Pushing the limits of in vivo diffusion MRI for the Human Connectome Project.

Perhaps more than any other "-omics" endeavor, the accuracy and level of detail obtained from mapping the major connection pathways in the living human brain with diffusion MRI depend on the capabilities of the imaging technology used. The current tools are remarkable; allowing the formation of an "image" of the water diffusion probability distribution in regions of complex crossing fibers at each of half a million voxels in the brain. Nonetheless our ability to map the connection pathways is limited by the image sensitivity and resolution, and also the contrast and resolution in encoding of the diffusion probability distribution. The goal of our Human Connectome Project (HCP) is to address these limiting factors by re-engineering the scanner from the ground up to optimize the high b-value, high angular resolution diffusion imaging needed for sensitive and accurate mapping of the brain's structural connections. Our efforts were directed based on the relative contributions of each scanner component. The gradient subsection was a major focus since gradient amplitude is central to determining the diffusion contrast, the amount of T2 signal loss, and the blurring of the water PDF over the course of the diffusion time. By implementing a novel 4-port drive geometry and optimizing size and linearity for the brain, we demonstrate a whole-body sized scanner with G(max) = 300 mT/m on each axis capable of the sustained duty cycle needed for diffusion imaging. The system is capable of slewing the gradient at a rate of 200 T/m/s as needed for the EPI image encoding. In order to enhance the efficiency of the diffusion sequence we implemented a FOV shifting approach to Simultaneous MultiSlice (SMS) EPI capable of unaliasing 3 slices excited simultaneously with a modest g-factor penalty allowing us to diffusion encode whole brain volumes with low TR and TE. Finally we combine the multi-slice approach with a compressive sampling reconstruction to sufficiently undersample q-space to achieve a DSI scan in less than 5 min. To augment this accelerated imaging approach we developed a 64-channel, tight-fitting brain array coil and show its performance benefit compared to a commercial 32-channel coil at all locations in the brain for these accelerated acquisitions. The technical challenges of developing the over-all system are discussed as well as results from SNR comparisons, ODF metrics and fiber tracking comparisons. The ultra-high gradients yielded substantial and immediate gains in the sensitivity through reduction of TE and improved signal detection and increased efficiency of the DSI or HARDI acquisition, accuracy and resolution of diffusion tractography, as defined by identification of known structure and fiber crossing.

[Imipenem resistance in Pseudomonas aeruginosa]. / Imipenem-Resistenz bei Pseudomonas aeruginosa.

In 1997 in western Austria, 9.9% of Pseudomonas aeruginosa strains from patients of general practitioners were resistant to imipenem as well as 18.2% of the isolates from hospitals and 20.2% of the strains at a university teaching hospital. Within the hospital the imipenem resistance varied from 9.9% among out-patients to 28.7% in isolates from intensive care units. In medical/surgical words, up to 15.1% of P. aeruginosa strains were resistant to imipenem. The incidence of imipenem-resistant P. aeruginosa strains correlates to the use of carbapenems. In June 1997, 10 consecutive isolates from 8 patients were obtained and typed using restriction fragment length polymorphism analysis (RFLP) and Pyocin typing. All 10 isolates were resistant to meropenem as well as to imipenem. The finding (by RFLP and Pyocin typing) of individual bacterial types in each isolate strongly contradicts the spread of infection by cross infection. However, all patients were proven to have been treated with imipenem during the 3 months prior to testing. In 1997, 13,880 g of imipenem were used at the university hospital in Innsbruck. The use of carbapenems appears to be the main cause for the increased incidence of imipenem-resistant P. aeruginosa strains.

Comparative pharmacodynamics of clarithromycin and azithromycin against respiratory pathogens.

