Clinical management of severe infections caused by carbapenem-resistant Gram-negative bacteria: a worldwide cross-sectional survey addressing the use of antibiotic combinations.

OBJECTIVES: Optimal treatment of carbapenem-resistant Gram-negative (CR-GNB) infections is uncertain due to the lack of good-quality evidence and the limited effectiveness of available antibiotics. The aim of this survey was to investigate clinicians' prescribing strategies for treating CR-GNB infections worldwide. METHODS: A 36-items-questionnaire was developed addressing the following aspects of antibiotic prescribing: respondent's background, diagnostic and therapeutic availability, preferred antibiotic strategies and rationale for selecting combination therapy. Prescribers were recruited following the snowball-sampling approach, and a post-stratification correction with inverse proportional weights was used to adjust the sample's representativeness. RESULTS: 1012 respondents from 95 countries participated in the survey. Overall, 298 (30%) of respondents had local guidelines for treating CR-GNB at their facility and 702 (71%) had access to Infectious Diseases consultation, with significant discrepancies according to country economic status: 85% (390/502) in High-Income-Countries vs 59% (194/283) in Upper-Medium-Income-Countries and 30% (118/196) in Lower-Middle-Income-Countries/Lower-Income-Countries). Targeted regimens varied widely, ranging from 40 regimens for CR-Acinetobacter spp. to more than 100 regimens for CR-Enterobacteriaceae. Although the majority of respondents acknowledged the lack of evidence behind this choice, dual combination was the preferred treatment scheme and carbapenem-polymyxin was the most prescribed regimen, irrespective of pathogen and infection source. Respondents noticeably disagreed around the meaning of 'combination therapy' with 20% (150/783) indicating the simple addition of multiple compounds, 42% (321/783) requiring the presence of in vitro activity and 38% (290/783) of in vitro-synergism. CONCLUSIONS: Management of CR-GNB infections is far from being standardized. Strategic public health focussed randomised controlled trials are urgently required to inform evidence-based treatment guidelines

Real-Time Imaging Reveals the Dynamics of Leukocyte Behaviour during Experimental Cerebral Malaria Pathogenesis

During experimental cerebral malaria (ECM) mice develop a lethal neuropathological syndrome associated with microcirculatory dysfunction and intravascular leukocyte sequestration. The precise spatio-temporal context in which the intravascular immune response unfolds is incompletely understood. We developed a 2-photon intravital microscopy (2P-IVM)-based brain-imaging model to monitor the real-time behaviour of leukocytes directly within the brain vasculature during ECM. Ly6Chi monocytes, but not neutrophils, started to accumulate in the blood vessels of Plasmodium berghei ANKA (PbA)-infected MacGreen mice, in which myeloid cells express GFP, one to two days prior to the onset of the neurological signs (NS). A decrease in the rolling speed of monocytes, a measure of endothelial cell activation, was associated with progressive worsening of clinical symptoms. Adoptive transfer experiments with defined immune cell subsets in recombinase activating gene (RAG)-1-deficient mice showed that these changes were mediated by Plasmodium-specific CD8+ T lymphocytes. A critical number of CD8+ T effectors was required to induce disease and monocyte adherence to the vasculature. Depletion of monocytes at the onset of disease symptoms resulted in decreased lymphocyte accumulation, suggesting reciprocal effects of monocytes and T cells on their recruitment within the brain. Together, our studies define the real-time kinetics of leukocyte behaviour in the central nervous system during ECM, and reveal a significant role for Plasmodium-specific CD8+ T lymphocytes in regulating vascular pathology in this disease. © 2014 Pai et al

Incidence of primary open angle glaucoma in the Andhra Pradesh Eye Disease Study (APEDS)

Background: To report 15-year incidence rate of primary open angle glaucoma (POAG) in the Andhra Pradesh Eye Disease Study (APEDS). Methods: A population-based longitudinal study was carried out at three rural study sites. Phakic participants aged ≥40 years who participated at baseline (APEDS I) and the mean 15-year follow-up visit (APEDS III) were included. A comprehensive ophthalmic examination was performed on all participants. Mean intraocular pressure (IOP) was average of IOPs of right and left eyes. The definition of glaucoma was based on the International Society of Geographical and Epidemiological Ophthalmology (ISGEO) classification. The main outcome measure was incidence of POAG during the follow-up period in participants without glaucoma or suspicion of glaucoma at baseline. Results: Data from the available and eligible participants from the original cohort (1241/2790; 44.4%) were analysed. The mean age (standard deviation) of participants at baseline was 50.2 (8.1) years; 580 (46.7%) were men. Thirty-six participants developed POAG [bilateral in 17 (47.2%)] over 15 years. The incidence rate of POAG per 100-person years (95% confidence interval) was 2.83 (2.6, 3.08). Compared to baseline, the reduction in mean IOP [median (range) mm Hg] was −0.75 (−7.5, 9) in participants with incident POAG and −2.5 (−14.5, 14.5) in those without. The inter-visit difference in mean IOP was a significant risk factor on logistic regression analysis. Conclusion: We report the long-term incidence of POAG in rural India. A longitudinal change in IOP, specifically a less pronounced reduction in IOP with increasing age, was a novel risk factor