Pharmacokinetics and safety of a single dose of telavancin in pediatric subjects 2-17 years of age.

Antimicrobial resistance increases infection morbidity in both adults and children, necessitating the development of new therapeutic options. Telavancin, an antibiotic approved in the United States for certain bacterial infections in adults, has not been examined in pediatric patients. The objectives of this study were to evaluate the short-term safety and pharmacokinetics (PK) of a single intravenous infusion of telavancin in pediatric patients. Single-dose safety and PK of 10 mg/kg telavancin was investigated in pediatric subjects >12 months to ≤17 years of age with known or suspected bacterial infection. Plasma was collected up to 24-h post-infusion and analyzed for concentrations of telavancin and its metabolite for noncompartmental PK analysis. Safety was monitored by physical exams, vital signs, laboratory values, and adverse events following telavancin administration. Twenty-two subjects were enrolled: 14 subjects in Cohort 1 (12-17 years), 7 subjects in Cohort 2 (6-11 years), and 1 subject in Cohort 3 (2-5 years). A single dose of telavancin was well-tolerated in all pediatric age cohorts without clinically significant effects. All age groups exhibited increased clearance of telavancin and reduced exposure to telavancin compared to adults, with mean peak plasma concentrations of 58.3 µg/mL (Cohort 1), 60.1 µg/mL (Cohort 2), and 53.1 µg/mL (Cohort 3). A 10 mg/kg dose of telavancin was well tolerated in pediatric subjects. Telavancin exposure was lower in pediatric subjects compared to adult subjects. Further studies are needed to determine the dose required in phase 3 clinical trials in pediatrics.

Maintaining the balance: the critical role of plasmin activity in orthopedic surgery injury response.

The musculoskeletal system plays vital roles in the body, facilitating movement, protecting vital structures, and regulating hematopoiesis and mineral metabolism. Injuries to this system are common and can cause chronic pain, loss of range of motion, and disability. The acute phase response (APR) is a complex process necessary for surviving and repairing injured musculoskeletal tissue. To conceptualize the APR, it is useful to divide it into 2 distinct phases, survival and repair. During the survival-APR, a "damage matrix" primarily composed of fibrin, via thrombin activity, is produced to contain the zone of injury. Once containment is achieved, the APR transitions to the repair phase, where reparative inflammatory cells use plasmin to systematically remove the damage matrix and replace it with new permanent matrices produced by differentiated mesenchymal stem cells. The timing of thrombin and plasmin activation during their respective APR phases is crucial for appropriate regulation of the damage matrix. This review focuses on evidence indicating that inappropriate exuberant activation of plasmin during the survival-APR can result in an overactive APR, leading to an "immunocoagulopathy" that may cause "immunothrombosis" and death. Conversely, preclinical data suggest that too little plasmin activity during the repair-APR may contribute to failed tissue repair, such as a fracture nonunion, and chronic inflammatory degenerative diseases like osteoporosis. Future clinical studies are required to affirm these findings. Therefore, the temporal-spatial functions of plasmin in response to musculoskeletal injury and its pharmacologic manipulation are intriguing new targets for improving orthopedic care.

A Multi-Center Evaluation of the Pharmacokinetics and Safety of Intravenous Ibuprofen in Infants 1-6 Months of Age.

