledge on the way antimicrobials should be dosed. He unexpectedly passed away in 2020, soon after his retirement.

This Special Issue is dedicated to the memory of H. Derendorf. Contributions in the field of antibiotic pharmacokinetics and pharmacodynamics or pharmacometrics, as well as studies of drug–drug interactions involving anti-infective agents are especially encouraged, as these disciplines were at the forefront of the interests of H. Derendorf. These works may include in vitro or in vivo data, mathematical models, as well as clinical trials, and concern registered antibiotics or molecules in development.

Prof. Dr. Françoise Van Bambeke
Prof. Dr. Sebastian Wicha
Dr. Markus Zeitlinger
Prof. Dr. Paul Tulkens
Guest Editors



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Published Papers (12 papers)

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Editorial

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2 pages, 184 KiB  
Editorial
Editorial for the Special Issue “A Themed Issue in Honor of Professor Hartmut Derendorf—Outstanding Contributions in the Fields of Quantitative Clinical Pharmacology”
Antibiotics 2023, 12(2), 353; https://doi.org/10.3390/antibiotics12020353 - 08 Feb 2023
Viewed by 549
Abstract
Pharmacokinetics (PK) is the discipline investigating the absorption, distribution, metabolization and elimination of a drug in the body [...] Full article

Research

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20 pages, 3486 KiB  
Article
Evaluation of In Vitro Activity of Double-Carbapenem Combinations against KPC-2-, OXA-48- and NDM-Producing Escherichia coli and Klebsiella pneumoniae
Antibiotics 2022, 11(11), 1646; https://doi.org/10.3390/antibiotics11111646 - 17 Nov 2022
Cited by 2 | Viewed by 1651
Abstract
Double-carbapenem combinations have shown synergistic potential against carbapenemase-producing Enterobacterales, but data remain inconclusive. This study evaluated the activity of double-carbapenem combinations against 51 clinical KPC-2-, OXA-48-, NDM-1, and NDM-5-producing Escherichia coli and Klebsiella pneumoniae and against constructed E. coli strains harboring genes encoding [...] Read more.
Double-carbapenem combinations have shown synergistic potential against carbapenemase-producing Enterobacterales, but data remain inconclusive. This study evaluated the activity of double-carbapenem combinations against 51 clinical KPC-2-, OXA-48-, NDM-1, and NDM-5-producing Escherichia coli and Klebsiella pneumoniae and against constructed E. coli strains harboring genes encoding KPC-2, OXA-48, or NDM-1 in an otherwise isogenic background. Two-drug combinations of ertapenem, meropenem, and doripenem were evaluated in 24 h time-lapse microscopy experiments with a subsequent spot assay and in static time-kill experiments. An enhanced effect in time-lapse microscopy experiments at 24 h and synergy in the spot assay was detected with one or more combinations against 4/14 KPC-2-, 17/17 OXA-48-, 2/17 NDM-, and 1/3 NDM-1+OXA-48-producing clinical isolates. Synergy rates were higher against meropenem- and doripenem-susceptible isolates and against OXA-48 producers. NDM production was associated with significantly lower synergy rates in E. coli. In time-kill experiments with constructed KPC-2-, OXA-48- and NDM-1-producing E. coli, 24 h synergy was not observed; however, synergy at earlier time points was found against the KPC-2- and OXA-48-producing constructs. Our findings indicate that the benefit of double-carbapenem combinations against carbapenemase-producing E. coli and K. pneumoniae is limited, especially against isolates that are resistant to the constituent antibiotics and produce NDM. Full article
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17 pages, 2718 KiB  
Article
A Minimal Physiologically Based Pharmacokinetic Model to Characterize CNS Distribution of Metronidazole in Neuro Care ICU Patients
Antibiotics 2022, 11(10), 1293; https://doi.org/10.3390/antibiotics11101293 - 22 Sep 2022
Cited by 1 | Viewed by 1335
Abstract
Understanding antibiotic concentration-time profiles in the central nervous system (CNS) is crucial to treat severe life-threatening CNS infections, such as nosocomial ventriculitis or meningitis. Yet CNS distribution is likely to be altered in patients with brain damage and infection/inflammation. Our objective was to [...] Read more.
