Antibiotics Treatment Optimization in Vulnerable Populations

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 May 2023) | Viewed by 20565

Special Issue Editors

1. Service de Pharmacologie clinique et Pharmacovigilance, Hôpital de la Timone, Marseille, France 2. Aix Marseille Université, Institut de Neurosciences des Systèmes, Inserm UMR 1106, Marseille, France
Interests: pharmacology; pharmacokinetics; PK/PD; therapeutic drug monitoring; treatment optimization
1. Laboratoire de Suivi Thérapeutique Pharmacologique et Pharmacocinétique, Faculty of Pharmacy, Université de Montréal, Montreal, QC, Canada
2. Centre de recherche, CHU Sainte-Justine, Montréal, QC, Canada
Interests: pharmacokinetic; pharmacology; pharmacotherapy; optimal use of drug; population health

Special Issue Information

Dear Colleagues, 

Optimizing antibiotic use is one of the goals outlined in the WHO Global Action Plan, adopted in 2015, to combat antimicrobial resistance. This objective has been reinforced by the publication of the 'O'Neil' report, which announces that by 2050 more patients will die from resistant infections than from cancer. The first element is that an antibiotic must be used only when necessary. Another difficulty is that many publications report significant interindividual pharmacokinetic variability, exposing patients to possible side effects or clinical failure. Secondly, the dose and treatment regimen must be adapted according to the characteristics of the patient, his or her clinical condition and the pathogens responsible for the infection.

Pharmacokinetic/pharmacodynamic studies allow new recommendations to be developed based on a patient's characteristics as well as clinical context and to move away from the ‘one dose fits all’ approach that seems to be more and more obsolete since the beginning of personalized medicine.In this Special Issue we aim to highlight new data that support new recommendations for antibiotic use to optimize care by ensuring that ‘the right treatments are given to the right patient at the right dose and at the right time’.

Dr. Romain Guilhaumou
Dr. Amélie Marsot
Guest Editors

Manuscript Submission Information

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Keywords

  • antibiotics
  • pharmacokinetics
  • pharmacodynamics
  • dose optimization
  • vulnerable populations
  • personalised dosing

Published Papers (10 papers)

