Optimization of Fluconazole Dosing for the Prevention and Treatment of Invasive Candidiasis Based on the Pharmacokinetics of Fluconazole in Critically Ill Patients.

The efficacy of fluconazole is related to the area under the plasma concentration-time curve (AUC) over the MIC of the microorganism. Physiological changes in critically ill patients may affect the exposure of fluconazole, and therefore dosing adjustments might be needed. The aim of this study was to evaluate variability in fluconazole drug concentration in intensive care unit (ICU) patients and to develop a pharmacokinetic model to support personalized fluconazole dosing. A prospective observational pharmacokinetic study was performed in critically ill patients receiving fluconazole either as prophylaxis or as treatment. The association between fluconazole exposure and patient variables was studied. Pharmacokinetic modeling was performed with a nonparametric adaptive grid (NPAG) algorithm using R package Pmetrics. Data from 33 patients were available for pharmacokinetic analysis. Patients on dialysis and solid organ transplant patients had a significantly lower exposure to fluconazole. The population was best described with a one-compartment model, where the mean volume of distribution was 51.52 liters (standard deviation [SD], 19.81) and the mean clearance was 0.767 liters/h (SD, 0.46). Creatinine clearance was tested as a potential covariate in the model, but was not included in the final population model. A significant positive correlation was found between the fluconazole exposure (AUC) and the trough concentration (Cmin). Substantial variability in fluconazole plasma concentrations in critically ill adults was observed, where the majority of patients were underexposed. Fluconazole Cmin therapeutic drug monitoring (TDM)-guided dosing can be used to optimize therapy in critically ill patients. (This study has been registered at ClinicalTrials.gov under identifier NCT02491151.).

MMP-9 mediated Syndecan-4 shedding correlates with osteoarthritis severity.

OBJECTIVE: Osteoarthritis (OA) is a degenerative joint disease inducing the degradation of the articular cartilage. Syndecan-4 (Sdc4) is a heparan sulfate proteoglycan, expressed under inflammatory conditions and by chondrocytes during OA. Little is known about Sdc4 shedding and its regulation in OA. Therefore, we investigated the regulation of Sdc4 shedding and underlying shedding mechanisms under OA conditions. DESIGN: Articular cartilage, serum, synovial fluid and synovial membrane from OA patients with different radiological severity were analyzed. ELISA, RT-qPCR and IHC for Sdc4, MMP-2 and -9 were performed. MMP inhibitors and siRNA were evaluated for their effect on Sdc4 shedding by ELISA and on IL-1 signaling by western blot (pERK/ERK). RESULTS: Shed Sdc4 was increased in synovial fluid of OA patients, but not in the serum and is a good predictor (AUC = 0.72) for OA severity with a sensitivity of 67.5% and specificity 65.2%. MMP-9, but not MMP-2, was increased in cartilage and synovial membrane at mRNA levels and in the synovial fluid at protein levels. Shed Sdc4 correlated with the amount of MMP-9 in synovial fluid. Further, the inhibition and knock-down of MMP-9 decreased the amount of shed Sdc4 in vitro. Increased Sdc4 shedding resulted in less phosphorylation of ERK upon IL-1ß stimulation. CONCLUSION: Shed Sdc4 might be a good prognostic biomarker for OA mediated cartilage degradation. MMP-9 seems to be the relevant sheddase for Sdc4 under OA conditions, desensitizing chondrocytes towards IL-1 signaling.

Clinical standards for the management of adverse effects during treatment for TB.

