The opportunistic pathogen Acinetobacter baumannii has emerged as a formidable challenge in the realm of healthcare-associated infections, primarily due to its remarkable capacity to develop resistance against a diverse array of antibiotics. In response to this pressing concern, this comprehensive study aims to design and validate a rapid and highly precise diagnostic tool, known as the Loop-Mediated Isothermal Amplification (LAMP) assay, for the detection of A. baumannii and its associated aminoglycoside resistance genes. Through meticulous comparative genomic analyses, the researchers have identified a unique 299-base pair segment within the glutathione S-transferase gene that exhibits exceptional specificity to A. baumannii. This discovery has enabled the development of a LAMP-based protocol that demonstrates complete specificity, with no cross-reactivity observed against other bacterial species. Furthermore, the assay has demonstrated a remarkable sensitivity threshold, capable of detecting as few as 10 colony-forming units per reaction for both the glutathione S-transferase target and the armA aminoglycoside resistance gene. Expanding the scope of the investigation, the researchers have also explored the distribution of five key aminoglycoside resistance genes (aadB, aacC1, aadA1, aphA6, and armA) across a diverse collection of bacterial isolates. Interestingly, the study has revealed that the aphA6 gene is the most widespread, being present in all the A. baumannii samples analyzed. The successful implementation of this LAMP-based diagnostic approach not only provides a rapid and precise means of identifying A. baumannii but also offers the ability to evaluate the presence of critical aminoglycoside resistance determinants. The adaptability of this methodology to other pathogens further underscores its potential as an invaluable tool in clinical diagnostics and epidemiological investigations. By enhancing the speed and accuracy of pathogen detection, this research holds promise for improving patient management and strengthening infection control strategies, ultimately contributing to better healthcare outcomes.

The recommended gentamicin peak plasma concentration range is 32-40 mg/L; we aimed to determine how frequently it was reached, and for which gentamicin doses.

We retrospectively reviewed 601 gentamicin peak plasma concentrations in 501 patients aged ≥15 in our institution between 2013 and 2023.

Median gentamicin dose was 5.9 mg/kg [IQR 4.1-7.9]. Median peak plasma concentration was 16.5 mg/L [IQR 10.8-22.8] and was strongly correlated with dose (p < 0.0001). Only 5.7 % of values were ≥32 mg/L, including 22.8 % for dose ≥10 mg/kg.

This suggests that existing recommendations regarding either dose or target concentration for gentamicin should be modified.

Amikacin (AMK) is used to treat gram-negative bacterial infections in intensive care unit (ICU) patients. However, its narrow therapeutic range and high interindividual variability can lead to toxicity and ineffectiveness. This study aimed to establish a roadmap for AMK therapeutic drug monitoring in critically ill patients with cancer to provide a Bayesian estimator of bedside applicability.

An observational retrospective study was conducted on oncological patients admitted to the ICU, treated with AMK as a 30-min intravenous infusion at 5.8-39.2 mg/kg. The plasma concentrations were analyzed using a nonlinear mixed-effects modeling approach. Covariate analyses were performed using anthropometric and laboratory data, concomitant drugs, and comorbidities. The model predictive performance was compared with previous AMK dosing approaches using the Bland-Altman method.

The concentration-time profiles were best described using a one-compartment model with linear elimination. The estimated glomerular filtration rate was a significant covariate of clearance (CL), explaining 16% of the interpatient variability. Body weight was positively correlated with the volume of distribution, accounting for 4% of the variability. Our model reduced the bias in the estimates of individual CL values compared with that of other available methods and was further implemented in DoseMeRx for real-time application at the bedside.

This study provides an effective example of a Bayesian estimation method for individualizing AMK doses in critically ill patients with cancer. Collecting more comprehensive patient information, including additional biomarkers for renal function, could further refine the model and improve its predictive performance in this special population.

Amikacin is frequently used for the treatment of neonatal sepsis. The Dutch Pediatric Formulary recommends a complex pharmacokinetic (PK) model-derived dosing regimen, which consists of dosing categories based on postnatal age and weight that results in adequate PK/pharmacodynamic (PK/PD) target attainment. However, a simplified dosing regimen may be easier to apply in clinical practice. We evaluated PK/PD target attainment of amikacin in neonates using this simplified or complex dosing regimen. This retrospective cohort study included neonates with routinely measured amikacin concentrations at the neonatal intensive care units of the Amsterdam University Medical Center (simplified dosing regimen) or University Hospitals Leuven (complex dosing regimen). Peak (Cmax) and trough (Cmin) concentrations and the area under the concentration-time curve (AUC) for the first dosing interval were calculated by Bayesian estimation for both populations. Targets of Cmax (≥15, ≥25, and ≥35 mg/L), Cmin (≤3 and ≤5 mg/L), and AUC/minimal inhibitory concentration (MIC: 2, 4, and 8 mg/L for Enterobacterales species) for bacteriostasis and 1-log reduction were evaluated. A target attainment of ≥90% was considered adequate. In total, 366 neonates (768 concentrations) and 579 neonates (1,195 concentrations) received the simplified and complex dosing regimen, respectively. Both regimens achieved target attainment of 100% for Cmax ≥ 15 mg/L, Cmin ≤ 5 mg/L, AUC/MIC for bacteriostasis, and AUC/MIC for 1-log reduction up to a MIC of 2 mg/L. Target attainment was achieved for less stringent targets (Cmax ≥ 15 mg/L, Cmin ≤ 5 mg/L, and AUC/MIC for bacteriostasis) with the simplified and complex amikacin dosing regimen. Clinicians can choose one of both dosing regimens, depending on their local circumstances, and the availability of integrated (electronic) prescription tools.

To quantify serum amikacin concentrations in dogs undergoing wound management with topical amikacin (45 mg/mL) 3% carboxymethylcellulose hydrogel.

Prospective clinical study.

Eleven client-owned dogs.

Dogs with naturally occurring wounds, undergoing treatment with topical amikacin gel, were enrolled. A whole blood sample was collected prior to initial application of the gel. Up to a maximum dose of 30 mg/kg of gel, was applied directly on the wound and the wound was bandaged. Serial blood sampling was performed at approximately 2, 4, 8, 12, 18, 24, 32, 40, 48, 56, 64, and 72 h after application of amikacin gel. The sampling schedule was reset following each bandage change and new application of the gel. Up to 20 samples per dog were collected. The Siemens Syva EMIT Amikacin Assay was used to quantify the concentration of amikacin in each blood serum sample. The lower limit of quantification (LLOQ) of the test was 2.5 μg/mL.

Amikacin gel was applied a total of 31 times (dose range, 0.1-24.9 mg/kg). A total of 153 samples were analyzed. Five samples in three different dogs were above the LLOQ at approximately 2 h after gel application (range 2.75-3.82 μg/mL). All other samples were below the LLOQ.

Routine use of amikacin gel for open wound management did not result in serum amikacin levels above 5 μg/mL.

Topical amikacin gel may be a safe treatment option for wounds in dogs with resistant infections or biofilms.

Acute kidney injury (AKI) requiring renal replacement therapy (RRT) is common in intensive care units (ICUs), yet optimal amikacin dosing in this context remains poorly understood.