The differences between the antibacterial activities of new macrolides such as clarithromycin (CLA) and azithromycin (AZI) against common respiratory tract pathogens are only minor. However, CLA and AZI constitute macrolides with extremely different pharmacokinetic profiles. This constellation presents an opportunity to evaluate the effect of the pharmacokinetic profile on antibacterial kinetics comparatively. In a pharmacodynamic model simulating the dynamics of serum concentrations in bacterial cultures, both CLA and AZI demonstrate bactericidal activity at concentrations reached in human blood at recommended dosages (CLA 250 mg b.i.d., AZI 500 mg o.i.d.). Bactericidal activity of CLA against the variety of pathogens included is superior to that of AZI in the rate and the extent of killing in this model. These results are considered to correlate with the antibacterial effect of macrolides in vivo in cases where pathogens enter the blood stream. Furthermore, mutants with susceptibility reduced between 8 and 16 times in relation to the initial strain of all strains having an initial minimal inhibitory concentration (MIC) < or = 0.25 mg/l, are selected during exposure to AZI, but not to CLA. The pharmacokinetic profiles of CLA and AZI thus strongly influence their antibacterial effect in the pharmacodynamic model, allowing both higher bactericidal activity and greater reduction of the risk of selection of resistant mutants with CLA than with AZI. As a whole, the pharmacodynamics of these macrolides are determined more by the proportion of the MICs to the maximum serum concentration than by the relation of the MICs to the area under the curve.

Spread of Klebsiella pneumoniae producing SHV-5 beta-lactamase among hospitalized patients.

The first outbreak of infections caused by an SHV-5 producing strain of Klebsiella pneumoniae is reported. Within a period of 1 year and 9 months, multiresistant K. pneumoniae strains caused severe infections, mostly of the lower respiratory tract, in 22 patients. The strains were resistant to penicillins, third-generation cephalosporins, aztreonam, chloramphenicol, tetracycline and co-trimoxazole. The resistance determinants were transferable to Escherichia coli. All isolates produced a beta-lactamase with a pI of 8.2. Ceftazidime was hydrolyzed at this band. These characteristics, together with the resistance phenotype, are identical to those of a reference strain producing the beta-lactamase SHV-5. The K. pneumoniae strains of all patients were identical in their capsular serotype (K1), plasmid pattern and plasmid fingerprint after digestion with Dra I restriction endonuclease. We conclude that this outbreak was caused by the spread of one clone of K. pneumoniae producing SHV-5 beta-lactamase among patients of different wards. Our results indicate a real risk for failure of therapy by third-generation cephalosporins in intensive care patients due to SHV-5 producing pathogens.

RU 29 246, the active compound of the cephalosporin-prodrug-ester HR 916. I. Antibacterial activity in vitro.

The aminothiazolyl-cephalosporin RU 29 246 is the active metabolite of the prodrug-pivaloyl-oxyethyl-ester HR 916. RU 29 246 in vitro activity includes a wide range of clinically relevant bacterial pathogens. Against methicillin-sensitive Staphylococci RU 29 246 (MIC90 of 0.25 approximately 2 micrograms/ml) was clearly more active than cefaclor, cefuroxime, cefpodoxime, cefixime and ceftibuten, but slightly less active than cefdinir. RU 29 246 inhibited hemolytic Streptococci of the serogroups A, B, C and G as well as penicillin-sensitive Streptococcus pneumoniae at concentrations similar to cefdinir, cefpodoxime and cefuroxime (MIC90 less than or equal to 0.13 micrograms/ml), but less than the other oral cephalosporins investigated (cefixime, cefaclor and ceftibuten). MIC90s of RU 29 246 against Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, Salmonella spp., Shigella spp., Proteus mirabilis and Haemophilus influenzae were less than or equal to 0.5 micrograms/ml. Only RU 29 246 and cefdinir demonstrated moderate activity against Acinetobacter baumannii (MIC90 greater than or equal to 4 micrograms/ml). Most strains of Pseudomonas spp., Serratia marcescens, Enterobacter spp., Hafnia alvei and Bacteroides spp. were resistant to RU 29 246. RU 29 246 killed Escherichia coli and Staphylococcus aureus at a rate of 99% to 99.9% at concentrations of two times MIC. The pH value of the medium (range 5.5 to 8.5) and the inoculum size (range 10(5) to 10(7) cfu/ml) had no or only low influence on the antibacterial activity of RU 29 246. RU 29 246 is a broad spectrum cephalosporin including in its activity both Gram-positive and Gram-negative pathogens and therefore--depending on the bioavailability of its prodrug--looks promising as to its therapeutic perspective.