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Research

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12 pages, 1601 KiB  
Article
β-Lactam Pharmacokinetic/Pharmacodynamic Target Attainment in Intensive Care Unit Patients: A Prospective, Observational, Cohort Study
by Romain Guilhaumou, Constance Chevrier, Jean Loup Setti, Elisabeth Jouve, Amélie Marsot, Nathan Julian, Olivier Blin, Pierre Simeone, David Lagier, Djamel Mokart, Nicolas Bruder, Marc Garnier and Lionel Velly
Antibiotics 2023, 12(8), 1289; https://doi.org/10.3390/antibiotics12081289 - 05 Aug 2023
Viewed by 1008
Abstract
Background: The aims of this study were to describe pharmacokinetic/pharmacodynamic target attainment in intensive care unit (ICU) patients treated with continuously infused ß-lactam antibiotics, their associated covariates, and the impact of dosage adjustment. Methods: This prospective, observational, cohort study was performed in [...] Read more.
Background: The aims of this study were to describe pharmacokinetic/pharmacodynamic target attainment in intensive care unit (ICU) patients treated with continuously infused ß-lactam antibiotics, their associated covariates, and the impact of dosage adjustment. Methods: This prospective, observational, cohort study was performed in three ICUs. Four ß-lactams were continuously infused, and therapeutic drug monitoring (TDM) was performed at days 1, 4, and 7. The primary pharmacokinetic/pharmacodynamic target was an unbound ß-lactam plasma concentration four times above the bacteria’s minimal inhibitory concentration during the whole dosing interval. The demographic and clinical covariates associated with target attainment were evaluated. Results: A total of 170 patients were included (426 blood samples). The percentages of empirical ß-lactam underdosing at D1 were 66% for cefepime, 43% for cefotaxime, 47% for ceftazidime, and 14% for meropenem. Indexed creatinine clearance was independently associated with treatment underdose if increased (adjusted odds ratio per unit, 1.01; 95% CI, 1.00 to 1.01; p = 0.014) or overdose if decreased (adjusted odds ratio per unit, 0.95; 95% CI, 0.94 to 0.97; p < 0.001). Pharmacokinetic/pharmacodynamic target attainment was significantly increased after ß-lactam dosage adjustment between day 1 and day 4 vs. no adjustment (53.1% vs. 26.2%; p = 0.018). Conclusions: This study increases our knowledge on the optimization of ß-lactam therapy in ICU patients. A large inter- and intra-patient variability in plasmatic concentrations was observed, leading to inadequate exposure. A combined indexed creatinine clearance and TDM approach enables adequate dosing for better pharmacokinetic/pharmacodynamic target attainment. Full article
(This article belongs to the Special Issue Antibiotics Treatment Optimization in Vulnerable Populations)
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19 pages, 986 KiB  
Article
Isavuconazole Exposure in Critically Ill Patients Treated with Extracorporeal Membrane Oxygenation: Two Case Reports and a Narrative Literature Review
by Beatrijs Mertens, Omar Elkayal, Erwin Dreesen, Joost Wauters, Philippe Meersseman, Yves Debaveye, Karlien Degezelle, Pieter Vermeersch, Matthias Gijsen and Isabel Spriet
Antibiotics 2023, 12(7), 1085; https://doi.org/10.3390/antibiotics12071085 - 21 Jun 2023
Viewed by 1424
Abstract
Effective dosing of isavuconazole in patients supported by extracorporeal membrane oxygenation (ECMO) is important due to the role of isavuconazole as a first-line treatment in patients with influenza- and COVID-19-associated pulmonary aspergillosis. To date, robust pharmacokinetic data in patients supported by ECMO are [...] Read more.
Effective dosing of isavuconazole in patients supported by extracorporeal membrane oxygenation (ECMO) is important due to the role of isavuconazole as a first-line treatment in patients with influenza- and COVID-19-associated pulmonary aspergillosis. To date, robust pharmacokinetic data in patients supported by ECMO are limited. Therefore, it is unknown whether ECMO independently impacts isavuconazole exposure. We measured isavuconazole plasma concentrations in two patients supported by ECMO and estimated individual pharmacokinetic parameters using non-compartmental analysis and two previously published population pharmacokinetic models. Furthermore, a narrative literature review on isavuconazole exposure in adult patients receiving ECMO was performed. The 24 h areas under the concentration–time curve and trough concentrations of isavuconazole were lower in both patients compared with exposure values published before. In the literature, highly variable isavuconazole concentrations have been documented in patients with ECMO support. The independent effect of ECMO versus critical illness itself on isavuconazole exposure cannot be deduced from our and previously published (case) reports. Pending additional data, therapeutic drug monitoring is recommended in critically ill patients, regardless of ECMO support. Full article