We conducted a prospective observational study across 18 French hospitals from April 2020 to January 2022. Adult ICU patients (aged > 18 years) receiving their first amikacin dose while on RRT were included. Data on demographics, RRT modalities, amikacin dosing, and therapeutic drug monitoring were collected. Using a pharmacokinetic modeling approach, we evaluated various amikacin regimens and simulated target attainment probabilities across different minimum inhibitory concentrations (MICs).

A total of 111 patients were included, with approximately two-thirds receiving continuous RRT. The median amikacin dose was 27 (25-30) mg/kg. Amikacin peak (Cmax) and trough concentrations were monitored in 53 (47.8%) and 76 (68.5%) patients, respectively. Continuous RRT and a history of chronic kidney disease reduced dialytic clearance. For a MIC ≤ 4 mg/L, a 15 mg/kg amikacin dose achieved Cmax/MIC and AUC/MIC targets in ≥ 90% of patients on intermittent dialysis, while 20 mg/kg was required for those on continuous dialysis. For a MIC = 8 mg/L, a 30 mg/kg dose was necessary to achieve Cmax/MIC ≥ 8.

Our findings highlight suboptimal adherence to amikacin monitoring guidelines in ICU patients on RRT. Using pharmacokinetic modeling, we identified amikacin dosing recommendations ranging from 15 to 35 mg/kg to optimize efficacy and minimize risks, depending on MIC and dialysis modality.

Investigate determinants of elevated gentamicin trough levels in neonates.

This single-center retrospective analysis used a multivariate linear regression model to explore the relationship between gentamicin trough concentrations and factors such as creatinine levels, dosage, day of life, sex, CRP levels, and dosing interval in neonates.

In 215 neonates, including 68 (31.6%) premature neonates with a postmenstrual age of ≤35 weeks, shorter dosing intervals, higher creatinine levels, and increased dosage were linked to higher gentamicin trough levels. Elevated CRP levels corresponded with lower trough levels.

This study highlights the critical role of dosing frequency, kidney function, and inflammatory status in influencing gentamicin trough levels in neonates. However, all gentamicin trough levels were within the 2 µg/ml threshold.

Addition of morphine to the perfusate while performing intravenous regional limb perfusion (IVRLP) may be helpful in treating painful infectious orthopaedic conditions of the distal limb.

The main objective of this study was to determine synovial morphine concentrations following IVRLP with morphine alone or in combination with amikacin.

Randomised cross-over in vivo experiment.

Six horses underwent IVRLP with 0.1 mg/kg morphine sulphate diluted to 60 mL using 0.9% NaCl (M group) or combined with 2 g amikacin and 0.9% NaCl (MA group) with a 2-week washout period between treatments. Synovial fluid was collected from the radiocarpal joint (RCJ) at 10, 20, 30, 120, 240, 480, 720 and 1440 min after IVRLP. The tourniquet was removed after the 30-min sample was collected. Synovial concentrations of morphine and major metabolites were measured using liquid chromatography-tandem mass spectrometry. Amikacin concentrations were quantified by a fluorescence polarisation immunoassay.

Measurable concentrations of morphine were apparent in the RCJ of all horses. Median CMAX of morphine in the M group was 4753.1 (2115.7-14 934.5) ng/mL and 4477 (3434.3-7363) ng/mL in the MA group (p = 0.5). Median CMAX of synovial amikacin was 322.6 (157.5-1371.6 μg/mL).

Limitations include small sample size. Investigators were not blinded to the treatments and a third treatment group where amikacin alone was administered via IVRLP to the study population was not included.

IVRLP using morphine is a feasible technique and synovial morphine concentrations were measurable following IVRLP and were not affected when used concurrently with amikacin. Administration of morphine via IVRLP may be beneficial as an analgesic technique for orthopaedic conditions of the distal limb while limiting potential serious systemic side-effects.

Newborn infants (particularly those born preterm) are frequently exposed to empiric antibiotics at birth, and antibiotics are among the most commonly prescribed medications in neonatal intensive care units. Challenges in optimizing neonatal antibiotic dosing include: technical and ethical barriers to neonatal pharmacoanalytic study design and sampling, difficulty in extrapolating adult and pediatric data due to unique neonatal physiology, and a lack of validated pharmacodynamic targets specific to neonatal populations. In this review, we summarize basic concepts in pharmacokinetics (PK) and pharmacodynamics (PD), describe pharmacometric strategies utilized in contemporary PK/PD analyses, and review the evolution of PK/PD data guiding neonatal dosing among 3 commonly used antibiotics.

Tobramycin dosing in patients with cystic fibrosis (CF) is challenged by its high pharmacokinetic (PK) variability and narrow therapeutic window. Doses are typically individualized using two-sample log-linear regression (LLR) to quantify the area under the concentration-time curve (AUC). Bayesian model-informed precision dosing (MIPD) may allow dose individualization with fewer samples; however, the relative performance of these methods is unknown. This single-center retrospective analysis included adult patients with CF receiving tobramycin from 2015 to 2022. Tobramycin concentrations were predicted using LLR or Bayesian estimation with two population PK models (Hennig and Alghanem). Then, both methods were used to estimate the AUC for simulated patients. For Bayesian estimation, AUC estimation with flattened priors and limited sampling strategies were also assessed. Predictions were evaluated using normalized root mean square error (nRMSE), mean percent error (MPE), and accuracy. The data set included 70 treatment courses, with 32 not evaluable by LLR due to detection limits or timing issues. Bayesian estimation demonstrated worse accuracy (47.1%-50.7% vs 75.7%), higher MPE (24.2%-32.4% vs -2.4%), and higher nRMSE (35.0%-39.4% vs 24.8%) than LLR for peak concentrations but performed better on troughs (accuracy: 92.0%-92.9% vs 84.6%). Bayesian estimation with flattened priors and a single sample at 4 h was comparable to LLR performance, with better accuracy (42.9%-68.0% vs 41.1% LLR), comparable MPE (-2.3% to -3.7% vs -0.5%) and nRMSE (11.3%-21.6% vs 17.3%). Bayesian estimation with one concentration and flattened priors can match LLR prediction accuracy. However, popPK models must be improved to better estimate peak samples.

The Gram-positive cocci Staphylococcus aureus, Streptococcus spp., and Enterococcus spp. are the most frequent causative organisms of bloodstream infections and infective endocarditis. "Complicated bacteremia" is a term used in S. aureus bloodstream infections and originally implied the presence of metastatic infectious foci (i.e. complications of S. aureus bacteremia). These complications demand longer antimicrobial treatment durations and, frequently, interventional source control. Several risk factors for the incidence of bacteremia complications have been identified and are often used for the definition of complicated bacteremia. Here, we discuss management and diagnostic approaches and treatment options for patients with complicated bacteremia, with particular focus on infective endocarditis. We also summarize the available evidence regarding imaging modalities and the choice of antimicrobial mono- or combination therapy according to resistance patterns for these pathogens as well as treatment durations and optimized application routes. Finally, we synopsize current and future areas of research in complicated bacteremia and infective endocarditis.

