Optimizing antibiotic therapy-the Aberdeen experience

ObjectiveTo study the quality and continuity of treatment in the Acute Medicines Assessment Unit (AMAU) with regard to empirical prescription of antibiotics, mode of administration, adherence to ward antibiotic policy, as well as collection, awareness and utilization of microbiological investigations.MethodsA prospective study over a 3-month period at the AMAU, Aberdeen Royal Infirmary (ARI), a teaching hospital in north-eastern Scotland, was performed. The study included all patients started on empirical antibiotics on admission to the AMAU and followed up until their discharge.ResultsOf 1303 patients admitted, 221 (17%) were started on empirical antibiotics. This was in accordance with hospital antibiotic policy in 52% of cases. Appropriate specimens were taken from 77% of patients. Culture results showed that 29% (n = 65) of the patients had clinically significant growth of organisms. Of the 65 patients with clinically significant culture results, 49% (n = 32) were on an inappropriate empirical regimen. In 55%, the medication was not changed to a more appropriate antibiotic. In 72% of the patients with a negative culture, the culture report had no obvious effect on the duration or type of antibiotic being administered. Intravenous antibiotics were used in 60% of patients.ConclusionThis study demonstrates a significant overuse of antibiotics, especially intravenous forms, despite a paucity of positive sepsis parameters and chest X-ray findings in these patients The duration of treatment could be shortened and an early switch policy introduced if culture results and sepsis profiles were taken into consideration, as there was a large number of unproven infections. Suggestions are made about how these improvements in prescribing could be made within the current administrative set-up of AMAUs

Singlet fission in a hexacene dimer: energetics dictate dynamics

Singlet fission (SF) is an exciton multiplication process with the potential to raise the efficiency limit of single junction solar cells from 33% to up to 45%. Most chromophores generally undergo SF as solid-state crystals. However, when such molecules are covalently coupled, the dimers can be used as model systems to study fundamental photophysical dynamics where a singlet exciton splits into two triplet excitons within individual molecules. Here we report the synthesis and photophysical characterization of singlet fission of a hexacene dimer. Comparing the hexacene dimer to analogous tetracene and pentacene dimers reveals that excess exoergicity slows down singlet fission, similar to what is observed in molecular crystals. Conversely, the lower triplet energy of hexacene results in an increase in the rate of triplet pair recombination, following the energy gap law for radiationless transitions. These results point to design rules for singlet fission chromophores: the energy gap between singlet and triplet pair should be minimal, and the gap between triplet pair and ground state should be large

Comparison of two dengue NS1 rapid tests for sensitivity, specificity and relationship to viraemia and antibody responses

<p>Abstract</p> <p>Background</p> <p>Dengue is a major public health problem in tropical and subtropical countries. Rapid and easy diagnosis of dengue can assist patient triage and care-management. The detection of DENV NS1 on rapid lateral flow tests offers a fast route to a presumptive dengue diagnosis but careful evaluations are urgently needed as more and more people use them.</p> <p>Methods</p> <p>The sensitivity and specificity of the Bio-Rad NS1 Ag Strip and SD Dengue Duo (NS1/IgM/IgG) lateral flow rapid tests were evaluated in a panel of plasma samples from 245 Vietnamese patients with RT-PCR confirmed dengue and 47 with other febrile illnesses.</p> <p>Results</p> <p>The NS1 rapid tests had similar diagnostic sensitivities (respectively 61.6% and 62.4%) in confirmed dengue cases but were 100% specific. When IgM/IgG results from the SD Dengue Duo were included in the test interpretation, the sensitivity improved significantly from 62.4% with NS1 alone to 75.5% when NS1 and/or IgM was positive and 83.7% when NS1 and/or IgM and/or IgG was positive. Both NS1 assays were significantly more sensitive for primary than secondary dengue. NS1 positivity was associated with the underlying viraemia as NS1-positive samples had a significantly higher viraemia than NS1-negative samples.</p> <p>Conclusions</p> <p>These data suggest that the NS1 test component of these assays are highly specific and have similar levels of sensitivity. The IgM parameter in the SD Duo test improved overall test sensitivity without compromising specificity. The SD Dengue Duo lateral flow rapid test deserves further prospective evaluation in dengue endemic settings.</p

