Population pharmacokinetic modeling and target attainment analyses of rezafungin for the treatment of candidemia and invasive candidiasis.

Rezafungin is a chemically and metabolically stable echinocandin with a longer half-life than other echinocandins, allowing for a once-weekly intravenous infusion versus a daily infusion. Rezafungin is approved in the US for the treatment of candidemia and/or invasive candidiasis and is in development for the prevention of invasive fungal disease caused by Candida, Aspergillus, and Pneumocystis spp. in immunosuppressed patients. A population pharmacokinetic (PPK) model was developed using data from five Phase 1, one Phase 2, and one Phase 3 study. The model found to best describe the available data was a three-compartment PPK model with first-order elimination characterized by the parameters clearance (CL), central volume (V1), peripheral volume (V23), intercompartmental clearance 1, and intercompartmental clearance 2. The variability model included correlated interindividual variability in CL, V1, and V23 and a proportional residual variability model. The following statistically significant covariates were identified: albumin concentrations on V23; body surface area (BSA) on CL, V1, and V23; and disease state on CL and V1. Disease states were defined as patients from the Phase 2 and Phase 3 studies and hepatically impaired subjects. Covariates of BSA, disease state, or albumin, included in the final model, were not associated with clinically meaningful changes in PK, nor were any other patient factors, indicating that a common dose regimen is adequate for all adult patients. Target attainment simulations were performed to estimate the probability of achieving PK/pharmacodynamic targets across the range of minimum inhibitory concentration values for six species of Candida.

Hydrodynamic Flow Characteristics of a Recirculating Pool: Examining the Ecological Validity for Training and Testing.

ABSTRACT: Krajewski, KT, Beethe, AZ, Dever, DE, Johnson, CD, Nindl, BC, Lovalekar, MT, Flanagan, SD, and Connaboy, C. Hydrodynamic flow characteristics of a recirculating pool: examining the ecological validity for training and testing. J Strength Cond Res 37(10): 2023-2031, 2023-Recirculating swimming flumes (RSFs) with elliptical multifeature designs have grown in popularity due to their multifunctionality for rehabilitation and training. Because of their smaller footprint, laboratories have adopted their use to investigate swimming and underwater treadmill running. However, little is known about the hydrodynamic characteristics of these RSFs and how they might influence outcomes. The purpose was to determine hydrodynamic flow characteristics of an RSF at the manufacturers' set "speeds" around the centroid of flow projection. Hydrodynamic velocity profiles were collected through a 3D profiling velocimeter, sampling at 200 Hz in an RSF. Data were collected 0.5 and 1.5 m from the projection channel at designated flume "speeds" of 30-95 (+99) in 5-unit increments. Velocity data were collected for 1 minute per trial (location × speed) to determine mean flow velocity (MFV) for 10, 20, 30, and 40 cm2 cross-sectional areas (CSAs). A two-way ANOVA was conducted comparing CSAs from the surface by distance from the current channel (4 × 2). Separate ANOVAs were conducted to assess differences in MFV across each CSA. Significant differences between flow CSAs indicated that MFV is less for a larger area at the same speed, indicative of variable and turbulent flow characteristics across the respective CSAs. Mean flow velocity was further diminished by distance from the flow channel as supported by the main effect, thus exposing an individual to variant flow velocities simultaneously. Limited stability of the flow velocity centroid could affect swim mechanics making the movement pattern no longer analogous to traditional pool and open water swimming, rather resembling swimming upstream in a river with turbulent flow.

Prevention of Lower Extremity Musculoskeletal Injuries in Tactical and First Responder Populations: A Systematic Review and Meta-Analysis of Randomized Trials From 1955 to 2020.