BACKGROUND: Enteral ibuprofen was first approved as a prescription drug in 1974 for the US market. An intravenous (IV) ibuprofen formulation is approved for use in children older than 6 months of age, but there are limited studies specifically evaluating the pharmacokinetics and safety in children 1-6 months of age. AIMS: The primary purpose of this study was to evaluate the pharmacokinetics of IV ibuprofen in infants younger than 6 months of age. The secondary objective was to evaluate the safety of single and repeated doses of IV ibuprofen in infants younger than 6 months of age. METHODS: This was an industry-sponsored multi-center study. Institutional Review Board approval and informed parental consent were obtained prior to enrollment. Hospitalized neonates and infants younger than 6 months of age with fever or expected postoperative pain were eligible. Enrolled patients received 10 mg/kg of IV ibuprofen every 6 h, with up to four doses per day. Patients were randomized to two sparse sampling technique pharmacokinetic sample time groups. Group 1 samples were drawn at 0, 30 min, and 2 h, while group 2 samples were drawn at 0 min, 1, and 4 h after administration. RESULTS: A total of 24 children were enrolled in the study, with 15 male patients and 9 female patients. The median age of the cohort was 4.4 months (range 1.1-5.9 months), and the median weight was 5.9 kg (range 2.3-8.8 kg). The arithmetic mean and standard error for peak plasma ibuprofen concentration was 56.28 ± 2.77 µg/mL. Plasma levels declined rapidly with a mean elimination half-life of 1.30 h. Time to peak ibuprofen effect and concentration were similar when compared with older pediatric patients. Clearance and volume of distribution were also similar to those reported in older pediatric patients. No drug-related adverse events were reported. CONCLUSIONS: The pharmacokinetic and short-term safety profiles of IV ibuprofen in pediatric patients 1-6 months of age are comparable to those in children older than 6 months of age. TRIAL REGISTRATION: Clinicaltrials.gov Trial Registration number and date: NCT02583399-Registered July 2017.

Sterility of Miniature C-arm Fluoroscopy in Hand and Upper Extremity Surgery.

Previous studies have demonstrated that sterile equipment is frequently contaminated intraoperatively, yet the incidence of miniature c-arm (MCA) contamination in hand and upper extremity surgery is unclear. To examine this incidence, a prospective study of MCA sterility in hand and upper extremity cases was performed in a hospital main operating room (MOR) ( n = 13) or an ambulatory surgery center operating room (AOR) ( n = 16) at a single tertiary care center. Case length, MCA usage parameters, and sterility of the MCA through the case were examined. We found that MOR surgical times trended toward significance ( p = 0.055) and that MOR MCAs had significantly more contamination prior to draping than AOR MCAs ( p < 0.001). In MORs and AORs, 46.2 and 37.5% of MCAs respectively were contaminated intraoperatively. In MORs and AORs, 85.7 and 80% of noncontaminated cases, respectively, used the above hand- table technique, while 50 and 83.3% of contaminated MOR and AOR cases, respectively, used a below hand-table technique. Similar CPT codes were noted in both settings. Thus, a high-rate of MCA intraoperative contamination occurs in both settings. MCA placement below the hand-table may impact intraoperative contamination, even to distant MCA areas. Regular sterilization of equipment and awareness of these possible risk factors could lower bacterial burden.

Variable Response to Antifibrinolytics Correlates with Blood-loss and Transfusion in Posterior Spinal Fusion.

PURPOSE: Posterior spinal fusion (PSF) activates the fibrinolytic protease plasmin, which is implicated in blood loss and transfusion. While antifibrinolytic drugs have improved blood loss and reduced transfusion, variable blood loss has been observed in similar PSF procedures treated with the same dose of antifibrinolytics. However, both the cause of this and the appropriate measures to determine antifibrinolytic efficacy during high-blood-loss spine surgery are unknown, making clinical trials to optimize antifibrinolytic dosing in PSF difficult. We hypothesized that patients undergoing PSF respond differently to antifibrinolytic dosing, resulting in variable blood loss, and that specific diagnostic markers of plasmin activity will accurately measure the efficacy of antifibrinolytics in PSF. METHODS: A prospective study of 17 patients undergoing elective PSF with the same dosing regimen of TXA was conducted. Surgery-induced plasmin activity was exhaustively analyzed in perioperative blood samples and correlated to measures of inflammation, bleeding, and transfusion. RESULTS: While markers of in vivo plasmin activation (PAP and D-dimer) suggested significant breakthrough plasmin activation and fibrinolysis (P < 0.01), in vitro plasmin assays, including TEG, did not detect plasmin activation. In vivo measures of breakthrough plasmin activation correlated with blood loss (R2 = 0.400, 0.264; P < 0.01), transfusions (R2 = 0.388; P < 0.01), and complement activation (R2 = 0.346, P < 0.05). CONCLUSIONS: Despite all patients receiving a high dose of TXA, its efficacy among patients was variable, indicated by notable intra-operative plasmin activity. Markers of in vivo plasmin activation best correlated with clinical outcomes. These findings suggest that the efficacy of antifibrinolytic therapy to inhibit plasmin in PSF surgery should be determined by markers of in vivo plasmin activation in future studies. LEVEL OF EVIDENCE: Level II-diagnostic.