Introduction: Aminoglycosides possess activity against aerobic gram-negative organisms and are often used in combination with beta-lactam antibiotics. Previous studies evaluating combination therapy in gram-negative bacteremia have not shown clear benefits, however antimicrobial resistance was not prevalent in these studies. Our objective is to elucidate potential benefits of adding a single dose of an aminoglycoside to a beta-lactam in patients with gram-negative bacteremia. Methods: This study was a single-center, retrospective, cohort study including patients 18 years old or older and treated for at least 24 hours for a confirmed gram-negative bacteremia. Patients were divided into two groups: receipt of beta-lactam monotherapy (n = 164) and receipt of a beta-lactam in addition to a single dose of an aminoglycoside (n = 79) within 24 hours of bacteremia onset. The primary endpoint was infection-related 30-day mortality per provider documentation. Key secondary outcomes include incidence of acute kidney injury (AKI) and time to improvement of AKI. Data were analyzed using Chi-square or Fisher's exact tests, student's T test, and descriptive statistics as appropriate. Results: The primary outcome occurred in 13/164 vs 2/79 patients in the monotherapy and combination groups (P = 0.10). Incidence of AKI (14% vs. 12%) and time to recovery from AKI (90 hours; IQR [50 - 133] vs 78 hours; IQR [42 - 128]) were comparable between groups (P = 1.00 and P = 0.73, respectively). Conclusions: The addition of a single-dose aminoglycoside was not significantly associated with reduced mortality or increased time to recovery from AKI in our patient population. Larger studies, particularly in more severely ill patient populations, are needed.

Antimicrobial resistance (AMR) poses a critical global health threat, necessitating the optimal use of existing antibiotics. Pharmacokinetic/pharmacodynamic (PK/PD) principles provide a scientific framework for optimizing antimicrobial therapy, particularly to respond to evolving resistance patterns. This review examines PK/PD strategies for antimicrobial dosing optimization, focusing on three key aspects. First, we discuss the importance of drug concentration management for enhancing efficacy while preventing toxicity, considering various patient populations, including pediatric and elderly patients with their unique physiological characteristics. Second, we analyze different PK modeling approaches: the classic top-down approach exemplified by population PK analysis, the bottom-up approach represented by physiologically based PK modeling, and hybrid models combining both approaches for enhanced predictive performance. Third, we explore clinical applications, including nomogram-based dosing strategies, Bayesian estimation, and emerging artificial intelligence applications, for real-time dose optimization. Critical challenges in implementing PK/PD simulation are addressed, particularly the selection of appropriate PK models, the optimization of PK/PD indices, and considerations concerning antimicrobial concentrations at infection sites. Understanding these principles and challenges is crucial for optimizing antimicrobial therapy and combating AMR through improved dosing strategies.

Background: Effective gentamicin dosing is crucial to the survival of neonates with suspected sepsis but requires a careful balance between attaining both effective peak and safe trough concentrations. We aimed to systematically compare existing gentamicin dosing guidelines for neonates in Australia to determine the extent to which they reach therapeutic targets. Methods: Simulations of a single gentamicin dose to a virtual representative neonatal population according to each Australian guideline were performed using population pharmacokinetic modelling. We determined the proportion of neonates who would achieve peak gentamicin concentrations of ≥5 or ≥10 mg/L and trough concentrations of ≤1 or ≤2 mg/L. We calculated the probability of target attainment (PTA) according to gestation at birth (22 to 40 weeks) and postnatal age (1-7, 8-14, 15-21, 22-28 days). Results: Five unique dosing guidelines were identified. Guidelines varied considerably with respect to dose (4.5 to 7 mg/kg), dosing interval (24 to 48 h), and characteristics used to individualise dosing regimens (e.g., gestation at birth and postnatal age). Guidelines were satisfactory in routinely achieving effective peak concentrations ≥ 5 mg/L, but PTAs for effective peak concentrations ≥ 10 mg/L varied considerably from 5% to 100% based on dose, gestation, and postnatal age. PTAs for trough concentrations ≤ 1 mg/L ranged from 0% to 100%, being lowest among extremely preterm infants. Conclusions: Current Australian gentamicin guidelines demonstrate significant variability in their ability to achieve defined therapeutic targets, necessitating efforts to improve standardisation of dosing recommendations. Further research to define optimal pharmacodynamic targets in neonates with respect to clinical outcomes are also urgently warranted.

Surgical site infection (SSI) continues to be a common complication of surgery. The real benefit of using topical antibiotics for the prevention of SSI in abdominal hernia repair surgery is still unknown. This study aimed to evaluate the usefulness of topical gentamicin in SSI prophylaxis in incisional hernia repair with mesh. A randomized controlled trial was conducted in patients undergoing open incisional hernia repair. Patients were randomly assigned to one of two groups: in the gentamicin group, each layer of the abdominal wall was irrigated with gentamicin solution before wound closure, and in the saline solution group (placebo), each layer of the abdominal wall was irrigated with normal saline solution. The incidence of SSI and other surgical site complications was compared between both groups, and the presence of adverse effects with the use of topical gentamicin. Data from 146 patients were included for analysis: 74 in the gentamicin group and 72 in the saline solution group. SSI was observed in six patients (8.1%) in the gentamicin group and eight patients (11.1%) in the saline solution group, with no significant differences (p = 0.538) between both groups. No statistically significant differences were observed in the presentation of seroma, hematoma, and surgical wound dehiscence between both groups. No adverse effects were reported from topical application of gentamicin. In this clinical trial, the use of topical gentamicin in incisional hernia repair with mesh did not significantly reduce the incidence of SSI. EU Clinical Trials Register: EudraCT 2018-001860-45 (04/07/2019).

Intraperitoneal (IP) aminoglycosides (AGs) continue to be the cornerstone of empiric management of peritonitis. AG dosing during automated peritoneal dialysis (APD), however, has not been well studied in patients with peritonitis. We sought to identify differences in AG exposure in the peritoneum and plasma for two different dosing regimens with little supporting evidence in patients on APD with peritonitis.

A retrospective design that utilised the peritoneal and plasma concentration-time data from a prior study of 18 continuous ambulatory peritoneal dialysis (CAPD) patients with peritonitis to generate an in silico peritoneal and plasma PK model. This model was then used to compare via simulation using Phoenix© WinNonlin Software with IP AG dosing for a loading-dose regimen (1.5 mg/kg first dose) versus a fixed-dose regimen (0.6 mg/kg/d) in patients on APD with peritonitis.

Outcome measures were (1) percentage of time where peritoneal peak concentrations/minimal inhibitory concentration (MIC) ratio >10, (2) AUC/MIC > 74 and (3) plasma Cmin concentrations. Both regimens resulted in > 90% optimal peak/MIC ratio and AUC/MIC ratios on days 1 and 5 of the dose protocol. The loading-dose regimen resulted in IP exposures that were 2.5 times greater in the peritoneal compartment on day 1. By day 5, both protocols resulted in similar accumulation of AG plasma Cmin concentrations of 2.5-3.4 mg/L versus 2.4-3.3 mg/L, respectively, for the loading-dose regimen versus fixed-dose regimen.

The current international guidelines for the treatment of peritoneal dialysis-associated peritonitis can continue to recommend the fixed-dose regimen for those on APD with the addition of plasma Cmin monitoring after 3 days to assess for drug accumulation.