ABSTRACT: Sinnott, AM, Krajewski, KT, LaGoy, AD, Beckner, ME, Proessl, F, Canino, MC, Nindl, BC, Turner, RL, Lovalekar, MT, Connaboy, C, and Flanagan, SD. Prevention of lower extremity musculoskeletal injuries in tactical and first responder populations: A systematic review and meta-analysis of randomized trials from 1955 to 2020. J Strength Cond Res 37(1): 239-252, 2023-Lower extremity musculoskeletal injuries (LEMSIs) impose a significant burden on tactical and first responder populations. To determine the effectiveness of LEMSI prevention strategies, we performed a systematic review and meta-analysis of randomized controlled trials published in English from 1955 to 2020 (PROSPERO: CRD42018081799). MEDLINE, EMBASE, Cochrane, CINAHL, ProQuest, and DTIC databases were searched for trials that assigned military service members, police, firefighters, or paramedics to LEMSI prevention interventions with a minimum surveillance period of 12 weeks. Evidence was synthesized as odds ratios (OR) for LEMSI occurrence between individuals assigned to interventions and those assigned to standard activities. Risk of bias was assessed with the Cochrane Risk of Bias tool 2.0. Random-effects meta-analyses were conducted for (a) physical training and (b) footwear modifications to reduce LEMSI and (c) footwear modifications to reduce stress fractures specifically. Certainty in the body of evidence was determined with the GRADE approach. Of 28,499 records, 18 trials comprised of more than 11,000 subjects were synthesized. Interventions included physical training (8, N = 6,838), footwear modifications (8, N = 3,792), nutritional supplementation (1, N = 324), and training modifications (1, N = 350). Overall risk of bias was generally moderate ( N = 7 of 18) or high ( N = 9 of 18). Physical training (OR = 0.87, 95% CI [0.71, 1.08], p = 0.22, I 2 = 58.4%) and footwear modification (OR = 1.13, 95% CI [0.85, 1.49], p = 0.42, I 2 = 0.0%) did not reduce LEMSI or stress fractures (OR = 0.76, 95% CI [0.45, 1.28], p = 0.30, I 2 = 70.7%). Our results indicate that there is weak evidence to support current LEMSI prevention strategies. Future efforts will benefit from longer surveillance periods, assessment of women and nonmilitary populations, improved methodological rigor, and a greater breadth of approaches.

Neuroendocrine, inflammatory, and extracellular vesicle responses during the Navy Special Warfare Screener Selection Course.

Military operational stress is known to increase adrenal hormones and inflammatory cytokines, while decreasing hormones associated with the anabolic milieu and neuroendocrine system. Less is known about the role of extracellular vesicles (EVs), a form of cell-to-cell communication, in military operational stress and their relationship to circulating hormones. The purpose of this study was to characterize the neuroendocrine, cytokine, and EV response to an intense. 24-h selection course known as the Naval Special Warfare (NSW) Screener and identify associations between EVs and cytokines. Blood samples were collected the morning of and following the NSW Screener in 29 men (18-26 yr). Samples were analyzed for concentrations of cortisol, insulin-like growth factor I (IGF-I), neuropeptide-Y (NPY), brain-derived neurotrophic factor (BDNF), α-klotho, tumor necrosis factor-α (TNFα), and interleukins (IL) -1ß, -6, and -10. EVs stained with markers associated with exosomes (CD63), microvesicles (VAMP3), and apoptotic bodies (THSD1) were characterized using imaging flow cytometry and vesicle flow cytometry. The selection event induced significant changes in circulating BDNF (-43.2%), IGF-I (-24.6%), TNFα (+17.7%), and IL-6 (+13.6%) accompanied by increases in intensities of THSD1+ and VAMP3+ EVs (all P < 0.05). Higher concentrations of IL-1ß and IL-10 were positively associated with THSD1+ EVs (P < 0.05). Military operational stress altered the EV profile. Surface markers associated with apoptotic bodies were positively correlated with an inflammatory response. Future studies should consider a multiomics assessment of EV cargo to discern canonical pathways that may be mediated by EVs during military stress.

Resistance exercise differentially alters extracellular vesicle size and subpopulation characteristics in healthy men and women: an observational cohort study.

Extracellular vesicles (EVs) are established mediators of adaptation to exercise. Currently, there are no published data comparing changes in EVs between men and women after resistance exercise. We tested the hypothesis that EV profiles would demonstrate a sex-specific signature following resistance exercise. Ten men and 10 women completed an acute heavy resistance exercise test for back squats using 75% of their one-repetition maximum. Blood was drawn before and immediately after exercise. EVs were isolated from plasma using size exclusion chromatography and stained with antibodies associated with exosomes (CD63), microvesicles (VAMP3), apoptotic bodies (THSD1), and a marker for skeletal muscle EVs (SGCA). CD63+ EV concentration and proportion of total EVs increased 23% (P = 0.006) and 113% (P = 0.005) in both sexes. EV mean size declined in men (P = 0.020), but not in women, suggesting a relative increase in small EVs in men. VAMP3+ EV concentration and proportion of total EVs increased by 93% (P = 0.025) and 61% (P = 0.030) in men and women, respectively. SGCA+ EV concentration was 69% higher in women compared with men independent of time (P = 0.007). Differences were also observed for CD63, VAMP3, and SGCA median fluorescence intensity, suggesting altered surface protein density according to sex and time. There were no significant effects of time or sex on THSD1+ EVs or fluorescence intensity. EV profiles, particularly among exosome-associated and muscle-derived EVs, exhibit sex-specific differences in response to resistance exercise which should be further studied to understand their relationship to training adaptations.