Bioactivity of umbelliprenin, the major component found in the seeds of Angelica sylvestris

Se ha evaluado la actividad antibacteriana y antioxidante de la umbelliprenina (1), una cumarina de sesquiterpenil, aislada como el componente principal presente en extractos de n-hexano y diclorometano de semillas de Angelica sylvestris (Apiaceae). También se ha evaluado la toxicidad general de 1 mediante el bioensayo de letalidad de gambas en salmuera (BSL).Umbelliprenin (1), a sesquiterpenyl coumarin, isolated as the major component present in the n-hexane and dichloromethane extracts of the seeds of Angelica sylvestris (Apiaceae), has been assessed for antibacterial and antioxidant activities. General toxicity of 1 has also been evaluated by the brine shrimp lethality (BSL) bioassay

Human neutrophil clearance of bacterial pathogens triggers anti-microbial gamma delta T cell responses in early infection

Human blood Vc9/Vd2 T cells, monocytes and neutrophils share a responsiveness toward inflammatory chemokines and are rapidly recruited to sites of infection. Studying their interaction in vitro and relating these findings to in vivo observations in patients may therefore provide crucial insight into inflammatory events. Our present data demonstrate that Vc9/Vd2 T cells provide potent survival signals resulting in neutrophil activation and the release of the neutrophil chemoattractant CXCL8 (IL-8). In turn, Vc9/Vd2 T cells readily respond to neutrophils harboring phagocytosed bacteria, as evidenced by expression of CD69, interferon (IFN)-c and tumor necrosis factor (TNF)-a. This response is dependent on the ability of these bacteria to produce the microbial metabolite (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMB-PP), requires cell-cell contact of Vc9/Vd2 T cells with accessory monocytes through lymphocyte function-associated antigen-1 (LFA-1), and results in a TNF-a dependent proliferation of Vc9/Vd2 T cells. The antibiotic fosmidomycin, which targets the HMB-PP biosynthesis pathway, not only has a direct antibacterial effect on most HMB-PP producing bacteria but also possesses rapid anti-inflammatory properties by inhibiting cd T cell responses in vitro. Patients with acute peritoneal-dialysis (PD)-associated bacterial peritonitis – characterized by an excessive influx of neutrophils and monocytes into the peritoneal cavity – show a selective activation of local Vc9/Vd2 T cells by HMB-PP producing but not by HMB-PP deficient bacterial pathogens. The cd T celldriven perpetuation of inflammatory responses during acute peritonitis is associated with elevated peritoneal levels of cd T cells and TNF-a and detrimental clinical outcomes in infections caused by HMB-PP positive microorganisms. Taken together, our findings indicate a direct link between invading pathogens, neutrophils, monocytes and microbe-responsive cd T cells in early infection and suggest novel diagnostic and therapeutic approaches.Martin S. Davey, Chan-Yu Lin, Gareth W. Roberts, Sinéad Heuston, Amanda C. Brown, James A. Chess, Mark A. Toleman, Cormac G.M. Gahan, Colin Hill, Tanya Parish, John D. Williams, Simon J. Davies, David W. Johnson, Nicholas Topley, Bernhard Moser and Matthias Eber

Spectroscopic and Mechanistic Studies of Heterodimetallic Forms of Metallo-β-lactamase NDM-1