Biofilms reduce antibiotic efficacy and lead to complications and mortality in human and equine patients with orthopedic infections. Equine bone marrow-derived mesenchymal stromal cells (MSC) kill planktonic bacteria and prevent biofilm formation, but their ability to disrupt established orthopedic biofilms is unknown. Our objective was to evaluate the ability of MSC to reduce established S. aureus or E. coli biofilms in vitro. We hypothesized that MSC would reduce biofilm matrix and colony-forming units (CFU) compared to no treatment and that MSC combined with the antibiotic, amikacin sulfate, would reduce these components more than MSC or amikacin alone. MSC were isolated from 5 adult Thoroughbred horses in antibiotic-free medium. 24-hour S. aureus or E. coli biofilms were co-cultured in triplicate for 24 or 48 hours in a transwell plate system: untreated (negative) control, 30 μg/mL amikacin, 1 x 106 passage 3 MSC, and MSC with 30 μg/mL amikacin. Treated biofilms were photographed and biofilm area quantified digitally. Biomass was quantified via crystal violet staining, and CFU quantified following enzymatic digestion. Data were analyzed using mixed model ANOVA with Tukey post-hoc comparisons (p < 0.05). MSC significantly reduced S. aureus biofilms at both timepoints and E. coli biofilm area at 48 hours compared to untreated controls. MSC with amikacin significantly reduced S. aureus biofilms versus amikacin and E. coli biofilms versus MSC at 48 hours. MSC significantly reduced S. aureus biomass at both timepoints and reduced S. aureus CFU at 48 hours versus untreated controls. MSC with amikacin significantly reduced S. aureus biomass versus amikacin at 24 hours and S. aureus and E. coli CFU versus MSC at both timepoints. MSC primarily disrupted the biofilm matrix but performed differently on S. aureus versus E. coli. Evaluation of biofilm-MSC interactions, MSC dose, and treatment time are warranted prior to testing in vivo.

The combination antimicrobial therapy consisting of amikacin, polymyxin-B, and sulbactam demonstrated in vitro synergy against multi-drug resistant Acinetobacter baumannii.

The objectives were to predict drug disposition and extrapolate their efficacy in the blood, lung, heart, muscle and skin tissues using a physiologically-based pharmacokinetic (PBPK) modeling approach and to evaluate achievement of target pharmacodynamic (PD) indices against A. baumannii.

A PBPK model was initially developed for amikacin, polymyxin-B, and sulbactam in adult subjects, and then scaled to pediatrics, accounting for both renal and non-renal clearances. The simulated plasma and tissue drug exposures were compared to the observed data from humans and rats. Efficacy was inferred using joint probability of target attainment of target PD indices.

The simulated plasma drug exposures in adults and pediatrics were within the 0.5 to 2 boundary of the mean fold error for the ratio between simulated and observed means. Simulated drug exposures in blood, skin, lung, and heart were consistent with reported penetration ratio between tissue and plasma drug exposure. In a virtual pediatric population from 2 to <18 years of age using pediatric dosing regimens, the interpretive breakpoints were achieved in 85-90% of the population.

The utility of PBPK to predict and simulate the amount of antibacterial drug exposure in tissue is a practical approach to overcome the difficulty of obtaining tissue drug concentrations in pediatric population. As combination therapy, amikacin/polymyxin-B/sulbactam drug concentrations in the tissues exhibited sufficient penetration to combat extremely drug resistant A. baumannii clinical isolates.

This phase I clinical study aimed to assess the safety, tolerability, and population pharmacokinetic-pharmacodynamics (PK-PD) target attainment analysis of etimicin sulfate in healthy participants, and to provide scientific reference for further development of clinical breakpoints.

A total of 24 healthy Chinese subjects were enrolled in this study and received an etimicin sulfate infusion. A population PK model was constructed for the estimation of the PK profiles of etimicin sulfate. The area under the concentration-time curve divided by the minimum inhibitory concentration (AUC0-24h/MIC) and the peak concentration divided by the MIC (Cmax/MIC) were selected as the PK/PD indices. The probability of target attainment (PTA) was calculated for each designed dosing regimen using Monte Carlo simulations. The minimum MIC value with a PTA ≥ 90% for each regimen was considered as the PK/PD cutoff values.

Etimicin sulfate demonstrated safety, tolerability, and predictable PK characteristics. No deaths or serious adverse events were reported. Seven treatment-emergent adverse events (TEAEs) were reported by five participants; all TEAEs were minor and were rapidly relieved. A two-compartment model was developed and validated for describing the PK features of etimicin sulfate among Chinese healthy participants. The diagnostic goodness-of-fit plots and visual predictive check plots showed that this developed model could describe these data well.

The PTA results showed that etimicin sulfate provided clinical improvement against strains with an MIC of 0.5-1 mg/L and below, and antibacterial effect against strains with an MIC of 0.25 mg/L and below. However, etimicin sulfate had limited clinical efficacy for clinical isolates with MIC values > 1 mg/L.

Pharmacokinetics of amikacin administered IV to neonatal foals are described, but little data are available regarding the plasma concentrations contributed by concurrent intra-articular (IA) administration.

Compare the pharmacokinetics of amikacin when the total dose is administered IV compared to being divided between IV and IA routes of administration in neonatal foals and predict the plasma concentrations from various combined IV and IA dosing regimens.

Eight healthy neonatal foals.

Foals received 3 amikacin treatment protocols: (1) IV-only (25 mg/kg q24h IV), (2) concurrent IV and IA (16.7 mg/kg q24h IV and 8.3 mg/kg q24h into 1 tarsocrural joint), and (3) IA-only (8.3 mg/kg q24h into 1 tarsocrural joint). Protocols were administered for 3 days beginning at 7, 14, and 21 days of age. Plasma concentrations ≥53 μg/mL at 30 minutes were considered therapeutic for isolates with intermediate susceptibility.

Foal age was a significant variable. The IV-only protocol met or exceeded the 30-minute plasma concentrations considered therapeutic (mean μg/mL [95% confidence interval, CI]) in 7- to 9-day-old (54.0 [52.2-56.9]), 14- to 16-day-old (58.1 [55.2-61.0]), and 21- to 23-day-old (66.6 [63.7-69.6]) foals. Concurrent IV and IA protocol did not reach the 30-minute concentration considered therapeutic in 7- to 9-day-old foals (46.5 [43.6-49.4]) but did in 14- to 16-day-old (62.9 [60.0-65.8]) and 21-to 23-day-old (62.6 [59.7-65.6]) foals.

Concurrent IV and IA administration of amikacin produces 30-minute plasma concentrations considered therapeutic in foals 14 to 23 days old, but concentrations observed in younger foals might be below those considered therapeutic for isolates with intermediate susceptibility to amikacin.

We aimed to determine whether implementing antimicrobial stewardship based on multiplex bacterial PCR examination of respiratory fluid can enhance outcomes of critically ill patients with hospital-acquired pneumonia (HAP).

We conducted a quality improvement study in two hospitals in France. Adult patients requiring invasive mechanical ventilation with a diagnosis of HAP were included. In the pre-intervention period (August 2019 to April 2020), antimicrobial therapy followed European guidelines. In the «intervention» phase (June 2020 to October 2021), treatment followed a multiplex PCR-guided protocol. The primary endpoint was a composite endpoint made of mortality on day 28, clinical cure between days 7 and 10, and duration of invasive mechanical ventilation on day 28. The primary outcome was analyzed with a DOOR strategy.