Metabolism, Excretion, and Mass Balance of [14C]-Rezafungin in Animals and Humans.

Rezafungin is a novel echinocandin being developed for treatment of candidemia and invasive candidiasis and for prevention of invasive fungal disease caused by Candida, Aspergillus, and Pneumocystis spp. in recipients of blood and marrow transplantation. Studies using [14C]-radiolabeled rezafungin were conducted in rats, monkeys, and humans to characterize the mass balance, excretion, and pharmacokinetics of [14C]-rezafungin and to evaluate relative amounts of rezafungin metabolites compared with parent drug. Fecal excretion was the main route of elimination in rats, monkeys, and humans. Radioactivity was primarily excreted as unchanged drug, with ≥95% average total recovery in rats (through 336 h) and monkeys (through 720 h). In humans, cumulative recovery of radioactivity through the first 17 days was 52% (38% in feces, 14% in urine) with estimated mean overall recovery through day 60 of 88.3% (73% in feces, 27% in urine). The clinical pharmacokinetics of rezafungin following a single 400-mg intravenous infusion (200 µCi of [14C]-rezafungin) were similar in plasma, plasma total radioactivity, and whole blood total radioactivity. Unchanged rezafungin represented the majority of total radioactivity in plasma, and the partitioning of total radioactivity into red blood cells was negligible. Across species, rezafungin was primarily metabolized by hydroxylation of the terphenyl, pentyl ether side chain. In these excretion/mass balance, metabolism, and PK studies, clinical observations were consistent with findings in the rat and monkey demonstrating the minimal metabolism and slow elimination of rezafungin after intravenous administration, with fecal excretion as the major route of elimination.

The Role of Age, Sex, Body Mass Index, and Sport Type on the Dynamic Exertion Test in Healthy Athletes: A Cross-Sectional Study.

BACKGROUND: The dynamic exertion test (EXiT) was developed to help inform return to play after sport-related concussion, but some factors may threaten the internal validity of EXiT and affect clinical interpretation. OBJECTIVE: To compare age, sex, BMI, and sport types across EXiT physiological [pre-EXiT and post-EXiT percentage of maximum heart rate (HR %max) and blood pressure (BP)], performance (change-of-direction task completion time and committed errors), and clinical [symptoms and rating of perceived exertion (RPE)] outcomes among healthy adolescents and adults. STUDY DESIGN: Cross-sectional. METHODS: Eighty-seven participants ( F = 55, 37.4%) reported symptoms and RPE during the EXiT, which consists of a 12-minute treadmill running protocol, and the dynamic circuit, ball toss, box shuffle (SHUF) and carioca (CAR), zig zag (ZZ), proagility (PA), and arrow agility (AA) tasks. Independent samples t tests were conducted for pre-EXiT and post-EXiT HR %max and BP and change-of-direction task completion time and Mann-Whitney U tests for errors, symptoms, and RPE. A series of 1-way analysis of variance (ANOVAs) and Kruskal-Wallis H tests were conducted to compare collision, contact, and noncontact sport types. RESULTS: Adolescents had lower completion time across AA ( P = 0.01) and male athletes lower than female athletes on CAR, ZZ, PA, and AA ( P < 0.04). Male athletes reported greater RPE after the SHUF, CAR, and AA ( P < 0.03). HR %max , errors, and symptoms were equivocal across all subgroups ( P > 0.05). CONCLUSION: Age and sex should be considered in the interpretation of performance and clinical, but not physiological, EXiT outcomes. The EXiT is a standardized exercise assessment and generalizable to healthy athletes.

Effects of Multi-ingredient Preworkout Supplements on Physical Performance, Cognitive Performance, Mood State, and Hormone Concentrations in Recreationally Active Men and Women.