In an effort to characterize the roles of each metal ion in metallo-β-lactamase NDM-1, heterodimetallic analogues (CoCo-, ZnCo-, and CoCd-) of the enzyme were generated and characterized. UV–vis, 1H NMR, EPR, and EXAFS spectroscopies were used to confirm the fidelity of the metal substitutions, including the presence of a homogeneous, heterodimetallic cluster, with a single-atom bridge. This marks the first preparation of a metallo-β-lactamase selectively substituted with a paramagnetic metal ion, Co(II), either in the Zn1 (CoCd-NDM-1) or in the Zn2 site (ZnCo-NDM-1), as well as both (CoCo-NDM-1). We then used these metal-substituted forms of the enzyme to probe the reaction mechanism, using steady-state and stopped-flow kinetics, stopped-flow fluorescence, and rapid-freeze-quench EPR. Both metal sites show significant effects on the kinetic constants, and both paramagnetic variants (CoCd- and ZnCo-NDM-1) showed significant structural changes on reaction with substrate. These changes are discussed in terms of a minimal kinetic mechanism that incorporates all of the data

Distinct properties of the triplet pair state from singlet fission

Singlet fission, the conversion of a singlet exciton (S1) to two triplets (2 × T1), may increase the solar energy conversion efficiency beyond the Shockley-Queisser limit. This process is believed to involve the correlated triplet pair state 1(TT). Despite extensive research, the nature of the 1(TT) state and its spectroscopic signature remain actively debated. We use an end-connected pentacene dimer (BP0) as a model system and show evidence for a tightly bound 1(TT) state. It is characterized in the near-infrared (IR) region (~1.0 eV) by a distinct excited-state absorption (ESA) spectral feature, which closely resembles that of the S1 state; both show vibronic progressions of the aromatic ring breathing mode. We assign these near-IR spectra to 1(TT)→Sn and S1→Sn′ transitions; Sn and Sn′ likely come from the antisymmetric and symmetric linear combinations, respectively, of the S2 state localized on each pentacene unit in the dimer molecule. The 1(TT)→Sn transition is an indicator of the intertriplet electronic coupling strength, because inserting a phenylene spacer or twisting the dihedral angle between the two pentacene chromophores decreases the intertriplet electronic coupling and diminishes this ESA peak. In addition to spectroscopic signature, the tightly bound 1(TT) state also shows chemical reactivity that is distinctively different from that of an individual T1 state. Using an electron-accepting iron oxide molecular cluster [Fe8O4] linked to the pentacene or pentacene dimer (BP0), we show that electron transfer to the cluster occurs efficiently from an individual T1 in pentacene but not from the tightly bound 1(TT) state. Thus, reducing intertriplet electronic coupling in 1(TT) via molecular design might be necessary for the efficient harvesting of triplets from intramolecular singlet fission

Failure to prescribe pneumocystis prophylaxis is associated with increased mortality, even in the cART era: results from the Treat Asia HIV observational database

<p>Abstract</p> <p>Background</p> <p>Pneumocystis jiroveci pneumonia (PCP) prophylaxis is recommended for patients with CD4 counts of less than 200 cells/mm³. This study examines the proportion of patients in the TREAT Asia HIV Observational Database (TAHOD) receiving PCP prophylaxis, and its effect on PCP and mortality.</p> <p>Methods</p> <p>TAHOD patients with prospective follow up had data extracted for prophylaxis using co-trimoxazole, dapsone or pentamidine. The proportion of patients on prophylaxis was calculated for each calendar year since 2003 among patients with CD4 counts of less than 200 cells/mm³. The effect of prophylaxis on PCP and survival were assessed using random-effect Poisson regression models.</p> <p>Results</p> <p>There were a total of 4050 patients on prospective follow up, and 90% of them were receiving combination antiretroviral therapy. Of those with CD4 counts of less than 200 cells/mm³, 58% to 72% in any given year received PCP prophylaxis, predominantly co-trimoxazole. During follow up, 62 patients developed PCP (0.5 per 100 person-years) and 169 died from all causes (1.36/100 person-years). After stratifying by site and adjusting for age, CD4 count, CDC stage and antiretroviral treatment, those without prophylaxis had no higher risk of PCP, but had a significantly higher risk of death (incident rate ratio 10.8, p < 0.001). PCP prophylaxis had greatest absolute benefit in patients with CD4 counts of less than 50 cells/mm³, lowering mortality rates from 33.5 to 6.3 per 100 person-years.</p> <p>Conclusions</p> <p>Approximately two-thirds of TAHOD patients with CD4 counts of less than 200 cells/mm³received PCP prophylaxis. Patients without prophylaxis had significantly higher mortality, even in the era of combination ART. Although PCP may be under-diagnosed, these data suggest that prophylaxis is associated with important survival benefits.</p