A total of 443 patients were included in 3 ICUs from 2 hospitals (220 pre-intervention; 223 intervention). No difference in the ranking of the primary composite outcome was found (DOOR: 50.3%; 95%CI, 49.9%-50.8%). The number of invasive mechanical ventilation-free days at day 28 was 10.0 [0.0; 19.0] in the baseline period and 9.0 [0.0; 20.0] days during the intervention period (p = 0.95). The time-to-efficient antimicrobial treatment was 0.43 ± 1.29 days before versus 0.55 ± 1.13 days after the intervention (p = 0.56).

Implementation of Rapid Multiplex PCR to guide empirical antimicrobial therapy for critically ill patients with HAP was not associated with better outcomes. However, adherence to stewardship was low, and the study may have had limited power to detect a clinically important difference.

Antimicrobial resistance increasingly complicates neonatal sepsis in a global context. Fosfomycin and amikacin are two agents being tested in an ongoing multicenter neonatal sepsis trial. Although neonatal pharmacokinetics (PKs) have been described for these drugs, the physiological variability within neonatal populations makes population PKs in this group uncertain. Physiologically-based pharmacokinetic (PBPK) models were developed in Simcyp for fosfomycin and amikacin sequentially for adult, pediatric, and neonatal populations, with visual and quantitative validation compared to observed data at each stage. Simulations were performed using the final validated neonatal models to determine drug exposures for each drug across a demographic range, with probability of target attainment (PTA) assessments. Successfully validated neonatal PBPK models were developed for both fosfomycin and amikacin. PTA analysis demonstrated high probability of target attainment for amikacin 15 mg/kg i.v. q24h and fosfomycin 100 mg/kg (in neonates aged 0-7 days) or 150 mg/kg (in neonates aged 7-28 days) i.v. q12h for Enterobacterales with fosfomycin and amikacin minimum inhibitory concentrations at the adult breakpoints. Repeat analysis in premature populations demonstrated the same result. PTA analysis for a proposed combination fosfomycin-amikacin target was also performed. The simulated regimens, tested in a neonatal sepsis trial, are likely to be adequate for neonates across different postnatal ages and gestational age. This work demonstrates a template for determining target attainment for antimicrobials (alone or in combination) in special populations without sufficient available PK data to otherwise assess with traditional pharmacometric methods.

Mycobacterium abscessus pulmonary disease is increasing in prevalence globally, particularly for individuals with cystic fibrosis. These infections are challenging to treat due to a high rate of resistance. Amikacin is critical to treatment, but the development of toxicity, amikacin resistance, and treatment failure are significant challenges. Amikacin has been characterized previously as peak-dependent and extended-interval dosing is commonly used. In our hollow fiber infection model of M. abscessus, amikacin exhibited time-dependent rather than the expected peak-dependent pharmacodynamics. Humanized amikacin exposures with more frequent, short-interval dosing (continuous infusion or every 12 hours) yielded improved microbiological response compared to extended-interval dosing (every 24 hours or 1-3 times per week). Short-interval dosing inhibited growth with a mean (SD) maximum Δlog10 colony forming units of -4.06 (0.52), significantly more than extended-interval dosing (P = 0.0013) every 24 hours, -2.40 (0.58), or 1-3 times per week, -2.39 (0.38). Growth recovery, an indicator of resistance emergence, occurred at 6.56 (0.70) days with short-interval dosing but was significantly earlier with extended-interval dosing (P = 0.0032) every 24 hours, 3.88 (0.85) days, and 1-3 times per week, 3.27 (1.72) days. Microbiological response correlated best with the pharmacodynamic index of %T > minimum inhibitory concentration (MIC), with an EC80 for growth inhibition of ~40%T > MIC. We used a previously published population model of amikacin to determine the probability of achieving 40%T > MIC and show that current dosing strategies are far below this target, which may partially explain why treatment failure remains so high for these infections. These data support a cautious approach to infrequent amikacin dosing for the treatment of M. abscessus.IMPORTANCEPulmonary disease caused by Mycobacterium abscessus complex (MABSC) is increasing worldwide, particularly in patients with cystic fibrosis. MABSC is challenging to treat due to high levels of antibiotic resistance. Treatment requires 2-4 antibiotics over more than 12 months and has a significant risk of toxicity but still fails to eradicate infection in over 50% of patients with cystic fibrosis. Antibiotic dosing strategies have been largely informed by common bacteria such as Pseudomonas aeruginosa. The "pharmacodynamic" effects of amikacin, a backbone of MABSC treatment, were thought to be related to maximum "peak" drug concentration, leading to daily or three times weekly dosing. However, we found that amikacin MABSC kill and growth recovery, an indicator of antibiotic resistance, are dependent on how long amikacin concentrations are above the minimum inhibitory concentration, not how high the peak concentration is. Therefore, we recommend a re-evaluation of amikacin dosing to determine if increased frequency can improve efficacy.

Apheresis is a modern medical approach in which plasma or cellular components are separated from the whole blood. Apheresis can be either diagnostic or therapeutic. Diagnostic apheresis is typically applied in hematology and cancer research. Therapeutic Apheresis (TA) includes a broad spectrum of extracorporeal treatments applied in various medical specialties, including Intensive Care Unit (ICU). Considering the complexity of the pathophysiologic characteristics of various clinical entities and in particular sepsis, apheresis methods are becoming increasingly applicable. Therapeutic Plasma Exchange (TPE) is the most common used method in ICU. It is considered as first line therapy for Thrombotic Thrombocytopenic Purpura (TTP) and Guillain Barre Syndrome, while the current data for sepsis are scarce. Over the last decades, technologic evolution has led to increasing application of new and more selective methods based on adsorptive techniques. In this review we will describe the current data of characteristics of different techniques, safety and clinical impact of apheresis methods used in ICUs.

Once daily intravenous (iv) treatment with tobramycin for Pseudomonas aeruginosa infection in patients with cystic fibrosis (pwCF) is frequently monitored by measuring tobramycin trough levels (TLs). Although the necessity of these TLs is recently questioned in pwCF without renal impairment, no study has evaluated this so far. The aim of this observational study was to evaluate the frequency of increased tobramycin TLs in pwCF treated with a once daily tobramycin dosing protocol.

Patient records of all consecutive once daily iv tobramycin courses in 35 pwCF between 07/2009 and 07/2019 were analyzed for tobramycin level, renal function, co-medication and comorbidity.

Eight elevated TLs (2.9% of 278 courses) were recorded in four patients, two with normal renal function. One of these resolved without adjustment of tobramycin dosages suggesting a test timing or laboratory error. In the other patient the elevated tobramycin level decreased after tobramycin dosage adjustment. Six of the elevated levels occurred in two patients with chronic renal failure. In 15 other patients with reduced glomerular filtration rate (GFR) (36 courses) but normal range creatinine no case of elevated tobramycin trough levels was detected. Neither cumulative tobramycin dosages nor concomitant diabetes or nutritional status were risk factors for elevated TLs.

Our data show that elevated tobramycin TLs are rare but cannot be excluded, so determination of tobramycin TLs is still recommended for safety.

Aminoglycosides are among the first-choice antibiotics for routine clinical use. However, dose-limiting factors such as ototoxicity and nephrotoxicity are considered as serious complications of aminoglycosides.

In this systematic review, the main goal was to investigate the efficacy and incidence of nephrotoxicity and ototoxicity of once-daily dosing (ODD) and multiple daily dosing (MDD) regimens of aminoglycosides through available randomized controlled trials (RCTs).