Understanding antibiotic concentration-time profiles in the central nervous system (CNS) is crucial to treat severe life-threatening CNS infections, such as nosocomial ventriculitis or meningitis. Yet CNS distribution is likely to be altered in patients with brain damage and infection/inflammation. Our objective was to develop a physiologically based pharmacokinetic (PBPK) model to predict brain concentration-time profiles of antibiotics and to simulate the impact of pathophysiological changes on CNS profiles. A minimal PBPK model consisting of three physiological brain compartments was developed from metronidazole concentrations previously measured in plasma, brain extracellular fluid (ECF) and cerebrospinal fluid (CSF) of eight brain-injured patients. Volumes and blood flows were fixed to their physiological value obtained from the literature. Diffusion clearances characterizing transport across the blood–brain barrier and blood–CSF barrier were estimated from system- and drug-specific parameters and were confirmed from a Caco-2 model. The model described well unbound metronidazole pharmacokinetic profiles in plasma, ECF and CSF. Simulations showed that with metronidazole, an antibiotic with extensive CNS distribution simply governed by passive diffusion, pathophysiological alterations of membrane permeability, brain ECF volume or cerebral blood flow would have no effect on ECF or CSF pharmacokinetic profiles. This work will serve as a starting point for the development of a new PBPK model to describe the CNS distribution of antibiotics with more limited permeability for which pathophysiological conditions are expected to have a greater effect. Full article
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11 pages, 903 KiB  
Article
Pharmacodynamics of Flucloxacillin in a Neutropenic Murine Thigh Infection Model: A Piece of the Puzzle towards Evidence-Based Dosing
Antibiotics 2022, 11(8), 1049; https://doi.org/10.3390/antibiotics11081049 - 03 Aug 2022
Cited by 1 | Viewed by 1802
Abstract
For decades, flucloxacillin has been used to treat methicillin-susceptible Staphylococcus aureus (MSSA). Little is still known about its pharmacodynamics (PD). The present study aimed to determine the pharmacokinetic (PK)/PD index and the PD-index value minimally required for efficacy. MICs of 305 MSSA isolates [...] Read more.
For decades, flucloxacillin has been used to treat methicillin-susceptible Staphylococcus aureus (MSSA). Little is still known about its pharmacodynamics (PD). The present study aimed to determine the pharmacokinetic (PK)/PD index and the PD-index value minimally required for efficacy. MICs of 305 MSSA isolates were measured to determine the wild-type distribution. The PD of 8 S. aureus, 1 S. pyogenes, and 1 S. agalactiae isolates were evaluated in a neutropenic murine thigh infection model. Two S. aureus isolates were used in a dose-fractionation study and a dose–response analysis was performed additionally in the in vivo model. Data were analyzed with a population PK and sigmoid maximum effect model. The end of the wild-type distribution was 1 mg/L. The percentage of time the unbound concentration was above MIC (%fT > MIC) was best correlated with efficacy. For S. aureus, median %fT > 0.25 × MIC required for 1-log reduction was 15%. The value for S. pyogenes was 10%fT > MIC and for S. agalactiae 22%fT > 0.25xMIC for a 1-log reduction. The effect of flucloxacillin reached a 2-log reduction of S. aureus at 20%fT > 0.25xMIC and also for S. pyogenes and S. agalactiae, a reduction was reached. These data may serve to optimize dosing regimens currently used in humans. Full article
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19 pages, 1206 KiB  
Article
Model-Informed Translation of In Vitro Effects of Short-, Prolonged- and Continuous-Infusion Meropenem against Pseudomonas aeruginosa to Clinical Settings
Antibiotics 2022, 11(8), 1036; https://doi.org/10.3390/antibiotics11081036 - 01 Aug 2022
Cited by 1 | Viewed by 1303
Abstract
Pharmacokinetic-pharmacodynamic (PKPD) models have met increasing interest as tools to identify potential efficacious antibiotic dosing regimens in vitro and in vivo. We sought to investigate the impact of diversely shaped clinical pharmacokinetic profiles of meropenem on the growth/killing patterns of Pseudomonas aeruginosa (ARU552, [...] Read more.