(This article belongs to the Special Issue Antibiotics Treatment Optimization in Vulnerable Populations)
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14 pages, 1231 KiB  
Article
Daptomycin Pharmacokinetics in Blood and Wound Fluid in Critical Ill Patients with Left Ventricle Assist Devices
by Stefanie Calov, Frederik Munzel, Anka C. Roehr, Otto Frey, Lina Maria Serna Higuita, Petra Wied, Peter Rosenberger, Helene A. Haeberle and Kristian-Christos Ngamsri
Antibiotics 2023, 12(5), 904; https://doi.org/10.3390/antibiotics12050904 - 13 May 2023
Viewed by 1193
Abstract
Daptomycin is a cyclic lipopeptide antibiotic with bactericidal effects against multidrug-resistant Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecalis (VRE). For critically ill patients, especially in the presence of implants, daptomycin is an important therapeutic option. Left ventricle assist devices [...] Read more.
Daptomycin is a cyclic lipopeptide antibiotic with bactericidal effects against multidrug-resistant Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecalis (VRE). For critically ill patients, especially in the presence of implants, daptomycin is an important therapeutic option. Left ventricle assist devices (LVADs) can be utilized for intensive care patients with end-stage heart failure as a bridge to transplant. We conducted a single-center prospective trial with critically ill adults with LVAD who received prophylactic anti-infective therapy with daptomycin. Our study aimed to evaluate the pharmacokinetics of daptomycin in the blood serum and wound fluids after LVAD implantation. Daptomycin concentration were assessed over three days using high-performance liquid chromatography (HPLC). We detected a high correlation between blood serum and wound fluid daptomycin concentration at 12 h (IC95%: 0.64 to 0.95; r = 0.86; p < 0.001) and 24 h (IC95%: −0.38 to 0.92; r = 0.76; p < 0.001) after antibiotic administration. Our pilot clinical study provides new insights into the pharmacokinetics of daptomycin from the blood into wound fluids of critically ill patients with LVADs. Full article
(This article belongs to the Special Issue Antibiotics Treatment Optimization in Vulnerable Populations)
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11 pages, 606 KiB  
Article
Adequacy of the 10 mg/kg Daily Dose of Antituberculosis Drug Isoniazid in Infants under 6 Months of Age
by Maria Goretti López-Ramos, Joan Vinent, Rob Aarnoutse, Angela Colbers, Eneritz Velasco-Arnaiz, Loreto Martorell, Lola Falcón-Neyra, Olaf Neth, Luis Prieto, Sara Guillén, Fernando Baquero-Artigao, Ana Méndez-Echevarría, David Gómez-Pastrana, Ana Belén Jiménez, Rebeca Lahoz, José Tomás Ramos-Amador, Antoni Soriano-Arandes, Begoña Santiago, Rosa Farré, Clàudia Fortuny, Dolors Soy and Antoni Noguera-Julianadd Show full author list remove Hide full author list
Antibiotics 2023, 12(2), 272; https://doi.org/10.3390/antibiotics12020272 - 30 Jan 2023
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Abstract
In 2010, the WHO recommended an increase in the daily doses of first-line anti-tuberculosis medicines in children. We aim to characterize the pharmacokinetics of the once-daily isoniazid (INH) dose at 10 mg/kg of body weight in infants <6 months of age. We performed [...] Read more.
In 2010, the WHO recommended an increase in the daily doses of first-line anti-tuberculosis medicines in children. We aim to characterize the pharmacokinetics of the once-daily isoniazid (INH) dose at 10 mg/kg of body weight in infants <6 months of age. We performed a multicenter pharmacokinetic study in Spain. The N-acetyltransferase 2 gene was analyzed to determine the acetylation status. Samples were analyzed using a validated UPLC-UV assay. A non-compartmental pharmacokinetic analysis was performed. Twenty-three pharmacokinetic profiles were performed in 20 infants (8 females) at a median (IQR) age of 19.0 (12.6–23.3) weeks. The acetylator statuses were homozygous fast (n = 1), heterozygous intermediate (n = 12), and homozygous slow (n = 7). INH median (IQR) Cmax and AUC0–24h values were 4.8 (3.7–6.7) mg/L and 23.5 (13.4–36.7) h*mg/L and the adult targets (>3 mg/L and 11.6–26.3 h*mg/L) were not reached in three and five cases, respectively. The age at assessment or acetylator status had no impact on Cmax values, but a larger INH AUC0–24h (p = 0.025) and trends towards a longer half-life (p = 0.055) and slower clearance (p = 0.070) were observed in homozygous slow acetylators. Treatment was well tolerated; mildly elevated alanine aminotransferase levels were observed in three cases. In our series of young infants receiving isoniazid, no major safety concerns were raised, and the target adult levels were reached in most patients. Full article
