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Optimizing Pharmacodynamic Target Attainment Using the MYSTIC Antibiogram: Data Collected in North America in 2002. Joseph L. Kuti, 2004.The OPTAMA Program is intended to examine typical antimicrobial regimens used in the treatment of common nosocomial pathogens and the likelihood of these regimens attaining appropriate pharmacodynamic exposure in different parts of the world . A 5,000-subject Monte Carlo simulation was used to estimate pharmacodynamic target attainment for meropenem, imipenem, ceftazidime, cefepime, piperacillin-tazobactam, and ciprofloxacin against Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa . Standard dosing regimens from North America were used . Pharmacokinetic parameter variability was derived from existing healthy volunteer data, and MIC data came from the 2002 MYSTIC Program . Ciprofloxacin displayed the lowest target attainment against all bacterial species (41 to 46% for A . baumannii, 53 to 59% for P . aeruginosa, and 80 to 85% for the Enterobacteriaceae) . Increasing the dose to 400 mg every 8 h did not significantly increase target attainment against nonfermenters . Piperacillin-tazobactam target attainments were similar to that of ceftazidime against all pathogens . Higher doses of both compounds were needed to achieve better target attainments against P . aeruginosa . Overall, meropenem, imipenem, and cefepime attained the highest probabilities of attainment against the Enterobacteriaceae (99 to 100%) . The carbapenems appear to be the most useful agents against A . baumannii (88 to 92%), and these agents, along with higher doses of any of the ß-lactams, would be the most appropriate choices for empirical therapy for P . aeruginosa infection . Given the lack of agreement between percent susceptibility and probability of target attainment for certain antimicrobial regimens, a methodology employing stochastic pharmacodynamic analyses may be a more useful tool for differentiating the most-optimal compounds and dosing regimens in the clinical setting of initial empirical therapy . Caulobacter crescentus Synthesizes an S-Layer-Editing Metalloprotease Possessing a Domain Sharing Sequence Similarity with Its Paracrystalline S-Layer Protein. Elizabeth Umelo-Njaka, 2002.Strains of Caulobacter crescentus elaborate an S-layer, a two-dimensional protein latticework which covers the cell surface . The S-layer protein (RsaA) is secreted by a type I mechanism (relying on a C-terminal signal) and is unusual among type I secreted proteins because high levels of protein are produced continuously . In efforts to adapt the S-layer for display of foreign peptides and proteins, we noted a proteolytic activity that affected S-layer monomers with foreign inserts . The cleavage was precise, resulting in fragments with an unambiguous N-terminal sequence . We developed an assay to screen for loss of this activity (i.e., presentation of foreign peptides without degradation), using transposon and traditional mutagenesis . A metalloprotease gene designated sap (S-layer-associated protease) was identified which could complement the protease-negative mutants . The N-terminal half of Sap possessed significant similarity to other type I secreted proteases (e.g., alkaline protease of Pseudomonas aeruginosa), including the characteristic RTX repeat sequences, but the C-terminal half which normally includes the type I secretion signal exhibited no such similarity . Instead, there was a region of significant similarity to the N-terminal region of RsaA . We hypothesize that Sap evolved by combining the catalytic portion of a type I secreted protease with an S-layer-like protein, perhaps to associate with nascent S-layer monomers to "scan" for modifications . Effect of Signal Compounds and Incubation Conditions on the Culturability of Freshwater Bacterioplankton. Alke Bruns, 2003.The effect of signal compounds and of different incubation conditions on the culturability (i.e., the fraction of all cells capable of growth) of natural bacterioplankton from the eutrophic lake Zwischenahner Meer was investigated over a period of 20 months . Numbers of growing cells were determined by the most-probable-number technique in liquid media containing low concentrations (10 µM) of the signal compounds N-(oxohexanoyl)-DL-homoserine lactone, N-(butyryl)-DL-homoserine lactone, cyclic AMP (cAMP), or ATP . cAMP was the most effective signal compound, leading to significantly increased cultivation efficiencies of up to 10% of the total bacterial counts . Microautoradiography with [2,8-3H]cAMP, combined with fluorescence in situ hybridization, demonstrated that cAMP was taken up by 18% of all cells . The bacterial cAMP uptake systems had a very low Km value of  1 nM . Analysis of the cultured bacteria by 16S rRNA gene fingerprinting showed that different bacterial phylotypes were recovered in the presence and in the absence of cAMP . Consequently, the addition of cAMP caused a stimulation of otherwise nonculturable bacteria . Phylogenetically different bacteria were also recovered at different temperatures and oxygen partial pressures . Throughout the study period, mainly members of the ß-subclass of the Proteobacteria were cultivated . In addition, some members of the Actinomycetales were enriched . Quantification by culture-independent fluorescence in situ hybridization demonstrated that ß-Proteobacteria and Actinomycetales also dominated the natural bacterioplankton assemblage . Sequence comparison revealed that two members of the Actinomycetales which reached high numbers in the natural bacterioplankton assemblage could actually be enriched by our cultivation approach .
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