We performed a literature-based research in relevant databases, including EMBASE, MEDLINE, and SCOPUS published between 1987 and 2023 using the keywords "aminoglycosides", "pharmacokinetics", "ODD", "MDD", "once daily", "multiple daily", "dosing regimen", "nephrotoxicity", "ototoxicity", "efficacy", "safety", and "toxicity". As so told, the results of this article were limited to papers available in English. Our initial search yielded 1124 results. After a review of the titles and abstracts of the articles, 803 articles were excluded from this study because they did not address the toxicity and effectiveness of ODD versus MDD of aminoglycosides. A total number of 20 studies on gentamicin, tobramycin, netilmicin, and amikacin met the inclusion criteria for the efficacy of aminoglycosides and their role in ototoxicity and nephrotoxicity were included in this review. Studies recruited different age classes, and the age of relevant cohorts varied from only a few days to more than 70 years.

The most common clinical condition in the included studies was cystic fibrosis.

In most studies, there were no significant differences between the two regimens regarding ototoxicity. In addition, the ODD regimens were safer than MDD concerning nephrotoxicity.

SUMMARYAminoglycosides (AGs) are long-known molecules successfully used against Gram-negative pathogens. While their use declined with the discovery of new antibiotics, they are now classified as critically important molecules because of their effectiveness against multidrug-resistant bacteria. While they can efficiently cross the Gram-negative envelope, the mechanism of AG entry is still incompletely understood, although this comprehension is essential for the development of new therapies in the face of the alarming increase in antibiotic resistance. Increasing antibiotic uptake in bacteria is one strategy to enhance effective treatments. This review aims, first, to consolidate old and recent knowledge about AG uptake; second, to explore the connection between AG-dependent bacterial stress and drug uptake; and finally, to present new strategies of potentiation of AG uptake for more efficient antibiotic therapies. In particular, we emphasize on the connection between sugar transport and AG potentiation.

New drugs targeting antimicrobial resistant pathogens, including Pseudomonas aeruginosa, have been challenging to evaluate in clinical trials, particularly for the non-ventilated hospital-acquired pneumonia and ventilator-associated pneumonia indications. Development of new antibacterial drugs is facilitated by preclinical animal models that could predict clinical efficacy in patients with these infections.

We report here an FDA-funded study to develop a rabbit model of non-ventilated pneumonia with Pseudomonas aeruginosa by determining the extent to which the natural history of animal disease reproduced human pathophysiology and conducting validation studies to evaluate whether humanized dosing regimens of two antibiotics, meropenem and tobramycin, can halt or reverse disease progression.

In a rabbit model of non-ventilated pneumonia, endobronchial challenge with live P. aeruginosa strain 6206, but not with UV-killed Pa6206, caused acute respiratory distress syndrome, as evidenced by acute lung inflammation, pulmonary edema, hemorrhage, severe hypoxemia, hyperlactatemia, neutropenia, thrombocytopenia, and hypoglycemia, which preceded respiratory failure and death. Pa6206 increased >100-fold in the lungs and then disseminated from there to infect distal organs, including spleen and kidneys. At 5 h post-infection, 67% of Pa6206-challenged rabbits had PaO2 <60 mmHg, corresponding to a clinical cut-off when oxygen therapy would be required. When administered at 5 h post-infection, humanized dosing regimens of tobramycin and meropenem reduced mortality to 17-33%, compared to 100% for saline-treated rabbits (P<0.001 by log-rank tests). For meropenem which exhibits time-dependent bactericidal activity, rabbits treated with a humanized meropenem dosing regimen of 80 mg/kg q2h for 24 h achieved 100% T>MIC, resulting in 75% microbiological clearance rate of Pa6206 from the lungs. For tobramycin which exhibits concentration-dependent killing, rabbits treated with a humanized tobramycin dosing regimen of 8 mg/kg q8h for 24 h achieved Cmax/MIC of 9.8 ± 1.4 at 60 min post-dose, resulting in 50% lung microbiological clearance rate. In contrast, rabbits treated with a single tobramycin dose of 2.5 mg/kg had Cmax/MIC of 7.8 ± 0.8 and 8% (1/12) microbiological clearance rate, indicating that this rabbit model can detect dose-response effects.

The rabbit model may be used to help predict clinical efficacy of new antibacterial drugs for the treatment of non-ventilated P. aeruginosa pneumonia.

Amikacin, an aminoglycoside, is a widely used parenteral antibiotic. Therapeutic drug monitoring (TDM) is recommended for aminoglycosides to avoid toxicity. However, the lack of infrastructure at most places precludes it. This pilot and novel study attempt to estimate the real-world serum levels of Amikacin in hospitalised patients.

Thirty admitted patients, given Amikacin injections, were included in the study. In addition, 15 clinical specimens isolated with gram-negative bacteria were tested for minimum inhibitory concentration (MIC) value of Amikacin. Trough and peak serum levels of Amikacin were estimated by high-pressure liquid chromatography (HPLC).

The average MIC value of Amikacin estimated in our laboratory was 3.92 mcg/mL. Peak and trough serum levels of Amikacin ranged from 12.1 to 66.4 mcg/ml and 1.1 to 20.7 mcg/ml, respectively. More than 83% of our patients achieved peak Amikacin levels of 15 mcg/mL, and 37% had trough levels above 5 mcg/mL. These levels are desirable watersheds as per available literature.

Trough levels of Amikacin in all cases and a review of dosing according to MIC values are recommended to achieve drug safety and therapeutic efficacy.

Modeling and simulation can support dosing recommendations for clinical practice, but a simple framework is missing. In this proof-of-concept study, we aimed to develop neonatal and infant gentamicin dosing guidelines, supported by a pragmatic physiologically-based pharmacokinetic (PBPK) modeling approach and a decision framework for implementation.

An already existing PBPK model was verified with data of 87 adults, 485 children and 912 neonates, based on visual predictive checks and predicted-to-observed pharmacokinetic (PK) parameter ratios. After acceptance of the model, dosages now recommended by the Dutch Pediatric Formulary (DPF) were simulated, along with several alternative dosing scenarios, aiming for recommended peak (i.e., 8-12 mg/L for neonates and 15-20 mg/L for infants) and trough (i.e., <1 mg/L) levels. We then used a decision framework to weigh benefits and risks for implementation.

The PBPK model adequately described gentamicin PK. Simulations of current DPF dosages showed that the dosing interval for term neonates up to 6 weeks of age should be extended to 36-48 h to reach trough levels <1 mg/L. For infants, a 7.5 mg/kg/24 h dose will reach adequate peak levels. The benefits of these dose adaptations outweigh remaining uncertainties which can be minimized by routine drug monitoring.

We used a PBPK model to show that current DPF dosages for gentamicin in term neonates and infants needed to be optimized. In the context of potential uncertainties, the risk-benefit analysis proved positive; the model-informed dose is ready for clinical implementation.

To determine the effect of a 10% dimethyl sulfoxide (DMSO) solution on the peak concentration (CMAX ) of amikacin in the radiocarpal joint (RCJ) during intravenous regional limb perfusion (IVRLP) compared with 0.9% NaCl.

Randomized crossover study.

Seven healthy adult horses.