(This article belongs to the Special Issue Antibiotics Treatment Optimization in Vulnerable Populations)
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12 pages, 1631 KiB  
Article
Development of a Predictive Dosing Nomogram to Achieve PK/PD Targets of Amikacin Initial Dose in Critically Ill Patients: A Non-Parametric Approach
by Anne Coste, Ronan Bellouard, Guillaume Deslandes, Laurence Jalin, Claire Roger, Séverine Ansart, Eric Dailly, Cédric Bretonnière and Matthieu Grégoire
Antibiotics 2023, 12(1), 123; https://doi.org/10.3390/antibiotics12010123 - 09 Jan 2023
Cited by 1 | Viewed by 1367
Abstract
French guidelines recommend reaching an amikacin concentration of ≥8 × MIC 1 h after beginning infusion (C1h), with MIC = 8 mg/L for probabilistic therapy. We aimed to elaborate a nomogram guiding clinicians in choosing the right first amikacin dose for [...] Read more.
French guidelines recommend reaching an amikacin concentration of ≥8 × MIC 1 h after beginning infusion (C1h), with MIC = 8 mg/L for probabilistic therapy. We aimed to elaborate a nomogram guiding clinicians in choosing the right first amikacin dose for ICU patients in septic shock. A total of 138 patients with 407 observations were prospectively recruited. A population pharmacokinetic model was built using a non-parametric, non-linear mixed-effects approach. The total body weight (TBW) influenced the central compartment volume, and the glomerular filtration rate (according to the CKD–EPI formula) influenced its clearance. A dosing nomogram was produced using Monte Carlo simulations of the amikacin amount needed to achieve a C1h ≥ 8 × MIC. The dosing nomogram recommended amikacin doses from 1700 mg to 4200 mg and from 28 mg/kg to 49 mg/kg depending on the patient’s TBW and renal clearance. However, a Cthrough ≤ 2.5 mg/L 24 h and 48 h after an optimal dose of amikacin was obtained with probabilities of 0.20 and 0.81, respectively. Doses ≥ 30 mg/kg are required to achieve a C1h ≥ 8 × MIC with MIC = 8 mg/L. Targeting a MIC = 8 mg/L should depend on local ecology. Full article
(This article belongs to the Special Issue Antibiotics Treatment Optimization in Vulnerable Populations)
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10 pages, 1664 KiB  
Article
Sorting Out the Risks and Benefits of the #797 Recommended Intrapartum Vancomycin Dosing Approach
by Andras Farkas and Arsheena Yassin
Antibiotics 2023, 12(1), 32; https://doi.org/10.3390/antibiotics12010032 - 25 Dec 2022
Viewed by 1114
Abstract
ACOG Committee Opinion #797 proposed intrapartum vancomycin dosing guidelines in the absence of thorough evaluation of its risk versus benefit profile on the maternal and neonatal systems. The previously published serum and cord-blood concentration–time data of vancomycin given to mothers in the intrapartum [...] Read more.
ACOG Committee Opinion #797 proposed intrapartum vancomycin dosing guidelines in the absence of thorough evaluation of its risk versus benefit profile on the maternal and neonatal systems. The previously published serum and cord-blood concentration–time data of vancomycin given to mothers in the intrapartum period was analyzed in this work with a two-compartment pharmacokinetic (PK) model. Monte Carlo simulation was used to establish exposure for the studied population for doses of 1000 mg to 2000 mg every 8 h for gestational ages (GA) of 33 to 40 weeks and for birth times up to 4-h intervals. Probabilities of target attainment (PTA) were calculated for efficacy and toxicity indices unique to the peripartum maternal and neonatal population. Neonatal evaluations indicate uniformly high PTAs for the evaluated dosing regimens when the efficacy target is considered. On the other hand, the PTAs for potentially nephrotoxic exposure is expected to reach undesirable levels when three or more doses were to be administered. The risk is profoundly high in GA below 36 weeks and birth times beyond 20 h after the initiation of intrapartum prophylaxis and with doses greater than 1250 mg. Maternal vancomycin exposures seem reasonable up to two intrapartum doses given at 8 h intervals when the dose is kept to 1250 mg or less. Most mothers (up to 83%) who receive three or more doses of the commonly administered regimens are subjected to nephrotoxic exposures. Thus, it appears that the current recommendations by #797 for dosing of vancomycin pose considerable risk to mother and newborn alike, especially in cases with lengthy duration of preterm labor. Capping of doses at 1250 mg may be considered to minimize the need for therapeutic drug monitoring (TDM) interventions. Alternatively, and irrespective of the baseline maternal renal function, TDM for all cases requiring more than two doses of 1500 mg or higher must be assured. Full article
