Abstract
Recent clinical data on vancomycin pharmacokinetics and pharmacodynamics suggest a reevaluation of current dosing and monitoring recommendations. The previous 2009 vancomycin consensus ...guidelines recommend trough monitoring as a surrogate marker for the target area under the curve over 24 hours to minimum inhibitory concentration (AUC/MIC). However, recent data suggest that trough monitoring is associated with higher nephrotoxicity. This document is an executive summary of the new vancomycin consensus guidelines for vancomycin dosing and monitoring. It was developed by the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the Society of Infectious Diseases Pharmacists vancomycin consensus guidelines committee. These consensus guidelines recommend an AUC/MIC ratio of 400–600 mg*hour/L (assuming a broth microdilution MIC of 1 mg/L) to achieve clinical efficacy and ensure safety for patients being treated for serious methicillin-resistant Staphylococcus aureus infections.
Memory B cells are found in lymphoid and non-lymphoid tissues, suggesting that some may be tissue-resident cells. Here we show that pulmonary influenza infection elicited lung-resident memory B cells ...(BRM cells) that were phenotypically and functionally distinct from their systemic counterparts. BRM cells were established in the lung early after infection, in part because their placement required local antigen encounter. Lung BRM cells, but not systemic memory B cells, contributed to early plasmablast responses following challenge infection. Following secondary infection, antigen-specific BRM cells differentiated in situ, whereas antigen-non-specific BRM cells were maintained as memory cells. These data demonstrate that BRM cells are an important component of immunity to respiratory viruses such as influenza virus and suggest that vaccines designed to elicit BRM cells must deliver antigen to the lungs.
Interleukin 2 (IL-2) promotes Foxp3
regulatory T (T
) cell responses, but inhibits T follicular helper (T
) cell development. However, it is not clear how IL-2 affects T follicular regulatory (T
) ...cells, a cell type with properties of both T
and T
cells. Using an influenza infection model, we found that high IL-2 concentrations at the peak of the infection prevented T
cell development by a Blimp-1-dependent mechanism. However, once the immune response resolved, some T
cells downregulated CD25, upregulated Bcl-6 and differentiated into T
cells, which then migrated into the B cell follicles to prevent the expansion of self-reactive B cell clones. Thus, unlike its effects on conventional T
cells, IL-2 inhibits T
cell responses.
The Infectious Diseases Society of America (IDSA) continues to view with concern the lean pipeline for novel therapeutics to treat drug-resistant infections, especially those caused by gram-negative ...pathogens. Infections now occur that are resistant to all current antibacterial options. Although the IDSA is encouraged by the prospect of success for some agents currently in preclinical development, there is an urgent, immediate need for new agents with activity against these panresistant organisms. There is no evidence that this need will be met in the foreseeable future. Furthermore, we remain concerned that the infrastructure for discovering and developing new antibacterials continues to stagnate, thereby risking the future pipeline of antibacterial drugs. The IDSA proposed solutions in its 2004 policy report, “Bad Bugs, No Drugs: As Antibiotic R&D Stagnates, a Public Health Crisis Brews”, and recently issued a “Call to Action” to provide an update on the scope of the problem and the proposed solutions. A primary objective of these periodic reports is to encourage a community and legislative response to establish greater financial parity between the antimicrobial development and the development of other drugs. Although recent actions of the Food and Drug Administration and the 110th US Congress present a glimmer of hope, significant uncertainly remains. Now, more than ever, it is essential to create a robust and sustainable antibacterial research and development infrastructure—one that can respond to current antibacterial resistance now and anticipate evolving resistance. This challenge requires that industry, academia, the National Institutes of Health, the Food and Drug Administration, the Centers for Disease Control and Prevention, the US Department of Defense, and the new Biomedical Advanced Research and Development Authority at the Department of Health and Human Services work productively together. This report provides an update on potentially effective antibacterial drugs in the late-stage development pipeline, in the hope of encouraging such collaborative action.
The selection of the right antibiotic and right dose necessitates clinicians understand the contribution of pharmacokinetic variability stemming from age‐related physiologic maturation and the ...pharmacodynamics to optimize drug exposure for clinical response. The complexity of selecting the right dose arises from the multiplicity of pediatric age groups, from premature neonates to adolescents. Body size and age (which relate to organ function) must be incorporated to optimize antibiotic dosing in this vulnerable population. In the effort to optimize and individualize drug dosing regimens, clinical pharmacometrics that incorporate population‐based pharmacokinetic modeling, Bayesian estimation, and Monte Carlo simulations are utilized as a quantitative approach to understanding and predicting the pharmacology and clinical and microbiologic efficacy of antibiotics. In addition, opportunistic study designs and alternative blood sampling strategies can serve as practical approaches to ensure successful conduct of pediatric studies. This review article examines relevant literature on optimization of antibiotic pharmacotherapy in pediatric populations published within the last decade. Specific pediatric antibiotic data, including beta‐lactam antibiotics, aminoglycosides, and vancomycin, are critically evaluated.