In vitro activity and stability against novel beta-lactamases of investigational beta-lactams (cefepime, cefpirome, flomoxef, SCE2787 and piperacillin plus tazobactam) in comparison with established compounds (cefotaxime, latamoxef and piperacillin).

The therapeutic perspectives of flomoxef, SCE 2787, cefpirome, cefepime, latamoxef, cefotaxime and of piperacillin plus tazobactam were comparatively evaluated by their in vitro activity against 1119 clinical isolates of 83 bacterial species. Escherichia coli, Klebsiella spp. Enterobacter sakazakii, Proteus spp. and Shigella spp. were about equally susceptible to the cephalosporins (MIC90: 0.06 to 0.5 mg/l), while the MIC90 for piperacillin plus tazobactam was between 2 and 16 mg/l. Enterobacter cloacae, Enterobacter aerogenes and Serratia spp. were most susceptible to SCE 2787, cefpirome and cefepime (MIC90: 0.06 to 2 mg/l) followed by latamoxef, cefotaxime, flomoxef and piperacillin plus tazobactam. For Citrobacter spp., Providencia spp. and Yersinia enterocolitica MIC90 were between 0.06 and 0.5 mg/l. Flomoxef was between 2 to 4 log2 less active against these species but more active than piperacillin plus tazobactam (MIC90: 2 and 8 mg/l). Morganella morganii and Hafnia alvei were most susceptible to cefepime, cefpirome and latamoxef (MIC90: 0.13 to 0.5 mg/l) while cefotaxime (MIC90: 8 mg/l) and piperacillin plus tazobactam (MIC90: 8 and greater than 64 mg/l) were the least active compounds. SCE 2787, cefepime and cefpirome were the most potent beta-lactams against the majority of the 13 species of non-fermentative bacilli (NFB) investigated (MIC90: 0.5 to 16 mg/l). The oxacephems were the least active compounds against NFB. Cefepime was the most active of the compounds included against Pseudomonas aeruginosa (MIC90: 16 mg/l). Haemophilus spp., Neisseria gonorrhoeae and Bordetella pertussis were most susceptible to cefotaxime (MIC90: 0.03 to 0.06 mg/l). Latamoxef had the lowest activity of all compounds against gram-positive cocci. Flomoxef was the most active compound against penicillinase producing Staphylococcus aureus and about equally active as the other betalactams against methicillin susceptible staphylococci of other staphylococcal species.(ABSTRACT TRUNCATED AT 250 WORDS)

Bactericidal kinetics of various dosages of fleroxacin simulated in bacterial cultures.

From in-vitro data, recommendations for dosing with fleroxacin are presented. Serum pharmacokinetics of 250, 400, 500, 800, 1000 and 1500 mg once daily dosages were simulated in bacterial cultures. The bactericidal kinetics of clinical isolates of Escherichia coli, Pseudomonas aeruginosa and Staphylococcus aureus with MICs for fleroxacin similar to MIC90 or above were investigated. Bacterial populations of all strains with MICs equal to or below 2 mg/l were reduced by at least 99% by a once daily dosage of 400 mg of fleroxacin. 500 mg once per day was high enough to induce a two log reduction of P. aeruginosa MIC 4 mg/l. At a 250 mg dosing mutants with MICs four times above the MICs of the initial strains were selected. The increased concentrations of fleroxacin after multiple dosing enhanced bactericidal activity. Once daily dosing increased the initial rate of killing but reduced the extent of inactivation in comparison with twice daily dosing of the same total amount. From our in-vitro investigation a once daily dosage of 400 mg of fleroxacin should be effective against causative organisms with an MIC of up to 2 mg/l, both in the rate and extent of killing and to minimize the risk for selection of resistant mutants.