(This article belongs to the Special Issue Antibiotics Treatment Optimization in Vulnerable Populations)
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17 pages, 3157 KiB  
Article
Longitudinal Study of Therapeutic Adherence in a Cystic Fibrosis Unit: Identifying Potential Factors Associated with Medication Possession Ratio
by Rosa Mª Girón, Adrián Peláez, Amparo Ibáñez, Elisa Martínez-Besteiro, Rosa Mar Gómez-Punter, Adrián Martínez-Vergara, Julio Ancochea and Alberto Morell
Antibiotics 2022, 11(11), 1637; https://doi.org/10.3390/antibiotics11111637 - 16 Nov 2022
Cited by 1 | Viewed by 1401
Abstract
Cystic fibrosis (CF) is a genetic and multisystemic disease that requires a high therapeutic demand for its control. The aim of this study was to assess therapeutic adherence (TA) to different treatments to study possible clinical consequences and clinical factors influencing adherence. This [...] Read more.
Cystic fibrosis (CF) is a genetic and multisystemic disease that requires a high therapeutic demand for its control. The aim of this study was to assess therapeutic adherence (TA) to different treatments to study possible clinical consequences and clinical factors influencing adherence. This is an ambispective observational study of 57 patients aged over 18 years with a diagnosis of CF. The assessment of TA was calculated using the Medication Possession Ratio (MPR) index. These data were related to exacerbations and the rate of decline in FEV1 percentage. Compliance was good for all CFTR modulators, azithromycin, aztreonam, and tobramycin in solution for inhalation. The patients with the best compliance were older; they had exacerbations and the greatest deterioration in lung function during this period. The three variables with the highest importance for the compliance of the generated Random Forest (RF) models were age, FEV1%, and use of Ivacaftor/Tezacaftor. This is one of the few studies to assess adherence to CFTR modulators and symptomatic treatment longitudinally. CF patient therapy is expensive, and the assessment of variables with the highest importance for a high MPR, helped by new Machine learning tools, can contribute to defining new efficient TA strategies with higher benefits. Full article
(This article belongs to the Special Issue Antibiotics Treatment Optimization in Vulnerable Populations)
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11 pages, 1200 KiB  
Article
Steering Away from Current Amoxicillin Dose Reductions in Hospitalized Patients with Impaired Kidney Function to Avoid Subtherapeutic Drug Exposure
by Cornelis Smit, Swapnoleena Sen, Elodie von Dach, Abderrahim Karmime, Pierre Lescuyer, David Tonoli, Julia Bielicki, Angela Huttner and Marc Pfister
Antibiotics 2022, 11(9), 1190; https://doi.org/10.3390/antibiotics11091190 - 02 Sep 2022
Cited by 1 | Viewed by 2382
Abstract
Current dose reductions recommended for amoxicillin in patients with impaired kidney function could lead to suboptimal treatments. In a prospective, observational study in hospitalized adults with varying kidney function treated with an IV or oral dose of amoxicillin, amoxicillin concentrations were measured in [...] Read more.
Current dose reductions recommended for amoxicillin in patients with impaired kidney function could lead to suboptimal treatments. In a prospective, observational study in hospitalized adults with varying kidney function treated with an IV or oral dose of amoxicillin, amoxicillin concentrations were measured in 1–2 samples on the second day of treatment. Pharmacometric modelling and simulations were performed to evaluate the probability of target attainment (PTA) for 40% of the time above MIC following standard (1000 mg q6h), reduced or increased IV dosing strategies. A total of 210 amoxicillin samples was collected from 155 patients with kidney function based on a CKD-EPI of between 12 and 165 mL/min/1.73 m2. Amoxicillin clearance could be well predicted with body weight and CKD-EPI. Recommended dose adjustments resulted in a clinically relevant reduction in the PTA for the nonspecies-related PK/PD breakpoint MIC of 8 mg/L (92%, 62% and 38% with a CKD-EPI of 10, 20 and 30 mL/min/1.73 m2, respectively, versus 100% for the standard dose). For MICs ≤ 2 mg/L, PTA > 90% was reached in these patients following both reduced and standard dose regimens. Our study showed that for amoxicillin, recommended dose reductions with impaired kidney function could lead to subtherapeutic amoxicillin concentrations in hospitalized patients, especially when targeting less susceptible pathogens. Full article
(This article belongs to the Special Issue Antibiotics Treatment Optimization in Vulnerable Populations)
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Review