The horses underwent IVRLP with 2 g of amikacin sulfate diluted to 60 mL using a 10% DMSO or 0.9% NaCl solution. Synovial fluid was collected from the RCJ at 5, 10, 15, 20, 25, and 30 minutes after IVRLP. The wide rubber tourniquet placed on the antebrachium was removed after the 30 min sample. Amikacin concentrations were quantified by a fluorescence polarization immunoassay. The mean CMAX and time to peak concentration (TMAX ) of amikacin within the RCJ were determined. A one-sided paired t-test was used to determine the differences between treatments. The significance level was p < .05.

The mean ± SD CMAX in the DMSO group was 1361.8 ± 593 μg/mL and in the 0.9% NaCl group it was 860 ± 481.6 μg/mL (p = .058). Mean TMAX using the 10% DMSO solution was 23 and 18 min using the 0.9% NaCl perfusate (p = .161). No adverse effects were associated with use of the 10% DMSO solution.

Although there were higher mean peak synovial concentrations using the 10% DMSO solution no difference in synovial amikacin CMAX between perfusate type was detected (p = .058).

Use of a 10% DMSO solution in conjunction with amikacin during IVRLP is a feasible technique and does not negatively affect the synovial amikacin levels achieved. Further research is warranted to determine other effects of using DMSO during IVRLP.

Certain classes of antibiotics show "concentration dependent" antimicrobial activity; higher concentrations result in increased bacterial killing rates, in contrast to "time dependent antibiotics", which show antimicrobial activity that depends on the time that antibiotic concentrations remain above the MIC. Aminoglycosides and fluoroquinolones are still widely used concentration-dependent antibiotics. These antibiotics are not hydrolyzed by beta-lactamases and are less sensitive to the inoculum effect, which can be defined as an increased MIC for the antibiotic in the presence of a relatively higher bacterial load (inoculum). In addition, they possess a relatively long Post-Antibiotic Effect (PAE), which can be defined as the absence of bacterial growth when antibiotic concentrations fall below the MIC. These characteristics make them interesting complementary antibiotics in the management of Multi-Drug Resistant (MDR) bacteria and/or (neutropenic) patients with severe sepsis. Global surveillance studies have shown that up to 90% of MDR Gram-negative bacteria still remain susceptible to aminoglycosides, depending on the susceptibility breakpoint (e.g., CLSI or EUCAST) being applied. This percentage is notably lower for fluoroquinolones but depends on the region, type of organism, and mechanism of resistance involved. Daily (high-dose) dosing of aminoglycosides for less than one week has been associated with significantly less nephro/oto toxicity and improved target attainment. Furthermore, higher-than-conventional dosing of fluoroquinolones has been linked to improved clinical outcomes. Beta-lactam antibiotics are the recommended backbone of therapy for severe sepsis. Since these antibiotics are time-dependent, the addition of a second concentration-dependent antibiotic could serve to quickly lower the bacterial inoculum, create PAE, and reduce Penicillin-Binding Protein (PBP) expression. Inadequate antibiotic levels at the site of infection, especially in the presence of high inoculum infections, have been shown to be important risk factors for inadequate resistance suppression and therapeutic failure. Therefore, in the early phase of severe sepsis, effort should be made to optimize the dose and quickly lower the inoculum. In this article, the authors propose a novel concept of "Inoculum Based Dosing" in which the decision for antibiotic dosing regimens and/or combination therapy is not only based on the PK parameters of the patient, but also on the presumed inoculum size. Once the inoculum has been lowered, indirectly reflected by clinical improvement, treatment simplification should be considered to further treat the infection.

Gentamicin is used to treat severe infections and has a small therapeutic window. This study aimed to optimize the dosing strategy of gentamicin in intermittently hemodialyzed patients by simulating concentration-time profiles during pre- and postdialysis dosing, based on a published pharmacokinetic model.

Pharmacokinetic simulations were performed with virtual patients, including septic patients, who were treated with gentamicin and received weekly hemodialysis with an interval of 48 h-48 h-72 h. The following dosing regimens were simulated: for nonseptic patients, 5 mg/kg gentamicin was given 1 h or 2 h before dialysis or a starting dose of 2.5 mg/kg and a maintenance dose of 1.5 mg/kg immediately after dialysis were given; for septic patients, 6 mg/kg gentamicin was given 1 h or 2 h before dialysis or a starting dose of 3 mg/kg and a maintenance dose of 1.8 mg/kg immediately were given after dialysis. The mean maximum concentration (C max ), area under the curve (AUC) 24 h , and target attainment (TA) of pharmacodynamic targets were calculated and compared. The following targets were adopted from the literature: C max >8 mg/L and <20 mg/L and AUC 24 h >70 mg·h/L and <120 mg·h/L.

In nonseptic patients, postdialysis dosing resulted in a TA of 35% for C max of >8 mg/L, 100% for <20 mg/L and AUC 24 h >70 mg·h/L, and 45% for <120 mg·h/L. Dosing 2 h before dialysis resulted in a TA of 100% for C max of >8 mg/L, 40% for <20 mg/L, 65% for AUC 24 h >70 mg·h/L, and 77% for <120 mg·h/L. Simulations of septic patients resulted in comparable outcomes with higher TAs for C max <20 mg/L (96%), AUC 24 h >70 mg·h/L (90%), and AUC 24 h <120 mg·h/L (53%) for dosing 1 h before dialysis.

Postdialysis dosing resulted in a low TA of C max >8 mg/L; however, predialysis dosing ensured a high TA of C max >8 mg/L and acceptable TA of C max <20 mg/L, AUC 24 h >70 mg·h/L, and AUC 24 h <120 mg·h/L, which could increase the efficacy of gentamicin. Therefore, clinicians should consider predialysis dosing of gentamicin in patients undergoing intermittent hemodialysis.

Antimicrobials' topical administration efficacy has not been assessed in dogs with upper respiratory tract disease. The aim was to compare the concentration of gentamicin in nasal lavage fluid (NALF) and in serum after three topical protocols. This was a prospective crossover study of ten healthy dogs. Gentamicin was nebulized for a duration of 1 week, twice a day, for 10 min in the first protocol (10-min protocol) and for 3 min in the second protocol (3-min protocol), while the third protocol consisted of the administration of 0.25 mL of gentamicin in each nostril (drop protocol). Median concentrations of gentamicin in NALF were 9.39 µg/mL (8.12-19.97 interquartile range), 4.96 µg/mL (4.60-6.43) and 137.00 µg/mL (110.5-162.00) in the 10-min protocol, 3-min protocol and drop protocol, respectively. The result for the drop protocol was significantly higher than those of both nebulization protocols in NALF (p = 0.039). In serum, the gentamicin concentration was 0.98 µg/mL (0.65-1.53) and 0.25 µg/mL (0.25-0.44) in the 10-min and 3-min protocols, respectively. Gentamicin was not detected in the serum of seven out of ten dogs in the drop protocol, and gentamicin was significantly higher in the 10-min protocol compared to the drop protocol (p = 0.001). This study found that the 10-min, 3-min and drop protocols achieved superior concentrations in NALF compared to the minimum inhibitory concentration for gentamicin-sensitive bacteria, while remaining below the toxic values in blood.