Plasmin drives burn-induced systemic inflammatory response syndrome.

Severe injuries, such as burns, provoke a systemic inflammatory response syndrome (SIRS) that imposes pathology on all organs. Simultaneously, severe injury also elicits activation of the fibrinolytic protease plasmin. While the principal adverse outcome of plasmin activation in severe injury is compromised hemostasis, plasmin also possesses proinflammatory properties. We hypothesized that, following a severe injury, early activation of plasmin drives SIRS. Plasmin activation was measured and related to injury severity, SIRS, coagulopathy, and outcomes prospectively in burn patients who are not at risk of hemorrhage. Patients exhibited early, significant activation of plasmin that correlated with burn severity, cytokines, coagulopathy, and death. Burn with a concomitant, remote muscle injury was employed in mice to determine the role of plasmin in the cytokine storm and inflammatory cascades in injured tissue distant from the burn injury. Genetic and pharmacologic inhibition of plasmin reduced the burn-induced cytokine storm and inflammatory signaling in injured tissue. These findings demonstrate (a) that severe injury-induced plasmin activation is a key pathologic component of the SIRS-driven cytokine storm and SIRS-activated inflammatory cascades in tissues distant from the inciting injury and (b) that targeted inhibition of plasmin activation may be effective for limiting both hemorrhage and tissue-damaging inflammation following injury.

Severe injury-induced osteoporosis and skeletal muscle mineralization: Are these related complications?

Severely injured patients are beleaguered by complications during convalescence, such as dysregulated biomineralization. Paradoxically, severely injured patients experience the loss of bone (osteoporosis), resulting in diminished skeletal integrity and increased risk of fragility fractures; yet they also accrue mineralization in soft tissues, resulting in complications such as heterotopic ossification (HO). The pathophysiology leading to dysregulated biomineralization in severely injured patients is not well defined. It has been postulated that these pathologies are linked, such that mineralization is "transferred" from the bone to soft tissue compartments. The goal of this study was to determine if severe injury-induced osteoporosis and soft tissue calcification are temporally coincident following injury. Using a murine model of combined burn and skeletal muscle injury to model severe injury, it was determined that mice developed significant progressive bone loss, detectable as early as 3 days post injury, and marked soft tissue mineralization by 7 days after injury. The observed temporal concordance between the development of severe injury-induced osteoporosis and soft tissue mineralization indicates the plausibility that these complications share a common pathophysiology, though further experiments are required.

Plasminogen activation in the musculoskeletal acute phase response: Injury, repair, and disease.

The musculoskeletal system is critical for movement and the protection of organs. In addition to abrupt injuries, daily physical demands inflict minor injuries, necessitating a coordinated process of repair referred to as the acute-phase response (APR). Dysfunctional APRs caused by severe injuries or underlying chronic diseases are implicated in pathologic musculoskeletal repair, resulting in decreased mobility and chronic pain. The molecular mechanisms behind these phenomena are not well understood, hindering the development of clinical solutions. Recent studies indicate that, in addition to regulating intravascular clotting, the coagulation and fibrinolytic systems are also entrenched in tissue repair. Although plasmin and fibrin are considered antithetical to one another in the context of hemostasis, in a proper APR, they complement one another within a coordinated spatiotemporal framework. Once a wound is contained by fibrin, activation of plasmin promotes the removal of fibrin and stimulates angiogenesis, tissue remodeling, and tissue regeneration. Insufficient fibrin deposition or excessive plasmin-mediated fibrinolysis in early convalescence prevents injury containment, causing bleeding. Alternatively, excess fibrin deposition and/or inefficient plasmin activity later in convalescence impairs musculoskeletal repair, resulting in tissue fibrosis and osteoporosis, while inappropriate fibrin or plasmin activity in a synovial joint can cause arthritis. Together, these pathologic conditions lead to chronic pain, poor mobility, and diminished quality of life. In this review, we discuss both fibrin-dependent and -independent roles of plasminogen activation in the musculoskeletal APR, how dysregulation of these mechanisms promote musculoskeletal degeneration, and the possibility of therapeutically manipulating plasmin or fibrin to treat musculoskeletal disease.