BACKGROUND: Adverse effects (AE) to TB treatment cause morbidity, mortality and treatment interruption. The aim of these clinical standards is to encourage best practise for the diagnosis and management of AE.METHODS: 65/81 invited experts participated in a Delphi process using a 5-point Likert scale to score draft standards.RESULTS: We identified eight clinical standards. Each person commencing treatment for TB should: Standard 1, be counselled regarding AE before and during treatment; Standard 2, be evaluated for factors that might increase AE risk with regular review to actively identify and manage these; Standard 3, when AE occur, carefully assessed and possible allergic or hypersensitivity reactions considered; Standard 4, receive appropriate care to minimise morbidity and mortality associated with AE; Standard 5, be restarted on TB drugs after a serious AE according to a standardised protocol that includes active drug safety monitoring. In addition: Standard 6, healthcare workers should be trained on AE including how to counsel people undertaking TB treatment, as well as active AE monitoring and management; Standard 7, there should be active AE monitoring and reporting for all new TB drugs and regimens; and Standard 8, knowledge gaps identified from active AE monitoring should be systematically addressed through clinical research.CONCLUSION: These standards provide a person-centred, consensus-based approach to minimise the impact of AE during TB treatment.

Clinical standards for drug-susceptible pulmonary TB.

BACKGROUND: The aim of these clinical standards is to provide guidance on 'best practice´ for diagnosis, treatment and management of drug-susceptible pulmonary TB (PTB).METHODS: A panel of 54 global experts in the field of TB care, public health, microbiology, and pharmacology were identified; 46 participated in a Delphi process. A 5-point Likert scale was used to score draft standards. The final document represents the broad consensus and was approved by all 46 participants.RESULTS: Seven clinical standards were defined: Standard 1, all patients (adult or child) who have symptoms and signs compatible with PTB should undergo investigations to reach a diagnosis; Standard 2, adequate bacteriological tests should be conducted to exclude drug-resistant TB; Standard 3, an appropriate regimen recommended by WHO and national guidelines for the treatment of PTB should be identified; Standard 4, health education and counselling should be provided for each patient starting treatment; Standard 5, treatment monitoring should be conducted to assess adherence, follow patient progress, identify and manage adverse events, and detect development of resistance; Standard 6, a recommended series of patient examinations should be performed at the end of treatment; Standard 7, necessary public health actions should be conducted for each patient. We also identified priorities for future research into PTB.CONCLUSION: These consensus-based clinical standards will help to improve patient care by guiding clinicians and programme managers in planning and implementation of locally appropriate measures for optimal person-centred treatment for PTB.

Clinical standards for the dosing and management of TB drugs.

BACKGROUND: Optimal drug dosing is important to ensure adequate response to treatment, prevent development of drug resistance and reduce drug toxicity. The aim of these clinical standards is to provide guidance on 'best practice´ for dosing and management of TB drugs.METHODS: A panel of 57 global experts in the fields of microbiology, pharmacology and TB care were identified; 51 participated in a Delphi process. A 5-point Likert scale was used to score draft standards. The final document represents the broad consensus and was approved by all participants.RESULTS: Six clinical standards were defined: Standard 1, defining the most appropriate initial dose for TB treatment; Standard 2, identifying patients who may be at risk of sub-optimal drug exposure; Standard 3, identifying patients at risk of developing drug-related toxicity and how best to manage this risk; Standard 4, identifying patients who can benefit from therapeutic drug monitoring (TDM); Standard 5, highlighting education and counselling that should be provided to people initiating TB treatment; and Standard 6, providing essential education for healthcare professionals. In addition, consensus research priorities were identified.CONCLUSION: This is the first consensus-based Clinical Standards for the dosing and management of TB drugs to guide clinicians and programme managers in planning and implementation of locally appropriate measures for optimal person-centred treatment to improve patient care.

How to design a study to evaluate therapeutic drug monitoring in infectious diseases?

BACKGROUND: Therapeutic drug monitoring (TDM) is a tool to personalize and optimize dosing by measuring the drug concentration and subsequently adjusting the dose to reach a target concentration or exposure. The evidence to support TDM is however often ranked as expert opinion. Limitations in study design and sample size have hampered definitive conclusions of the potential added value of TDM. OBJECTIVES: We aim to give expert opinion and discuss the main points and limitations of available data from antibiotic TDM trials and emphasize key elements for consideration in design of future clinical studies to quantify the benefits of TDM. SOURCES: The sources were peer-reviewed publications, guidelines and expert opinions from the field of TDM. CONTENT: This review focuses on key aspects of antimicrobial TDM study design: describing the rationale for a TDM study, assessing the exposure of a drug, assessing susceptibility of pathogens and selecting appropriate clinical endpoints. Moreover we provide guidance on appropriate study design. IMPLICATIONS: This is an overview of different aspects relevant for the conduct of a TDM study. We believe that this paper will help researchers and clinicians to design and conduct high-quality TDM studies.