Pharmacokinetic-pharmacodynamic (PKPD) models have met increasing interest as tools to identify potential efficacious antibiotic dosing regimens in vitro and in vivo. We sought to investigate the impact of diversely shaped clinical pharmacokinetic profiles of meropenem on the growth/killing patterns of Pseudomonas aeruginosa (ARU552, MIC = 16 mg/L) over time using a semi-mechanistic PKPD model and a PK/PD index-based approach. Bacterial growth/killing were driven by the PK profiles of six patient populations (infected adults, burns, critically ill, neurosurgery, obese patients) given varied pathogen features (e.g., EC50, growth rate, inoculum), patient characteristics (e.g., creatinine clearance), and ten dosing regimens (including two dose levels and 0.5-h, 3-h and continuous-infusion regimens). Conclusions regarding the most favourable dosing regimen depended on the assessment of (i) the total bacterial load or fT>MIC (time that unbound concentrations exceed the minimum inhibitory concentration); (ii) the median or P0.95 profile of the population; and (iii) 8 h or 24 h time points. Continuous infusion plus loading dose as well as 3-h infusions (3-h infusions: e.g., for scenarios associated with low meropenem concentrations, P0.95 profiles, and MIC ≥ 16 mg/L) appeared superior to standard 0.5-h infusions at 24 h. The developed platform can serve to identify promising strategies of efficacious dosing for clinical trials. Full article
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13 pages, 1298 KiB  
Article
Intermittent Short-Term Infusion vs. Continuous Infusion of Piperacillin: Steady State Concentrations in Porcine Cervical Spine Tissue Evaluated by Microdialysis
Antibiotics 2022, 11(7), 910; https://doi.org/10.3390/antibiotics11070910 - 07 Jul 2022
Cited by 3 | Viewed by 1304
Abstract
Background: Piperacillin is a central drug in the treatment of Pseudomonas aeruginosa spondylodiscitis. Intermittent short-term infusion (STI) remains standard treatment in most centres, although the application of continuous infusion (CI) has shown promising results in other clinical settings. We aimed to evaluate time [...] Read more.
Background: Piperacillin is a central drug in the treatment of Pseudomonas aeruginosa spondylodiscitis. Intermittent short-term infusion (STI) remains standard treatment in most centres, although the application of continuous infusion (CI) has shown promising results in other clinical settings. We aimed to evaluate time above the minimal inhibitory concentration (fT > MIC) of the free fraction of piperacillin in steady state conditions in porcine cervical spine tissue following CI and STI using microdialysis with MIC targets of 4, 8, and 16 μg/mL. Methods: 16 female pigs were randomized to receive piperacillin/tazobactam as STI (4/0.5 g every 6 h) or CI (4/0.5 g as a bolus followed by 12/1.5 g) for 18 h. Microdialysis catheters were placed for sampling of piperacillin concentrations from the intervertebral disc, vertebral cancellous bone, paravertebral muscle, and adjacent subcutaneous tissue during the third dosing interval (12–18 h). Blood samples were collected as reference. Results: CI resulted in fT > MIC > 82% across all compartments and targets, except for intervertebral disc (37%) and vertebral cancellous bone (28%) at MIC = 16 μg/mL. In Group STI, >72% fT > MIC was reached for MIC = 4 μg/mL in all investigated compartments, while for MIC = 16 μg/mL only subcutaneous tissue exhibited fT > MIC > 50%. Conclusion: CI of piperacillin resulted in higher fT > MIC compared to STI infusion across the investigated tissues and targets. CI should therefore be considered in spondylodiscitis cases requiring piperacillin treatment. Full article
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19 pages, 1536 KiB  
Article
Population Pharmacokinetics of Temocillin Administered by Continuous Infusion in Patients with Septic Shock Associated with Intra-Abdominal Infection and Ascitic Fluid Effusion
Antibiotics 2022, 11(7), 898; https://doi.org/10.3390/antibiotics11070898 - 05 Jul 2022
Cited by 2 | Viewed by 1381
Abstract
Temocillin is active against Gram-negative bacteria, including many extended-spectrum β-lactamase (ESBL)-producing Enterobacterales. We studied its pharmacokinetics in plasma and ascitic fluid after intravenous administration of a loading dose of 2 g over 30 min, followed by continuous infusion of 6 g/24 h, to [...] Read more.
Temocillin is active against Gram-negative bacteria, including many extended-spectrum β-lactamase (ESBL)-producing Enterobacterales. We studied its pharmacokinetics in plasma and ascitic fluid after intravenous administration of a loading dose of 2 g over 30 min, followed by continuous infusion of 6 g/24 h, to 19 critically-ill patients with septic shock associated with complicated intra-abdominal infection. We established a pharmacokinetic model describing unbound temocillin concentrations in plasma and ascitic fluid and performed Monte-Carlo simulations to evaluate the probability of target attainment (PTA) of unbound concentrations (100% fT > MIC, i.e., unbound concentrations remaining above the MIC during 100% of the time) for the applied and hypothetical dosing regimens. The temocillin AUC in ascitic fluid was 46% of the plasma AUC. Plasma unbound concentrations were best described by a two-compartment model, and an additional compartment was added to describe unbound concentration in ascitic fluid, with renal clearance as a covariate. Dosing simulations showed that 90% PTA was achieved in the plasma with the current dosing regimen for MIC ≤ 16 mg/L (EUCAST susceptibility breakpoint) but not in the ascitic fluid if renal clearance was ≥40 mL/min. Hypothetical dosing with a higher (a) loading dose or (b) infused dose allowed to reach target concentrations in ascitic fluid (a) more rapidly or (b) sustainably, but these simulations need to be evaluated in the clinics for safety and efficacy. Full article
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12 pages, 1016 KiB  
Article
Tigecycline Dosing Strategies in Critically Ill Liver-Impaired Patients
Antibiotics 2022, 11(4), 479; https://doi.org/10.3390/antibiotics11040479 - 03 Apr 2022
Cited by 3 | Viewed by 2532
Abstract
This study investigated tigecycline exposure in critically ill patients from a population pharmacokinetic perspective to support rational dosing in intensive care unit (ICU) patients with acute and chronic liver impairment. A clinical dataset of 39 patients served as the basis for the development [...] Read more.
