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Invasive fungal infections are a major cause of morbidity and mortality for immunocompromised patients. Posaconazole is approved for treatment and prophylaxis of invasive fungal infection in adult patients, with intravenous, oral suspension, and gastroresistant/delayed-released tablet formulations available. In Europe, until very recently, posaconazole was used off-label in children, although a new delayed-release suspension approved for pediatric use is expected to become available soon. A population pharmacokinetic model was developed which uses posaconazole therapeutic drug monitoring data following intravenous and oral dosing in hospitalized children, thus enabling estimation of pediatric suspension and tablet oral bioavailability. In total, 297 therapeutic drug monitoring plasma levels from 104 children were included in this analysis. The final model was a one-compartment model with first-order absorption and nonlinear elimination. Allometric scaling on clearance and volume of distribution was included a priori . Tablet bioavailability was estimated to be 66%. Suspension bioavailability was estimated to decrease with increasing doses, ranging from 3.8% to 32.2% in this study population. Additionally, concomitant use of proton pump-inhibitors was detected as a significant covariate, reducing suspension bioavailability by 41.0%. This is the first population pharmacokinetic study to model posaconazole data from hospitalized children following intravenous, tablet, and suspension dosing simultaneously. The incorporation of saturable posaconazole clearance into the model has been key to the credible joint estimation of tablet and suspension bioavailability. To aid rational posaconazole dosing in children, this model was used alongside published pharmacodynamic targets to predict the probability of target attainment using typical pediatric dosing regimen.

Objective: To assess pharmacokinetics and changes to sodium levels in addition to adverse events (AEs) associated with fosfomycin among neonates with clinical sepsis., Design: A single-centre open-label randomised controlled trial., Setting: Kilifi County Hospital, Kenya., Patients: 120 neonates aged ≤28 days admitted being treated with standard-of-care (SOC) antibiotics for sepsis: ampicillin and gentamicin between March 2018 and February 2019., Intervention: We randomly assigned half the participants to receive additional intravenous then oral fosfomycin at 100 mg/kg two times per day for up to 7 days (SOC-F) and followed up for 28 days., Main Outcomes and Measures: Serum sodium, AEs and fosfomycin pharmacokinetics., Results: 61 and 59 infants aged 0-23 days were assigned to SOC-F and SOC, respectively. There was no evidence of impact of fosfomycin on serum sodium or gastrointestinal side effects. We observed 35 AEs among 25 SOC-F participants and 50 AEs among 34 SOC participants during 1560 and 1565 infant-days observation, respectively (2.2 vs 3.2 events/100 infant-days; incidence rate difference -0.95 events/100 infant-days (95% CI -2.1 to 0.20)). Four SOC-F and 3 SOC participants died. From 238 pharmacokinetic samples, modelling suggests an intravenous dose of 150 mg/kg two times per day is required for pharmacodynamic target attainment in most children, reduced to 100 mg/kg two times per day in neonates aged <7 days or weighing <1500 g., Conclusion and Relevance: Fosfomycin offers potential as an affordable regimen with a simple dosing schedule for neonatal sepsis. Further research on its safety is needed in larger cohorts of hospitalised neonates, including very preterm neonates or those critically ill. Resistance suppression would only be achieved for the most sensitive of organisms so fosfomycin is recommended to be used in combination with another antimicrobial., Trial Registration Number: NCT03453177., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Objectives: This study aimed to simultaneously investigate the pharmacokinetics of ampicillin and gentamicin, currently the WHO standard of care for treating neonatal sepsis., Methods: Pharmacokinetic data were collected in 59 neonates receiving ampicillin and gentamicin for suspected or proven sepsis in the NeoFosfo trial (NCT03453177). A panel of 23 clinical Escherichia coli isolates from neonates with sepsis, resistant to either ampicillin, gentamicin or both, were tested for susceptibility using chequerboards. Pharmacokinetic/pharmacodynamic (PKPD) modelling and simulations were used to compare single-agent (EUCAST MIC) and combination (chequerboard MIC) target attainment with standard dosing regimens., Results: A model was established that simultaneously estimated parameters of a one-compartment ampicillin model and a two-compartment gentamicin model. A common clearance for both drugs was used (6.89 L/h/70 kg) relating to glomerular filtration (CLGFR), with an additional clearance term added for ampicillin (5.3 L/h/70 kg). Covariate modelling included a priori allometric weight and post-menstrual age scaling of clearance. Further covariate relationships on renal clearance were postnatal age and serum creatinine.Simulation-based PKPD assessments suggest good Gram-positive (MIC ≤ 0.25 mg/L) cover. However, less than one-quarter of neonates were predicted to receive efficacious coverage against Enterobacterales (MIC ≤ 2 mg/L). The benefit of the ampicillin/gentamicin combination was limited, with only 2/23 E. coli clinical strains showing FIC index < 0.5 (synergy) and most in the range 0.5-1 (suggesting additivity). Simulations showed that feasible dosing strategies would be insufficient to cover resistant strains., Conclusions: PKPD simulations showed ampicillin and gentamicin combination therapy was insufficient to cover Enterobacterales, suggesting the need for alternative empirical treatment options for neonatal sepsis., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy.)