ABSTRACT: Beckner, ME, Pihoker, AA, Darnell, ME, Beals, K, Lovalekar, M, Proessl, F, Flanagan, SD, Arciero, PJ, Nindl, BC, and Martin, BJ. Effects of multi-ingredient preworkout supplements on physical performance, cognitive performance, mood state, and hormone concentrations in recreationally active men and women. J Strength Cond Res 36(9): 2493-2501, 2022-Performance enhancement supplement research has primarily focused on the effectiveness of individual ingredients, rather than the combination. This study investigated the acute effects of 2 multi-ingredient preworkout supplements (MIPS), with beta-alanine and caffeine (BAC) and without (NBAC), compared with placebo (PLA) on anaerobic performance, endurance capacity, mood state, cognitive function, vascular function, and anabolic hormones. Thirty exercise-trained individuals (24.4 ± 4.9 years, 15 men and 15 women) completed a fatiguing exercise protocol on 3 separate occasions, 30 minutes after ingestion of BAC, NBAC, or PLA. Outcomes were analyzed using one-way or two-way repeated-measures analysis of variance, as appropriate (alpha = 0.05). Anaerobic power was greater when supplementing with NBAC (10.7 ± 1.2 W·kg -1 ) and BAC (10.8 ± 1.4 W·kg -1 ) compared with PLA (10.4 ± 1.2 W·kg -1 ) ( p = 0.014 and p = 0.022, respectively). BAC improved V̇ o2 peak time to exhaustion ( p = 0.006), accompanied by an increase in blood lactate accumulation ( p < 0.001), compared with PLA. Both NBAC and BAC demonstrated improved brachial artery diameter after workout ( p = 0.041 and p = 0.005, respectively), but PLA did not. L-arginine concentrations increased from baseline to postsupplement consumption of BAC ( p = 0.017). Reaction time significantly decreased after exercise for all supplements. There was no effect of supplement on mood states. Exercise-trained individuals looking to achieve modest improvements in power and endurance may benefit from consuming MIPS before exercise.

Differences in brain structure and theta burst stimulation-induced plasticity implicate the corticomotor system in loss of function after musculoskeletal injury.

Traumatic musculoskeletal injury (MSI) may involve changes in corticomotor structure and function, but direct evidence is needed. To determine the corticomotor basis of MSI, we examined interactions among skeletomotor function, corticospinal excitability, corticomotor structure (cortical thickness and white matter microstructure), and intermittent theta burst stimulation (iTBS)-induced plasticity. Nine women with unilateral anterior cruciate ligament rupture (ACL) 3.2 ± 1.1 yr prior to the study and 11 matched controls (CON) completed an MRI session followed by an offline plasticity-probing protocol using a randomized, sham-controlled, double-blind, cross-over study design. iTBS was applied to the injured (ACL) or nondominant (CON) motor cortex leg representation (M1LEG) with plasticity assessed based on changes in skeletomotor function and corticospinal excitability compared with sham iTBS. The results showed persistent loss of function in the injured quadriceps, compensatory adaptations in the uninjured quadriceps and both hamstrings, and injury-specific increases in corticospinal excitability. Injury was associated with lateralized reductions in paracentral lobule thickness, greater centrality of nonleg corticomotor regions, and increased primary somatosensory cortex leg area inefficiency and eccentricity. Individual responses to iTBS were consistent with the principles of homeostatic metaplasticity; corresponded to injury-related differences in skeletomotor function, corticospinal excitability, and corticomotor structure; and suggested that corticomotor adaptations involve both hemispheres. Moreover, iTBS normalized skeletomotor function and corticospinal excitability in ACL. The results of this investigation directly confirm corticomotor involvement in chronic loss of function after traumatic MSI, emphasize the sensitivity of the corticomotor system to skeletomotor events and behaviors, and raise the possibility that brain-targeted therapies could improve recovery.NEW & NOTEWORTHY Traumatic musculoskeletal injuries may involve adaptive changes in the brain that contribute to loss of function. Our combination of neuroimaging and theta burst transcranial magnetic stimulation (iTBS) revealed distinct patterns of iTBS-induced plasticity that normalized differences in muscle and brain function evident years after unilateral knee ligament rupture. Individual responses to iTBS corresponded to injury-specific differences in brain structure and physiological activity, depended on skeletomotor deficit severity, and suggested that corticomotor adaptations involve both hemispheres.

Population Pharmacokinetics of Rezafungin in Patients with Fungal Infections.