This study investigated tigecycline exposure in critically ill patients from a population pharmacokinetic perspective to support rational dosing in intensive care unit (ICU) patients with acute and chronic liver impairment. A clinical dataset of 39 patients served as the basis for the development of a population pharmacokinetic model. The typical tigecycline clearance was strongly reduced (8.6 L/h) as compared to other populations. Different models were developed based on liver and kidney function-related covariates. Monte Carlo simulations were used to guide dose adjustments with the most predictive covariates: Child–Pugh score, total bilirubin, and MELD score. The best performing covariate, guiding a dose reduction to 25 mg q12h, was Child–Pugh score C, whereas patients with Child–Pugh score A/B received the standard dose of 50 mg q12h. Of note, the obtained 24 h steady-state area under the concentration vs. time curve (AUCss) range using this dosing strategy was predicted to be equivalent to high-dose tigecycline exposure (100 mg q12h) in non-ICU patients. In addition, 26/39 study participants died, and therapy failure was most correlated with chronic liver disease and renal failure, but no correlation between drug exposure and survival was observed. However, tigecycline in special patient populations needs further investigations to enhance clinical outcome. Full article
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14 pages, 1941 KiB  
Article
Population Pharmacokinetic Model of Piperacillin in Critically Ill Patients and Describing Interethnic Variation Using External Validation
Antibiotics 2022, 11(4), 434; https://doi.org/10.3390/antibiotics11040434 - 24 Mar 2022
Viewed by 1807
Abstract
Objectives: This study aimed to develop a piperacillin population PK model for critically ill Brazil-ian patients and describe interethnic variation using an external validation. Methods: Plasma samples were obtained from 24 ICU patients during the fifth day of piperacillin treatment and assayed by [...] Read more.
Objectives: This study aimed to develop a piperacillin population PK model for critically ill Brazil-ian patients and describe interethnic variation using an external validation. Methods: Plasma samples were obtained from 24 ICU patients during the fifth day of piperacillin treatment and assayed by HPLC-UV. Population pharmacokinetic modelling was conducted using Pmetrics. Empiric dose of 4 g IV 6- and 8-hourly were simulated for 50 and 100% fT > MIC and the probabil-ity of target attainment (PTA) and the fractional target attainment (FTA) determined. Results: A two-compartment model was designed to describe the pharmacokinetics of critically ill Brazillian patients. Clearance and volume of distribution were (mean ± SD) 3.33 ± 1.24 L h−1 and 10.69 ± 4.50 L, respectively. Creatinine clearance was positively correlated with piperacillin clearance and a high creatinine clearance was associated with lower values of PTA and FTA. An external vali-dation was performed using data from two different ethnic ICU populations (n = 30), resulting in acceptable bias and precision. Conclusion: The primary pharmacokinetic parameters obtained from critically ill Brazilian patients were similar to those observed in studies performed in critically ill patients of other ethnicities. Based on our results, the use of dose adjustment based on creati-nine clearance is required in Brazilian patients. Full article
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Review

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20 pages, 798 KiB  
Review
Pharmacokinetic/Pharmacodynamic Modeling and Application in Antibacterial and Antifungal Pharmacotherapy: A Narrative Review
Antibiotics 2022, 11(8), 986; https://doi.org/10.3390/antibiotics11080986 - 22 Jul 2022
Cited by 7 | Viewed by 3277
Abstract
Pharmacokinetics and pharmacodynamics are areas in pharmacology related to different themes in the pharmaceutical sciences, including therapeutic drug monitoring and different stages of drug development. Although the knowledge of these disciplines is essential, they have historically been treated separately. While pharmacokinetics was limited [...] Read more.