The effect of lengthening of the femur on the extensors of the knee. An electromyographic study.

Surface electromyography of the quadriceps femoris muscle was performed in seven patients in order to determine the effect of extensive lengthening of the femur on the muscles that extend the knee. Electromyograms were made during sustained (thirty-second) isometric extension of the knee, at an angle of flexion of the knee of 30 degrees, while a load equal to 15 per cent of body weight was applied to the leg just proximal to the ankle. The average circumference of the thigh was smaller, the motor-unit recruitment of the muscles was slower, and the fatigability was greater on the involved side compared with the uninvolved side. The vastus medialis exhibited greater fatigability and slower motor-unit recruitment than the rectus femoris or the vastus lateralis. The atrophy index of the involved muscles correlated well with the muscle fatigability, the preoperative limb-length discrepancy, the percentage of lengthening, and the motor-unit recruitment. Analysis also revealed a correlation between muscle fatigability and the percentage of lengthening of the bone and between muscle fatigability and the preoperative limb-length discrepancy. The percentage of lengthening correlated with the extent of motor-unit recruitment. The results of this study suggest that the amount of damage to neuromuscular tissue varies according to the extent of the lengthening of the femur. Of all of the knee extensors, the vastus medialis was affected the most.

Lack of a central role for osteoprogenitor cells from the femoral canal in heterotopic ossification of the hip: an experimental study in a rat model.

We have developed an animal model to examine the formation of heterotopic ossification using standardised muscular damage and implantation of a beta-tricalcium phosphate block into a hip capsulotomy wound in Wistar rats. The aim was to investigate how cells originating from drilled femoral canals and damaged muscles influence the formation of heterotopic bone. The femoral canal was either drilled or left untouched and a tricalcium phosphate block, immersed either in saline or a rhBMP-2 solution, was implanted. These implants were removed at three and 21 days after the operation and examined histologically, histomorphometrically and immunohistochemically. Bone formation was seen in all implants in rhBMP-2-immersed, whereas in those immersed in saline the process was minimal, irrespective of drilling of the femoral canals. Bone mineralisation was somewhat greater in the absence of drilling with a mean mineralised volume to mean total volume of 18.2% (sd 4.5) versus 12.7% (sd 2.9, p < 0.019), respectively. Our findings suggest that osteoinductive signalling is an early event in the formation of ectopic bone. If applicable to man the results indicate that careful tissue handling is more important than the prevention of the dissemination of bone cells in order to avoid heterotopic ossification.

Inter-observer reliability in the assessment of heterotopic ossification: proposal of a combined classification.

We applied four published classifications for assessment of heterotopic ossification after total hip arthroplasty (Arcq, Brooker, DeLee and Della Valle [1, 2, 5, 6]. The average incidence of heterotopic ossification varied from 19.8% to 27.7%. The inter-observer reliability of the various classifications was determined by Cohen's Kappa statistic. Kappa values ranged from 0.897 for Arcq's to 0.814 for Brooker's classification. In order to increase the reliability and consistency, we propose a new classification system combining Brooker's and Della Valle's classifications. This new classification preserves the high reliability of Della Valle's system and is comparable to previous publications since it includes Brooker's criteria.

Posttraumatic limb shortening: treatment with the Ilizarov distraction device.