Osteoarticular Infections in Children Arnold, John C; Bradley, John S
Infectious disease clinics of North America,
09/2015, Letnik:
29, Številka:
3
Journal Article
Recenzirano
For a child with a suspected bone or joint infection, knowledge of the workup and initial therapy is important to provide quality care. Fever and pain are hallmarks of a pediatric osteoarticular ...infection, although occasionally the signs and symptoms can be more subtle. The use of C-reactive protein to diagnose and validate effective management of treatment has become standard. Multiple reports confirm the success of much shorter intravenous (IV) courses than traditionally taught. The ideal IV and oral antibiotic duration, as well as defining the markers indicating need for surgical intervention, are questions yet to be answered.
Tofacitinib (CP-690,550) is a novel oral Janus kinase inhibitor that is being investigated as a targeted immunomodulator and disease-modifying therapy for rheumatoid arthritis.
In this phase 3, ...double-blind, placebo-controlled, parallel-group, 6-month study, 611 patients were randomly assigned, in a 4:4:1:1 ratio, to 5 mg of tofacitinib twice daily, 10 mg of tofacitinib twice daily, placebo for 3 months followed by 5 mg of tofacitinib twice daily, or placebo for 3 months followed by 10 mg of tofacitinib twice daily. The primary end points, assessed at month 3, were the percentage of patients with at least a 20% improvement in the American College of Rheumatology scale (ACR 20), the change from baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) scores (which range from 0 to 3, with higher scores indicating greater disability), and the percentage of patients with a Disease Activity Score for 28-joint counts based on the erythrocyte sedimentation rate (DAS28-4ESR) of less than 2.6 (with scores ranging from 0 to 9.4 and higher scores indicating more disease activity).
At month 3, a higher percentage of patients in the tofacitinib groups than in the placebo groups met the criteria for an ACR 20 response (59.8% in the 5-mg tofacitinib group and 65.7% in the 10-mg tofacitinib group vs. 26.7% in the combined placebo groups, P<0.001 for both comparisons). The reductions from baseline in HAQ-DI scores were greater in the 5-mg and 10-mg tofacitinib groups than in the placebo groups (-0.50 and -0.57 points, respectively, vs. -0.19 points; P<0.001). The percentage of patients with a DAS28-4(ESR) of less than 2.6 was not significantly higher with tofacitinib than with placebo (5.6% and 8.7% in the 5-mg and 10-mg tofacitinib groups, respectively, and 4.4% with placebo; P=0.62 and P=0.10 for the two comparisons). Serious infections developed in six patients who were receiving tofacitinib. Common adverse events were headache and upper respiratory tract infection. Tofacitinib treatment was associated with elevations in low-density lipoprotein cholesterol levels and reductions in neutrophil counts.
In patients with active rheumatoid arthritis, tofacitinib monotherapy was associated with reductions in signs and symptoms of rheumatoid arthritis and improvement in physical function. (Funded by Pfizer; ORAL Solo ClinicalTrials.gov number, NCT00814307.).
Understanding the genecology of forest trees is critical for gene conservation, for predicting the effects of climate change and climate change adaptation, and for successful reforestation. Although ...common genecological patterns have emerged, species-specific details are also important. Which species are most vulnerable to climate change? Which are the most important adaptive traits and environmental drivers of natural selection? Even though species have been classified as adaptive specialists vs. adaptive generalists, large-scale studies comparing different species in the same experiment are rare. We studied the genecology of Norway spruce (Picea abies) and silver fir (Abies alba), two co-occurring but ecologically distinct European conifers in Central Europe. For each species, we collected seed from more than 90 populations across Switzerland, established a seedling common-garden test, and developed genecological models that associate population variation in seedling growth and phenology to climate, soil properties, and site water balance. Population differentiation and associations between seedling traits and environmental variables were much stronger for Norway spruce than for silver fir, and stronger for seedling height growth than for bud phenology. In Norway spruce, height growth and second flushing were strongly associated with temperature and elevation, with seedlings from the lowlands being taller and more prone to second flush than seedlings from the Alps. In silver fir, height growth was more weakly associated with temperature and elevation, but also associated with water availability. Soil characteristics explained little population variation in both species. We conclude that Norway spruce has become an adaptive specialist because trade-offs between rapid juvenile growth and frost avoidance have subjected it to strong diversifying natural selection based on temperature. In contrast, because silver fir has a more conservative growth habit, it has evolved to become an adaptive generalist. This study demonstrates that co-occurring tree species can develop very different adaptive strategies under identical environmental conditions, and suggests that Norway spruce might be more vulnerable to future maladaptation due to rapid climate change than silver fir.
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