Rezafungin is a novel antifungal agent of the echinocandin class with potent activity against species of Candida and Aspergillus, including subsets of resistant strains, and Pneumocystis jirovecii. The objective of this analysis was to develop a population pharmacokinetic (PK) model to characterize the disposition of rezafungin in plasma following intravenous (IV) administration in healthy volunteers and in patients with candidemia and/or invasive candidiasis. The population PK model was based on a previous model from phase 1 data; formal covariate analyses were conducted to identify any relationships between subject characteristics and rezafungin PK variability. A four-compartment model with linear elimination and zero-order drug input provided a robust fit to the pooled data. Several statistically significant relationships between subject descriptors (sex, infection status, serum albumin, and body surface area [BSA]) and rezafungin PK parameters were identified, but none were deemed clinically relevant. Previous dose justification analyses conducted using data from phase 1 subjects alone are expected to remain appropriate. The final model provided a precise and unbiased fit to the observed concentrations and can be used to reliably predict rezafungin PK in infected patients.

Network Analysis of Research on Mild Traumatic Brain Injury in US Military Service Members and Veterans During the Past Decade (2010-2019).

OBJECTIVE: To evaluate trends in the extant literature on mild traumatic brain injury (mTBI) in military service members and veterans using network analysis based on a comprehensive search of original, peer-reviewed research articles involving human participants published between January 1, 2010, and December 31, 2019. Specifically, we employed network analysis to evaluate associations in the following areas: (1) peer-reviewed journals, (2) authors, (3) organizations/institutions, and (4) relevant key words. PARTICIPANTS: Included studies were published in peer-reviewed journals available on Web of Science database, using US military service members or veterans. DESIGN: Bibliometric network analytical review. MAIN MEASURES: Outcomes for each analysis included number of articles, citations, total link strength, and clusters. RESULTS: The top publishing journals were (1) Journal of Head Trauma and Rehabilitation, (2) Military Medicine, (3) Brain Injury, (4) Journal of Neurotrauma, and (5) Journal of Rehabilitation Research and Development. The top publishing authors were (1) French, (2) Lange, (3) Cooper, (4) Vanderploeg, and (5) Brickell. The top research institutions were (1) Defense and Veterans Brain Injury Center, (2) Uniformed Services University of the Health Sciences, (3) University of California San Diego, (4) Walter Reed National Military Medical Center, and (5) Boston University. The top co-occurring key words in this analysis were (1) posttraumatic stress disorder (PTSD), (2) persistent postconcussion symptoms (PPCS), (3) blast injury, (4) postconcussion syndrome (PCS), and (5) Alzheimer's disease. CONCLUSIONS: The results of this network analysis indicate a clear focus on veteran health, as well as investigations on chronic effects of mTBI. Research in civilian mTBI indicates that delaying treatment for symptoms and impairments related to mTBI may not be the most precise treatment strategy. Increasing the number of early, active, and targeted treatment trials in military personnel could translate to meaningful improvements in clinical practices for managing mTBI in this population.

Increases in Load Carriage Magnitude and Forced Marching Change Lower-Extremity Coordination in Physically Active, Recruit-Aged Women.

The objective was to examine the interactive effects of load magnitude and locomotion pattern on lower-extremity joint angles and intralimb coordination in recruit-aged women. Twelve women walked, ran, and forced marched at body weight and with loads of +25%, and +45% of body weight on an instrumented treadmill with infrared cameras. Joint angles were assessed in the sagittal plane. Intralimb coordination of the thigh-shank and shank-foot couple was assessed with continuous relative phase. Mean absolute relative phase (entire stride) and deviation phase (stance phase) were calculated from continuous relative phase. At heel strike, forced marching exhibited greater (P < .001) hip flexion, knee extension, and ankle plantar flexion compared with running. At mid-stance, knee flexion (P = .007) and ankle dorsiflexion (P = .04) increased with increased load magnitude for all locomotion patterns. Forced marching (P = .009) demonstrated a "stiff-legged" locomotion pattern compared with running, evidenced by the more in-phase mean absolute relative phase values. Running (P = .03) and walking (P = .003) had greater deviation phase than forced marching. Deviation phase increased for running (P = .03) and walking (P < .001) with increased load magnitude but not for forced marching. With loads of >25% of body weight, forced marching may increase risk of injury due to inhibited energy attenuation up the kinetic chain and lack of variability to disperse force across different supportive structures.

Utility of a novel perceptual-motor control test for identification of sport-related concussion beyond current clinical assessments.