Purpose: To investigate the effect of bursal acromial reconstruction (BAR) using an acellular dermal allograft on glenohumeral joint kinematics including maximum abduction angle, glenohumeral superior translation, cumulative deltoid force, and subacromial contact pressure., Methods: In this dynamic biomechanical cadaveric shoulder study, 8 fresh-frozen cadaveric shoulders (age 53.4 ± 14.2 years, mean ± standard deviation) were tested using a dynamic shoulder testing system. Maximum abduction angle (MAA), glenohumeral superior translation (ghST), maximum cumulative deltoid force (cDF), and subacromial peak contact pressure (sCP) were compared across 3 conditions: (1) intact shoulder; (2) massive retracted irreparable posterosuperior rotator cuff tear (psRCT) according to Patte III; and (3) BAR. Additionally, humeral head containment was measured using contact pressure., Results: Compared with the simulated psRCT, BAR significantly increased mean MAA and significantly decreased ghST (P < .001, respectively) and cDF (P = .017) Additionally, BAR was found to significantly decrease sCP compared with psRCT (P = .024)., Conclusion: In a dynamic biomechanical cadaveric shoulder simulator, resurfacing the undersurface of the acromion using the BAR technique leads to significantly improved ghST, MAA, cDF, and sCP compared with the irreparable rotator cuff tear., Clinical Relevance: With the BAR technique, native humeral containment may be restored, which can potentially delay progressive subacromial and glenoidal abrasive wear and improve overall shoulder function. As such, the proposed BAR technique can be considered as a technically feasible and potentially cost- and timesaving procedure, as no bone anchors are needed, glenoidal or humeral side graft ruptures can be avoided, and postoperative rehabilitation can be started immediately. However, future clinical studies are needed., (Copyright © 2021 Arthroscopy Association of North America. Published by Elsevier Inc. All rights reserved.)

Background: Tranexamic acid (TXA) is an antifibrinolytic drug that reduces surgical blood loss and death due to bleeding after trauma and post-partum haemorrhage. Treatment success is dependant on early intervention and rapid systemic exposure to TXA. The requirement for intravenous (IV) administration can in some situations limit accessibility to TXA therapy. Here we employ physiologically based pharmacokinetic modelling (PBPK) to evaluate if adequate TXA exposure maybe achieved when given via different routes of administration., Methods: A commercially available PBPK software (GastroPlus®) was used to model published TXA pharmacokinetics. IV, oral and intramuscular (IM) models were developed using healthy volunteer PK data from twelve different single dose regimens (n = 48 participants). The model was verified using separate IV and oral validation datasets (n = 26 participants). Oral, IM and sub-cutaneous (SQ) dose finding simulations were performed., Results: Across the different TXA regimens evaluated TXA plasma concentrations varied from 0.1 to 94.0 µg/mL. Estimates of the total plasma clearance of TXA ranged from 0.091 to 0.104 L/h/kg, oral bioavailability from 36 to 67% and Tmax from 2.6 to 3.2 and 0.4 to 1.0 h following oral and intramuscular administration respectively. Variability in the observed TXA PK could be captured through predictable demographic effects on clearance, combined with intestinal permeability and stomach transit time following oral administration and muscle blood flow and muscle/plasma partition coefficients following intra-muscular dosing., Conclusions: This study indicates that intramuscular administration is the non-intravenous route of administration with the most potential for achieving targeted TXA exposures. Plasma levels following an IM dose of 1000 mg TXA are predicted to exceed 15 mg/mL in < 15 min and be maintained above this level for approximately 3 h, achieving systemic exposure (AUC0-6) of 99 to 105 µg*hr/mL after a single dose. Well-designed clinical trials to verify these predictions and confirm the utility of intramuscular TXA are recommended., (Copyright © 2021. Published by Elsevier B.V.)