Specificity and affinity of the N-terminal residues in staphylocoagulase in binding to prothrombin.

In Staphylococcus aureus-caused endocarditis, the pathogen secretes staphylocoagulase (SC), thereby activating human prothrombin (ProT) and evading immune clearance. A previous structural comparison of the SC(1-325) fragment bound to thrombin and its inactive precursor prethrombin 2 has indicated that SC activates ProT by inserting its N-terminal dipeptide Ile1-Val2 into the ProT Ile16 pocket, forming a salt bridge with ProT's Asp194, thereby stabilizing the active conformation. We hypothesized that these N-terminal SC residues modulate ProT binding and activation. Here, we generated labeled SC(1-246) as a probe for competitively defining the affinities of N-terminal SC(1-246) variants preselected by modeling. Using ProT(R155Q,R271Q,R284Q) (ProTQQQ), a variant refractory to prothrombinase- or thrombin-mediated cleavage, we observed variant affinities between ∼1 and 650 nm and activation potencies ranging from 1.8-fold that of WT SC(1-246) to complete loss of function. Substrate binding to ProTQQQ caused allosteric tightening of the affinity of most SC(1-246) variants, consistent with zymogen activation through occupation of the specificity pocket. Conservative changes at positions 1 and 2 were well-tolerated, with Val1-Val2, Ile1-Ala2, and Leu1-Val2 variants exhibiting ProTQQQ affinity and activation potency comparable with WT SC(1-246). Weaker binding variants typically had reduced activation rates, although at near-saturating ProTQQQ levels, several variants exhibited limiting rates similar to or higher than that of WT SC(1-246). The Ile16 pocket in ProTQQQ appears to favor nonpolar, nonaromatic residues at SC positions 1 and 2. Our results suggest that SC variants other than WT Ile1-Val2-Thr3 might emerge with similar ProT-activating efficiency.

Trauma-Induced Nanohydroxyapatite Deposition in Skeletal Muscle is Sufficient to Drive Heterotopic Ossification.

Heterotopic ossification (HO), or the pathologic formation of bone within soft tissues, is a significant complication following severe injuries as it impairs joint motion and function leading to loss of the ability to perform activities of daily living and pain. While soft tissue injury is a prerequisite of developing HO, the exact molecular pathology leading to trauma-induced HO remains unknown. Through prior investigations aimed at identifying the causative factors of HO, it has been suggested that additional predisposing factors that favor ossification within the injured soft tissues environment are required. Considering that chondrocytes and osteoblasts initiate physiologic bone formation by depositing nanohydroxyapatite crystal into their extracellular environment, we investigated the hypothesis that deposition of nanohydroxyapatite within damaged skeletal muscle is likewise sufficient to predispose skeletal muscle to HO. Using a murine model genetically predisposed to nanohydroxyapatite deposition (ABCC6-deficient mice), we observed that following a focal muscle injury, nanohydroxyapatite was robustly deposited in a gene-dependent manner, yet resolved via macrophage-mediated regression over 28 days post injury. However, if macrophage-mediated regression was inhibited, we observed persistent nanohydroxyapatite that was sufficient to drive the formation of HO in 4/5 mice examined. Together, these results revealed a new paradigm by suggesting the persistent nanohydroxyapatite, referred to clinically as dystrophic calcification, and HO may be stages of a pathologic continuum, and not discrete events. As such, if confirmed clinically, these findings support the use of early therapeutic interventions aimed at preventing nanohydroxyapatite as a strategy to evade HO formation.