Clinically feasible metrics, that can inform the concussion recovery decision making process by evaluating a unique domain beyond current testing domains (e.g., balance, neurocognition, symptoms, vestibular/ocular function) are still in need. The purpose of this study was to compare perceptual-motor control in adolescent athletes ≤21 days of sport-related concussion and healthy controls and evaluate the association of perceptual-motor control to the outcomes of commonly-used sport-related concussion clinical assessments. Athletes (age: 12-18 years) with sport-related concussion (n = 48) and healthy controls (n = 24) completed the Perception-Action Coupling Task (PACT), whose outcomes are mean reaction, movement, initiation, response time, and accuracy. ImPACT outcomes are verbal/visual memory scores, motor processing speed, and reaction time. Vestibular-Ocular Motor Screen (VOMS) outcomes are symptoms from: smooth pursuit, horizontal/vertical saccades, near-point of convergence, horizontal/vestibular ocular-reflex, and visual motion sensitivity. CONCUSSED demonstrated ~5% deficit in overall perceptual-motor accuracy during PACT compared to CONTROLS (p = 0.03). PACT accuracy negatively correlated with smooth pursuits(r = -0.29), and horizontal (r = -0.35)/vertical (r = -0.30) saccades. The C5.0 decision tree determined PACT accuracy was the most relevant predictor of sport-related concussion when no visual motion sensitivity symptoms were reported and Visual Memory was >66. Perceptual-motor control tests may complement current sport-related concussion assessments when neurocognition and vestibular/ocular motor system are not grossly impaired.

Effects of Short-Term Unilateral Strength Training on Measures of Postural Control When Wearing "Operationally Relevant" Backpack Loads.

Krajewski, KT, Bansbach, HM, McLean, L, McKenzie, C, Rawcliffe, A, Graham, SM, Flanagan, SD, Pourmoghaddam, A, Dettmer, M, and Connaboy, C. Effects of short-term unilateral strength training on measures of postural control when wearing "operationally relevant" backpack loads. J Strength Cond Res 34(10): 2743-2750, 2020-To examine the effects of "operationally relevant" loads on postural stability and to determine the effects of unilateral and bilateral strength training programs on postural stability in healthy, recruit-aged men. Fifteen subjects were randomly assigned to either a unilateral (UL; n = 7) or bilateral (BL; n = 8) strength training group, which performed strength training 3 times a week for 4 weeks. Subjects completed the following pretest and post-test assessments: 1 repetition maximum in bilateral (1RM-BL) and unilateral (1RM-UL) stance positions and bilateral and unilateral balance tasks with eyes open and eyes closed. Balance tasks were performed over 3 loading conditions: body mass (BM), 50% BM, and 70% BM. Sample entropy (SE) and root mean square (RMS) were calculated from the center of pressures collected during each balance assessment. The UL strength training group showed significant improvement after training in both 1RM-UL (p < 0.01) and 1RM-BL (p < 0.01). The BL strength training group only showed significant improvement in 1RM-BL (p = 0.01). There was a significant main effect of load on RMS (p < 0.05) across all balance tasks with RMS increasing with increasing load. Sample entropy was found to decrease with increasing load in the unilateral eyes open and bilateral stance tasks. Significant increases in strength (∼10 to -29%) were observed; however, increased strength alone is not enough to mitigate the effects of load carriage on the postural control, even when training is performed in stance positions that are posturally challenging. Therefore, "operationally relevant" loads negatively impact postural stability in novice load carriers when assessing nonlinear measures.

Compromised Dynamic Postural Stability Under Increased Load Carriage Magnitudes.

Warfighter performance may be compromised through the impact of load carriage on dynamic postural stability. Men and women may experience this impact to differing extents due to postural stability differences. Therefore, the authors investigated the effect of load magnitude on dynamic postural stability in men and women during a landing and stabilization task. Dynamic postural stability of 32 subjects (16 women) was assessed during the unilateral landing of submaximal jumps under 3 load conditions: +0%, +20%, and +30% body weight. Dynamic postural stability was measured using the dynamic postural stability index, which is calculated from ground reaction force data sampled at 1200 Hz. Two-way mixed-measures analysis of variance compared dynamic postural stability index scores between sexes and loads. Dynamic postural stability index scores were significantly affected by load (P = .001) but not by sex or by the sex by load interaction (P > .05). Dynamic postural stability index scores increased between the 0% (0.359 ± 0.041), 20% (0.396 ± 0.034), and 30% (0.420 ± 0.028) body weight conditions. Increased load negatively affects dynamic postural stability with similar performance decrements displayed by men and women. Men and women warfighters may experience similar performance decrements under load carriage conditions of similar relative magnitudes.