Background: Injuries to the Kaplan fiber complex (KFC) are not routinely assessed for in the anterior cruciate ligament (ACL)-deficient knee during preoperative magnetic resonance imaging (MRI). As injuries to the KFC lead to anterolateral rotatory instability (ALRI) in the ACL-deficient knee, preoperative detection of these injuries on MRI scans may help surgeons to individualize treatment and improve outcomes, as well as to reduce failure rates., Purpose: To retrospectively determine the rate of initially overlooked KFC injuries on routine MRI in knees with isolated primary ACL deficiency., Study Design: Case series; Level of evidence, 4., Methods: Patients who underwent isolated ACL reconstruction between August 2013 and December 2019 were identified. No patient had had Kaplan fiber (KF) injury identified on the initial reading of the MRI scan or at the time of surgery. Preoperative knee MRI scans (minimum 1.5 T) were reviewed and injuries to the proximal and distal KFs were recorded by 3 independent reviewers. KF length and distance to nearby anatomic landmarks (the lateral joint line and the lateral femoral epicondyle) were measured. Additional radiological findings, including bleeding, lateral femoral notch sign, and bone marrow edema (BME), were identified to detect correlations with KFC injury., Results: The intact KFC could reliably be identified by all 3 reviewers (85.9% agreement; Kappa, 0.716). Also, 53% to 56% of the patients with initially diagnosed isolated ACL ruptures showed initially overlooked injuries to the KFC. Injuries to the distal KFs were more frequent (48.1%, 53.8%, and 43.3% by the first, second, and third reviewers, respectively) than injuries to the proximal KFs (35.6%, 47.1%, and 45.2% by the first, second, and third reviewers, respectively). Bleeding in the lateral supracondylar region was associated with KFC injuries ( P = .023). Additionally, there was a positive correlation between distal KF injuries and lateral tibial plateau BME ( P = .035), but no associations were found with the lateral femoral notch sign or other patterns of BME, including pivot-shift BME., Conclusion: KF integrity and injury can be reliably detected on routine knee MRI scans. Also, 53% to 56% of the patients presenting with initially diagnosed isolated ACL ruptures had concomitant injuries to the KFC. This is of clinical relevance, as ACL injuries diagnosed by current routine MRI examination protocols may come with a high number of occult or hidden KFC injuries. As injuries to the KFC contribute to persistent ALRI, which may influence ACL graft failure or reoperation rates, significant improvements in preoperative diagnostic imaging are required to determine the exact injury pattern and to assist in surgical decision making.

Background: Fosfomycin has the potential to be re-purposed as part of a combination therapy to treat neonatal sepsis where resistance to current standard of care (SOC) is common. Limited data exist on neonatal fosfomycin pharmacokinetics and estimates of bioavailability and CSF/plasma ratio in this vulnerable population are lacking., Objectives: To generate data informing the appropriate dosing of IV and oral fosfomycin in neonates using a population pharmacokinetic analysis of plasma and CSF data., Methods: The NeoFosfo study (NCT03453177) was a randomized trial that examined the safety and pharmacokinetics of fosfomycin comparing SOC versus SOC plus fosfomycin. Sixty-one neonates received fosfomycin (100 mg/kg IV q12h for 48 h) and then they converted to oral therapy at the same dose. Two plasma pharmacokinetic samples were taken following the first IV and oral doses, sample times were randomized to cover the whole pharmacokinetic profile and opportunistic CSF pharmacokinetic samples were collected. A population pharmacokinetic model was developed in NONMEM and simulations were performed., Results: In total, 238 plasma and 15 CSF concentrations were collected. A two-compartment disposition model, with an additional CSF compartment and first-order absorption, best described the data. Bioavailability was estimated as 0.48 (95% CI = 0.347-0.775) and the CSF/plasma ratio as 0.32 (95% CI = 0.272-0.409). Allometric weight and postmenstrual age (PMA) scaling was applied; additional covariates included postnatal age (PNA) on clearance and CSF protein on CSF/plasma ratio., Conclusions: Through this analysis a population pharmacokinetic model has been developed that can be used alongside currently available pharmacodynamic targets to select a neonatal fosfomycin dose based on an infant's PMA, PNA and weight., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy.)

Starting with the molecular scaffold of the DA(2)/β(2) dual agonist sibenadet (Viozan™), a number of molecular changes were incorporated, which were designed to increase the potency and selectivity of the target molecule, and improve its pharmacokinetics. Through this process a novel, high potency, full β(2)-agonist with high selectivity and long duration capable of being dosed once daily has been discovered., (Copyright © 2011. Published by Elsevier Ltd.)