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14 pages, 914 KiB  
Review
Hypoalbuminemia and Pharmacokinetics: When the Misunderstanding of a Fundamental Concept Leads to Repeated Errors over Decades
by Peggy Gandia, Sarah Decheiver, Manon Picard, Romain Guilhaumou, Sarah Baklouti and Didier Concordet
Antibiotics 2023, 12(3), 515; https://doi.org/10.3390/antibiotics12030515 - 04 Mar 2023
Cited by 3 | Viewed by 4441
Abstract
Surprisingly, misinterpretation of the influence of hypoalbuminemia on pharmacokinetics and the clinical effects of drugs seems to be a current problem, even though hypoalbuminemia has no impact on the pharmacologically active exposure. Exceptions to this fact are highly protein-bound anaesthetics with high elimination [...] Read more.
Surprisingly, misinterpretation of the influence of hypoalbuminemia on pharmacokinetics and the clinical effects of drugs seems to be a current problem, even though hypoalbuminemia has no impact on the pharmacologically active exposure. Exceptions to this fact are highly protein-bound anaesthetics with high elimination capacity (i.e., <5 drugs on the market). To assess the frequency of misinterpretation of the influence of hypoalbuminemia on pharmacokinetics and the clinical effects of drugs between 1975 and 2021, a PubMed literature review was conducted. Each paragraph on albumin binding was classified as correct, ambiguous or incorrect, creating two acceptable categories: (1) content without any errors, and (2) content containing some incorrect and/or ambiguous statements. The analyses of these articles showed that fewer than 11% of articles contained no interpretation errors. In order to contain this misinterpretation, several measures are proposed: (1) Make the message accessible to a wide audience by offering a simplified and didactic video representation of the lack of impact of albumin binding to drugs. (2) Precise terminology (unbound/free form/concentration) should be used for highly bound drugs. (3) Unbound/free forms should be systematically quantified for highly plasma protein bound drugs for clinical trials as well as for therapeutic drug monitoring. Full article
(This article belongs to the Special Issue Antibiotics Treatment Optimization in Vulnerable Populations)
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21 pages, 1668 KiB  
Review
β-Lactam Dosing in Critical Patients: A Narrative Review of Optimal Efficacy and the Prevention of Resistance and Toxicity
by João Gonçalves Pereira, Joana Fernandes, Ana Rita Duarte and Susana Mendes Fernandes
Antibiotics 2022, 11(12), 1839; https://doi.org/10.3390/antibiotics11121839 - 18 Dec 2022
Cited by 6 | Viewed by 3818
Abstract
Antimicrobial prescription in critically ill patients represents a complex challenge due to the difficult balance between infection treatment and toxicity prevention. Underexposure to antibiotics and therapeutic failure or, conversely, drug overexposure and toxicity may both contribute to a worse prognosis. Moreover, changes in [...] Read more.
Antimicrobial prescription in critically ill patients represents a complex challenge due to the difficult balance between infection treatment and toxicity prevention. Underexposure to antibiotics and therapeutic failure or, conversely, drug overexposure and toxicity may both contribute to a worse prognosis. Moreover, changes in organ perfusion and dysfunction often lead to unpredictable pharmacokinetics. In critically ill patients, interindividual and intraindividual real-time β-lactam antibiotic dose adjustments according to the patient’s condition are critical. The continuous infusion of β-lactams and the therapeutic monitoring of their concentration have both been proposed to improve their efficacy, but strong data to support their use are still lacking. The knowledge of the pharmacokinetic/pharmacodynamic targets is poor and is mostly based on observational data. In patients with renal or hepatic failure, selecting the right dose is even more tricky due to changes in drug clearance, distribution, and the use of extracorporeal circuits. Intermittent usage may further increase the dosing conundrum. Recent data have emerged linking overexposure to β-lactams to central nervous system toxicity, mitochondrial recovery delay, and microbiome changes. In addition, it is well recognized that β-lactam exposure facilitates resistance selection and that correct dosing can help to overcome it. In this review, we discuss recent data regarding real-time β-lactam antibiotic dose adjustment, options in special populations, and the impacts on mitochondria and the microbiome. Full article
(This article belongs to the Special Issue Antibiotics Treatment Optimization in Vulnerable Populations)
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