Characterization of an IncFII Plasmid Encoding NDM-1 from Escherichia coli ST131

Background: The current spread of the gene encoding the metallo-ß-lactamase NDM-1 in Enterobacteriaceae is linked to a variety of surrounding genetic structures and plasmid scaffolds. Methodology: The whole sequence of plasmid pGUE-NDM carrying the bla NDM-1 gene was determined by high-density pyrosequencing and a genomic comparative analysis with other blaNDM-1-negative IncFII was performed. Principal Findings: Plasmid pGUE-NDM replicating in Escherichia coli confers resistance to many antibiotic molecules including b-lactams, aminoglycosides, trimethoprim, and sulfonamides. It is 87,022 bp in-size and carries the two b-lactamase genes bla NDM-1 and bla OXA-1, together with three aminoglycoside resistance genes aacA4, aadA2, and aacC2. Comparative analysis of the multidrug resistance locus contained a module encompassing the blaNDM-1 gene that is actually conserved among different structures identified in other enterobacterial isolates. This module was constituted by the blaNDM-1 gene, a fragment of insertion sequence ISAba125 and a bleomycin resistance encoding gene. Significance: This is the first characterized bla NDM-1-carrying IncFII-type plasmid. Such association between the bla NDM-1 gene and an IncFII-type plasmid backbone is extremely worrisome considering that this plasmid type is known to sprea

Characterization of volatile compounds of Daucus crinitus Desf. Headspace Solid Phase Microextraction as alternative technique to Hydrodistillation

<p>Abstract</p> <p>Background</p> <p>Traditionally, the essential oil of aromatic herbs is obtained using hydrodistillation (HD). Because the emitted volatile fraction plays a fundamental role in a plant's life, various novel techniques have been developed for its extraction from plants. Among these, headspace solid phase microextraction (HS-SPME) can be used to obtain a rapid fingerprint of a plant's headspace. <it>Daucus crinitus </it>Desf. is a wild plant that grows along the west coast of Algeria. Only a single study has dealt with the chemical composition of the aerial part oils of Algerian <it>D. crinitus</it>, in which isochavicol isobutyrate (39.0%), octyl acetate (12.3%), and β-caryophyllene (5.4%) were identified. Using GC-RI and GC-MS analysis, the essential oils and the volatiles extracted from separated organs of <it>D. crinitus </it>Desf. were studied using HS-SPME.</p> <p>Results</p> <p>GC-RI and GC-MS analysis identified 72 and 79 components in oils extracted using HD and in the volatile fractions extracted using SPME, respectively. Two types of essential oils were produced by the plant: the root oils had aliphatic compounds as the main component (87.0%-90.1%), and the aerial part oils had phenylpropanoids as the main component (43.1%-88.6%). HS-SPME analysis showed a more precise distribution of compounds in the organs studied: oxygenated aliphatic compounds were well represented in the roots (44.3%-84.0%), hydrocarbon aliphatic compounds were in the leaves and stems (22.2%-87.9%), and phenylpropanoids were in the flowers and umbels (47.9%-64.2%). Moreover, HS-SPME allowed the occurrence of isochavicol (29.6 - 34.7%) as main component in <it>D. crinitus </it>leaves, but it was not detected in the oils, probably because of its solubility in water.</p> <p>Conclusions</p> <p>This study demonstrates that HD and HS-SPME modes could be complimentary extraction techniques in order to obtain the complete characterization of plant volatiles.</p