BACKGROUND AND AIMS: Limb length inequality is not only a cosmetic problem, it is also a functional concern. The aim of the study was to analyse the cases of limb lengthening after their posttraumatic shortening. The study design is descriptive and comparative. MATERIAL AND METHODS: During the years 1979-1994 14 patients between 4-18 years of age were treated. Limb shortening was the result of premature closure of physeal plate and severe traumas with large bone defects. Ilizarov external devices for limb lengthening were used. The lengthening index was counted. The patients were divided into four groups: minor lengthening, bone transport, femoral lengthening, lengthening with using bone allografting. RESULTS: In group I the lengthening index was 29.9 days per centimetre (d/cm), in group II 21.7 d/cm, in group III 33.5 d/cm, in group IV 20.5 d/cm. The complication rate was 28%: 14% "minor" and 14% "major"-stiffness, wound necrosis. None of them affected the final result. In almost all cases the lengthening index was below 30 d/cm. CONCLUSIONS: The result of limb lengthening is not predictable in every separate case. Multiple lengthening may act on bone regeneration capacity.

Orthopedic surgery in Estonia.

We did a survey on the development of orthopedic surgery in Estonia, especially during the past 10 years, including education, hospital-based orthopedic surgery and orthopedic research. The main types of orthopedic operations were analyzed, on the basis of data from the Estonian Social Ministry, Bureau of Medical Statistics and several departments of orthopedic. On the average, 11,831 orthopedic operations were performed yearly during the years 1996-1998 in hospital departments.

Treatment of children with Osteogenesis imperfecta in Estonia.

AIM: To analyse the changes in fracture rate, bone density and histology in children with Osteogenesis imperfecta receiving treatment with alendronate (oral bisphosphonate) and calcitriol. METHODS: Children treated at Tartu University Hospital from 1995 to 2001 were examined for Osteogenesis imperfecta. Radiographs and bone density measurements were obtained for all patients at the beginning of the study. Four patients also had bone biopsies prior to and one year after beginning treatment. The children were then given alendronate in weight-dependent dosages and also calcitriol. The number of fractures during the treatment period was recorded and follow-up bone density measurements were made. RESULTS: Fifteen patients were treated during the 6-y period; mean follow-up approximately 3 y. It was found that the number of bone fractures had decreased significantly (p < 0.0001). Bone density improved in all 15 patients. Histologic studies revealed an increased number of osteoblasts and thickness of bone trabeculae as well as a more regular bone lamellar structure at the time of the second operation. CONCLUSION: The complex treatment of Osteogenesis imperfecta should include alendronate and calcitriol to decrease fractures and improve bone mineral density.

Bone healing models in rat tibia after different injuries.

AIMS: Gradual elaboration of an adequate and efficient multistage method for experimental remodelling of specific wound healing process--bone repair. Comparison of clinical characteristics with the results of microanatomy, histology, electronmicroscopy and computer morphometry. MATERIAL AND METHODS: An investigation of posttraumatic bone repair after internal fracture, excision and cortical perforation was carried out on 142 young adult male Wistar rats. The repair was studied in normal and affected animals (exercises, immobilization, isolation of periost) at 1-42 days after operation. RESULTS: The posttraumatic bone callus development and the related soft tissue repair, likewise the continuous remodelling, is an ordinary process of osteohisto- and organogenese. In trained rats the blood supply and bone formation is increased, whereas in immobilized animals it is inhibited and destroyed (osteoporose, pseudoarthrosis). After the injury some characteristics of bone repair histogenese will be became evident (after the perforation the primary endosteal and secondary periosteal ossification, inhibition of endosteal bone repair after the isolation of periost etc.). CONCLUSION: The posttraumatic bone healing, like embryohistogenese, has similar repair stages in all models of the experiments as well as similar tissue and cell responses (callus formation, its replacement, bone remodelling, etc.). However, the repair process in general (order of chondrous and/or bone callus stages, etc.) is variable and dependent on the mode and degree of injury. The use of bone cortex perforation in wound healing study is more recommendable as compared to internal fracture and excision (possibility of in situ study the periost and callus tissue compartments in bone repair machinery separately).