Use of Translational Pharmacokinetic/Pharmacodynamic Infection Models To Understand the Impact of Neutropenia on the Efficacy of Tedizolid Phosphate.

Tedizolid phosphate, the prodrug of the active antibiotic tedizolid, is an oxazolidinone for the treatment of acute bacterial skin and skin structure infections. Studies in a mouse thigh infection model demonstrated that tedizolid has improved potency and pharmacokinetics/pharmacodynamics (PK/PD) compared with those of linezolid. Subsequent studies showed that the efficacy of tedizolid was enhanced in immunocompetent (IC) mice compared with neutropenic (immunosuppressed [IS]) mice, with stasis at clinically relevant doses being achieved only in the presence of granulocytes. The tedizolid label therefore contains a warning about its use in neutropenic patients. This study reevaluated the PK/PD of tedizolid and linezolid in the mouse thigh infection model in IC and IS mice using a methicillin-resistant Staphylococcus aureus (MRSA) strain (ATCC 33591) and a methicillin-susceptible S. aureus (MSSA) strain (ATCC 29213). The antistaphylococcal effect of doses ranging from 1 to 150 mg/kg of body weight tedizolid (once daily) or linezolid (twice daily) was determined at 24, 48, and 72 h after initiating treatment. In IC mice, stasis was achieved in the absence of antibiotics, and both tedizolid and linezolid reduced the burden further beyond a static effect. In IS mice, tedizolid achieved stasis against MRSA ATCC 33591 and MSSA ATCC 29213 at 72 h at a human clinical dose of 200 mg, severalfold lower than that in earlier studies. Linezolid achieved a static effect against MRSA ATCC 33591 in IS mice at a dose lower than that used clinically. This study demonstrates that, with time, both tedizolid and linezolid at clinically relevant exposures achieve stasis in neutropenic mice with an MRSA or MSSA thigh infection.

Population Pharmacokinetic Analyses for Rezafungin (CD101) Efficacy Using Phase 1 Data.

Rezafungin (CD101) is a novel echinocandin antifungal agent currently in clinical development for the treatment of candidemia and invasive candidiasis. Rezafungin has potent in vitro activity against Candida albicans and Candida glabrata, including azole- and echinocandin-resistant isolates. The objective of this analysis was to develop a population pharmacokinetic (PK) model to characterize the disposition of rezafungin in plasma following intravenous (i.v.) administration. Data from two phase 1 studies, a single-ascending-dose study and a multiple-ascending-dose study, were available. Candidate population PK models were fit to the pooled data using the Monte Carlo parametric expectation maximization algorithm in S-ADAPT. The data were best described using a linear four-compartment model with zero-order drug input via i.v. infusion and first-order elimination. In order to account for the relationships between the structural PK parameters and subject body weight, all parameters in the model were scaled to subject body weight using standard allometric coefficients (a power of 0.75 for the clearance terms and 1.0 for the volume terms). The final model fit the observed data with very little bias and excellent precision. The prediction-corrected visual predictive check demonstrated that the final model could accurately simulate both the central tendency and the variability of observed rezafungin plasma concentrations. Given this, the final rezafungin population PK model is expected to provide reliable simulated concentration-time profiles and can provide dose selection decision support for future clinical studies.

Overcoming the Resistance Hurdle: Pharmacokinetic-Pharmacodynamic Target Attainment Analyses for Rezafungin (CD101) against Candida albicans and Candida glabrata.

Rezafungin (CD101) is a novel echinocandin antifungal agent with activity against Aspergillus and Candida species, including azole- and echinocandin-resistant isolates. The objective of these analyses was to conduct pharmacokinetic (PK)-pharmacodynamic (PD) target attainment analyses to evaluate single and once-weekly rezafungin dosing to provide dose selection support for future clinical studies. Using a previously developed rezafungin population PK model, Monte Carlo simulations were conducted utilizing the following three intravenous rezafungin regimens: (i) a single 400 mg dose, (ii) 400 mg for week 1 followed by 200 mg weekly for 5 weeks, and (iii) 400 mg weekly for 6 weeks. Percent probabilities of achieving the nonclinical PK-PD targets associated with net fungal stasis and 1-log10 CFU reductions from baseline for Candida albicans and Candida glabrata were calculated for each rezafungin regimen. At the MIC90 for C. albicans and C. glabrata, a single 400 mg dose of rezafungin achieved probabilities of PK-PD target attainment of ≥90% through week 3 of therapy for all PK-PD targets evaluated. When evaluating the multiple-dose (i.e., weekly) regimens under these conditions, percent probabilities of PK-PD target attainment of 100% were achieved through week 6. Moreover, high (>90%) probabilities of PK-PD target attainment were achieved through week 6 following administration of the weekly regimens at or above the MIC100 values for C. albicans and C. glabrata based on contemporary in vitro surveillance data. These analyses support the use of single and once-weekly rezafungin regimens for the treatment of patients with candidemia and/or candidiasis due to C. albicans or C. glabrata.