Updated European Committee on Antimicrobial Susceptibility Testing (EUCAST) amikacin breakpoints for Enterobacterales and Pseudomonas aeruginosa included revised dosing recommendations of 25-30 mg/kg to achieve key pharmacokinetic/pharmacodynamic parameters, higher than recommended in the British National Formulary. The objectives of this review were to identify clinical evidence for high-dose amikacin regimens and to determine drug exposures that are related to adverse events and toxicity.

The literature search was conducted in October 2021 and updated in May 2022 using electronic databases for any study reporting adult participants treated with amikacin at doses ≥20 mg/kg/day. Reference lists of included papers were also screened for potential papers. Data were extracted for pharmacokinetic parameters and clinical outcomes, presented in a summary table and consolidated narratively. Meta-analysis was not possible. Each study was assessed for bias before, during and after the intervention using the ROBINS-I tool.

Nine studies (total 501 participants in 10 reports) were identified and included, eight of which were observational studies. Assessment of bias showed substantial flaws. Dosing regimens ranged from 25 to 30 mg/kg/day. Six studies adjusted the dose in obesity when participants had a body mass index of ≥30 kg/m2. Target peak serum concentrations ranged from 60 mg/L to 80 mg/L and 59.6-81.8% of patients achieved these targets, but there was no information on clinical outcomes. Two studies reported the impact of high-dose amikacin on renal function. No studies reporting auditory or vestibular toxicity were identified.

All included papers were limited by a significant risk of bias, while methodological and reporting heterogeneity made drawing conclusions challenging. Lack of information on the impact on renal function or ototoxicity means high-dose regimens should be used cautiously in older people. There is a need for a consensus guideline for high-dose amikacin to be written.

PROSPERO (CRD42021250022).

Aminoglycosides are a family of rapidly bactericidal antibiotics that often remain active against resistant Gram-negative bacterial infections. Over the past decade, their use in critically ill patients has been refined; however, due to their renal and cochleovestibular toxicity, their indications in the treatment of sepsis and septic shock have been gradually reduced. This article reviews the spectrum of activity, mode of action, and methods for optimizing the efficacy of aminoglycosides. We discuss the current indications for aminoglycosides, with an emphasis on multidrug-resistant Gram-negative bacteria, such as extended-spectrum β-lactamase-producing Enterobacterales, carbapenemase-producing Enterobacterales, multidrug-resistant Pseudomonas aeruginosa, and carbapenem-resistant Acinetobacter baumannii. Additionally, we review the evidence for the use of nebulized aminoglycosides.

Although aminoglycosides are frequently prescribed to neonates and children, the ability to reach effective and safe target concentrations with the currently used dosing regimens remains unclear. This study aims to evaluate the target attainment of the currently used dosing regimens for gentamicin in neonates and children. We conducted a retrospective single-center cohort study in neonates and children receiving gentamicin between January 2019 and July 2022, in the Beatrix Children's Hospital. The first gentamicin concentration used for therapeutic drug monitoring was collected for each patient, in conjunction with information on dosing and clinical status. Target trough concentrations were ≤1 mg/L for neonates and ≤0.5 mg/L for children. Target peak concentrations were 8-12 mg/L for neonates and 15-20 mg/L for children. In total, 658 patients were included (335 neonates and 323 children). Trough concentrations were outside the target range in 46.2% and 9.9% of neonates and children, respectively. Peak concentrations were outside the target range in 46.0% and 68.7% of neonates and children, respectively. In children, higher creatinine concentrations were associated with higher gentamicin trough concentrations. This study corroborates earlier observational studies showing that, with a standard dose, drug concentration targets were met in only approximately 50% of the cases. Our findings show that additional parameters are needed to improve target attainment.

Tobramycin is widely used to treat pulmonary exacerbations of cystic fibrosis. Height has been previously found to be significantly more predictive of tobramycin pharmacokinetics than body weight. This study aimed to develop a height-based initial dosing nomogram and evaluate its performance in peak concentration (Cmax) precision relative to standard and fixed dosing. Monte Carlo simulations were performed to develop a nomogram representing the doses required to reach Cmax targets at different heights. Cmax data observed at 2 clinical centers [McGill University Health Centre (MUHC) and Institut universitaire de cardiologie et pneumologie de Québec (IUCPQ-UL)] were compared with population-predicted Cmax using the doses derived from the nomogram alongside a fixed dose. Height-based dosing resulted in significantly less variable-predicted Cmax values [coefficient of variation (CV) MUHC = 15.7% and IUCPQ-UL = 10.8%] than the Cmax values observed in clinical practice (CV MUHC = 30.0% and CV IUCPQ-UL = 26.9%) and predicted Cmax values obtained from a fixed dose (CV MUHC = 21.2% and CV IUCPQ-UL = 16.3%). An initial dosing nomogram was developed to help reduce pharmacokinetic variability in the observed Cmax. More precise dosing would allow for better clinical outcomes in adult patients with cystic fibrosis.

Antimicrobial stewardship programs are important for reducing antimicrobial resistance because they can readjust antibiotic prescriptions to local guidelines, switch intravenous to oral administration, and reduce hospitalization times. Pharmacokinetics-pharmacodynamics (PK-PD) empirically based prescriptions and therapeutic drug monitoring (TDM) programs are essential for antimicrobial stewardship, but there is a need to fit protocols according to cost benefits. The cost benefits can be demonstrated by reducing toxicity and hospital stay, decreasing the amount of drug used per day, and preventing relapses in infection. Our aim was to review the data available on whether PK-PD empirically based prescriptions and TDM could improve the cost benefits of an antimicrobial stewardship program to decrease global hospital expenditures.

A narrative review based on PubMed search with the relevant studies of vancomycin, aminoglycosides, beta-lactams, and voriconazole.

TDM protocols demonstrated important cost benefit for patients treated with vancomycin, aminoglycosides, and voriconazole mainly due to reduce toxicities and decreasing the hospital length of stay. In addition, PK-PD strategies that used infusion modifications to meropenem, piperacillin-tazobactam, ceftazidime, and cefepime, such as extended or continuous infusion, demonstrated important cost benefits, mainly due to reducing daily drug needs and lengths of hospital stays.

TDM protocols and PK-PD empirically based prescriptions improve the cost-benefits and decrease the global hospital expenditures.

Pseudomonas aeruginosa (PA) is an opportunistic human pathogen, which is involved in a wide range of dangerous infections. It develops alarming resistances toward antibiotic treatment. Therefore, alternative strategies, which suppress pathogenicity or synergize with antibiotic treatments are in great need to combat these infections more effectively. One promising approach is to disarm the bacteria by interfering with their quorum sensing (QS) system, which regulates the release of various virulence factors as well as biofilm formation. Herein, this work reports the rational design, optimization, and in-depth profiling of a new class of Pseudomonas quinolone signaling receptor (PqsR) inverse agonists. The resulting frontrunner compound features a pyrimidine-based scaffold, high in vitro and in vivo efficacy, favorable pharmacokinetics as well as clean safety pharmacology characteristics, which provide the basis for potential pulmonary as well as systemic routes of administration. An X-ray crystal structure in complex with PqsR facilitated further structure-guided lead optimization. The compound demonstrates potent pyocyanin suppression, synergizes with aminoglycoside antibiotic tobramycin against PA biofilms, and is active against a panel of clinical isolates from bronchiectasis patients. Importantly, this in vitro effect translated into in vivo efficacy in a neutropenic thigh infection model in mice providing a proof-of-principle for adjunctive treatment scenarios.