Pharmacokinetics and pharmacodynamics are areas in pharmacology related to different themes in the pharmaceutical sciences, including therapeutic drug monitoring and different stages of drug development. Although the knowledge of these disciplines is essential, they have historically been treated separately. While pharmacokinetics was limited to describing the time course of plasma concentrations after administering a drug-dose, pharmacodynamics describes the intensity of the response to these concentrations. In the last decades, the concept of pharmacokinetic/pharmacodynamic modeling (PK/PD) emerged, which seeks to establish mathematical models to describe the complete time course of the dose-response relationship. The integration of these two fields has had applications in optimizing dose regimens in treating antibacterial and antifungals. The anti-infective PK/PD models predict the relationship between different dosing regimens and their pharmacological activity. The reviewed studies show that PK/PD modeling is an essential and efficient tool for a better understanding of the pharmacological activity of antibacterial and antifungal agents. Full article
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17 pages, 1744 KiB  
Review
Protein Binding in Translational Antimicrobial Development-Focus on Interspecies Differences
Antibiotics 2022, 11(7), 923; https://doi.org/10.3390/antibiotics11070923 - 08 Jul 2022
Cited by 8 | Viewed by 4248
Abstract
Background/Introduction: Plasma protein binding (PPB) continues to be a key aspect of antibiotic development and clinical use. PPB is essential to understand several properties of drug candidates, including antimicrobial activity, drug-drug interaction, drug clearance, volume of distribution, and therapeutic index. Focus areas of [...] Read more.
Background/Introduction: Plasma protein binding (PPB) continues to be a key aspect of antibiotic development and clinical use. PPB is essential to understand several properties of drug candidates, including antimicrobial activity, drug-drug interaction, drug clearance, volume of distribution, and therapeutic index. Focus areas of the review: In this review, we discuss the basics of PPB, including the main drug binding proteins i.e., Albumin and α-1-acid glycoprotein (AAG). Furthermore, we present the effects of PPB on the antimicrobial activity of antibiotics and the current role of PPB in in vitro pharmacodynamic (PD) models of antibiotics. Moreover, the effect of PPB on the PK/PD of antibiotics has been discussed in this review. A key aspect of this paper is a concise evaluation of PPB between animal species (dog, rat, mouse, rabbit and monkey) and humans. Our statistical analysis of the data available in the literature suggests a significant difference between antibiotic binding in humans and that of dogs or mice, with the majority of measurements from the pre-clinical species falling within five-fold of the human plasma value. Conversely, no significant difference in binding was found between humans and rats, rabbits, or monkeys. This information may be helpful for drug researchers to select the most relevant animal species in which the metabolism of a compound can be studied for extrapolating the results to humans. Furthermore, state-of-the-art methods for determining PPB such as equilibrium dialysis, ultracentrifugation, microdialysis, gel filtration, chromatographic methods and fluorescence spectroscopy are highlighted with their advantages and disadvantages. Full article
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19 pages, 1276 KiB  
Review
Key Factors in Effective Patient-Tailored Dosing of Fluoroquinolones in Urological Infections: Interindividual Pharmacokinetic and Pharmacodynamic Variability
Antibiotics 2022, 11(5), 641; https://doi.org/10.3390/antibiotics11050641 - 11 May 2022
Cited by 6 | Viewed by 4691
Abstract
Fluoroquinolones (FQs) are a critical group of antimicrobials prescribed in urological infections as they have a broad antimicrobial spectrum of activity and a favorable tissue penetration at the site of infection. However, their clinical practice is not problem-free of treatment failure, risk of [...] Read more.
Fluoroquinolones (FQs) are a critical group of antimicrobials prescribed in urological infections as they have a broad antimicrobial spectrum of activity and a favorable tissue penetration at the site of infection. However, their clinical practice is not problem-free of treatment failure, risk of emergence of resistance, and rare but important adverse effects. Due to their critical role in clinical improvement, understanding the dose-response relation is necessary to optimize the effectiveness of FQs therapy, as it is essential to select the right antibiotic at the right dose for the right duration in urological infections. The aim of this study was to review the published literature about inter-individual variability in pharmacological processes that can be responsible for the clinical response after empiric dose for the most commonly prescribed urological FQs: ciprofloxacin, levofloxacin, and moxifloxacin. Interindividual pharmacokinetic (PK) variability, particularly in elimination, may contribute to treatment failure. Clearance related to creatinine clearance should be specifically considered for ciprofloxacin and levofloxacin. Likewise, today, undesired interregional variability in FQs antimicrobial activity against certain microorganisms exists. FQs pharmacology, patient-specific characteristics, and the identity of the local infecting organism are key factors in determining clinical outcomes in FQs use. Full article
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