Effects of Tedizolid Phosphate on Survival Outcomes and Suppression of Production of Staphylococcal Toxins in a Rabbit Model of Methicillin-Resistant Staphylococcus aureus Necrotizing Pneumonia.

The protective efficacy of tedizolid phosphate, a novel oxazolidinone that potently inhibits bacterial protein synthesis, was compared to those of linezolid, vancomycin, and saline in a rabbit model of Staphylococcus aureus necrotizing pneumonia. Tedizolid phosphate was administered to rabbits at 6 mg/kg of body weight intravenously twice daily, which yielded values of the 24-h area under the concentration-time curve approximating those found in humans. The overall survival rate was 83% for rabbits treated with 6 mg/kg tedizolid phosphate twice daily and 83% for those treated with 50 mg/kg linezolid thrice daily (P = 0.66 by the log-rank test versus the results obtained with tedizolid phosphate). These survival rates were significantly greater than the survival rates of 17% for rabbits treated with 30 mg/kg vancomycin twice daily (P = 0.003) and 17% for rabbits treated with saline (P = 0.002). The bacterial count in the lungs of rabbits treated with tedizolid phosphate was significantly decreased compared to that in the lungs of rabbits treated with saline, although it was not significantly different from that in the lungs of rabbits treated with vancomycin or linezolid. The in vivo bacterial production of alpha-toxin and Panton-Valentine leukocidin, two key S. aureus-secreted toxins that play critical roles in the pathogenesis of necrotizing pneumonia, in the lungs of rabbits treated with tedizolid phosphate and linezolid was significantly inhibited compared to that in the lungs of rabbits treated with vancomycin or saline. Taken together, these results indicate that tedizolid phosphate is superior to vancomycin for the treatment of S. aureus necrotizing pneumonia because it inhibits the bacterial production of lung-damaging toxins at the site of infection.

Characterization of the haematological profile of 21 days of tedizolid in healthy subjects.

OBJECTIVES: Tedizolid is a novel oxazolidinone antibacterial. Oxazolidinones carry concerns for time-dependent myelosuppression. To further explore tedizolid's haematological tolerability, we analysed data from a 21 day study comparing safety and pharmacokinetics of tedizolid and linezolid. METHODS: This was a Phase 1 study in healthy volunteers comparing five treatments (each n = 8) over 21 days: tedizolid at 200, 300 or 400 mg once daily; linezolid at 600 mg twice daily; and placebo. Routine laboratory haematological parameters (platelet, absolute neutrophil, white blood cell, red blood cell and reticulocyte counts) were compared between groups. Adverse haematological outcomes were pre-specified as any parameter below the standard lower limits of normal (LLN), substantially abnormal (<50% LLN for neutrophils; <75% LLN for other parameters) or ≥50% below baseline (platelets only). ClinicalTrials.gov identifier: NCT00671814. RESULTS: During the 21 day study period, pre-specified adverse platelet outcomes were observed in the linezolid (n = 2), tedizolid 300 mg (n = 1) and tedizolid 400 mg (n = 3) groups. Mean platelet counts decreased over time in a dose-dependent manner for tedizolid, with higher doses being similar to linezolid. The magnitude of platelet count decreases from baseline was influenced by unbound drug trough plasma concentrations, which were generally higher in subjects with at least a 20% decrease in platelet count. Substantially abnormal haematological parameters were only observed with linezolid and tedizolid 400 mg. One linezolid and two tedizolid 400 mg subjects discontinued due to meeting criteria for pre-specified adverse haematological outcomes. CONCLUSIONS: Although limited to small groups of healthy volunteers, these exploratory results support clinical study of extended treatment durations with tedizolid at 200 mg once daily.