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This document only includes an excerpt of the corresponding thesis or dissertation. To request a digital scan of the full text, please contact the Ruth Lilly Medical Library's Interlibrary Loan Department (rlmlill@iu.edu).

Thesis (M.S. in chemical engineering)--Washington State University, December 2009. / Title from PDF title page (viewed on Jan. 20, 2010). "Department of Chemical Engineering and Bioengineering." Includes bibliographical references (p. 63-65).

The order of events in the Deacetoxycephalosporin C/Deacetylcephalosporrn C Synthetase (DAOC/DAC Synthetase) catalysed ring expansion of penicillin N to deacetoxycephalosporin C has been investigated by the use of labelled/unlabelled penicillin N mixed competitive kinetic isotope effect experiments, in which the labelled penicillin N substrates were either labelled in the pro <strong>R</strong>- and pro <strong>S</strong>-methyl groups or at C-3. In addition, to assisting in the determination of the position of the first irreversible event in this reaction, deuteration at C-3 gave rise to a bifurcation of the natural biosynthetic pathway which led to enhanced production of the shunt metabolite, (2<strong>R</strong>,3<strong>S</strong>,6<strong>R</strong>,7<strong>R</strong>)-l-aza-3- methyl-3-hydroxy-7-[(5<strong>R</strong>)-5-amino-5-carboxy-pentanamido]-8-oxo-5-thiabicyclo[4.2.0]octane-2-carboxylate. The biosynthetic precursor to the 3<strong>S</strong>-hydroxycepham shunt metabolite has been investigated and the origin of the 3<strong>S</strong>-hydroxyl oxygen atom has been determined by the use of labelling studies with ¹⁸O₂ and shown to be derived from molecular oxygen. ¹³C-labelling studies are described which indicate that the ring expansion process is stereospecific to within the limits of the detection system employed. These experiments confirm earlier investigations but, in addition to improving upon the assessment of the degree of stereospecificity, have shown that the 3<strong>S</strong>- hydroxycepham shunt metabolite is produced with the same stereospecificity as that observed for the usual biosynthetic products, DAOC and DAC. Chapter 5 describes an investigation of the anomalous C-2 deuterium exchange detected in DAOC produced by incubation of di-(²H₃-methyl)-penicillin N with DAOC/DAC synthetase. The preliminary results from this study indicate that initially exchange occurs stereospecifically with the pro <strong>R</strong> C-2 deuterium atom being replaced by a hydrogen atom. The origins of the unusual tripeptides <strong>L</strong>-α-aminoadipyl-<strong>L</strong>-serinyl-<strong>D</strong>-valine (<strong>L</strong>,<strong>L</strong>,<strong>D</strong>-ASV), α-aminoadipyl-serinyl-isodehydrovaline (ASdV) and α-aminoadipyl-cysteinyl- β-hydroxyvaline (AC-[β-OH]-V) isolated from Penicillium chrysogenum and Cephalosporium acremonium, have been examined by the use of variously ¹³C-labelled <strong>L</strong>,<strong>L</strong>,<strong>D</strong>-α-aminoadipyl-cysteinyl-valine (<strong>L</strong>,<strong>L</strong>,<strong>D</strong>-ACV) and <strong>D</strong>,<strong>L</strong>,<strong>D</strong>-α-aminoadipyl- cysteinyl-valine (<strong>D</strong>,<strong>L</strong>,<strong>D</strong>-ACV) tripeptide isotopomers. The initial results obtained from this investigation may be considered as circumstantial evidence that ASdV is formed by the action of IPNS upon <strong>L</strong>,<strong>L</strong>,<strong>D</strong>-ACV. Finally, various substrate analogues have been prepared and evaluated as substrates for the ring expansion and hydroxylation activities of the bifunctional DAOC/DAC synthetase enzyme.

Thesis (Ph.D.)--University of Western Australia, 2003.

Thesis (M.Sc.) - Carleton University, 2002. / Includes bibliographical references (p. 98-101). Also available in electronic format on the Internet.

The in vitro activity of twelve cephalosporins (first generation: Cephalothin, Cefazolin; second generation: Cefoxitin, Cefamandole, Cefuroxime, Cedonicid; third generation: Ceftazidime, Ceftizoxime, Cefotaxime, Cefoperazone, Ceftriaxone, Moxalactam) were studied against 146 strains of Gram negative bacilli belonging to the following families: Enterobacteriaceae Proteus vulgarius (2), P. mirabilis (5), Providencia stuartti (6), P. alkalifaciens (5), Morganella morganii (16), Serratia marcescens (14), Enterobacter cloacae (17), E. aerogenes (9), Kluyvera ascorbata (3), Citrobacter freundii (14), C. diversus (3), C. amalonaticus (1), Yersinia intermedia (1), Y. enterocolitica (2); Pseudomonadaceae: Pseudomonas aeruginosa (31), P. fluorescens (3); Neisseriacaee: Acinetobacter anitratus (3), Acinetobacter lwoffi (1); and Vibrionaceae: Aeromonas hydrophilia (4), Plesiomonas shigelloides (1), Campylobacter jejuni (5)). This investigation, which studied the activity of all the mentioned cephalosporins against each strain, suggests that resistance to the third generation cephalosporins has already emerged in such species as S. marcescens, E. cloacae, E. aerogenes, C. freundii, P. aeruginosa, P. fluorescens, A. anitratus, A. lwoffi, and Campylobacter jejuni. This resistance is most pronounced in Enterobacter spp., Serratia marcescens, and Pseudomonas aeruginosa. The second generation cephalosporins, particularly Cefoxitin and perhaps Cefuroxime, are chief inducers of resistance in Enterobacter and Serratia. In the pseudomonads difference mechanisms seem to operate than those taking place in Enterobacter-Serratia. The study also shows that resistance is not a generic characteristic in Proteus, Providencia, or Citrobacter but rather specific. Some aspects of mechanisms of resistance to cephalosporins are discussed. Concern is here indicated that at least in certain groups of bacteria, the use of the second generation cephalosporins may lead to emergence of resistance to the third generation group.

We report here the first case of severe Immune thrombocytopenia induced by a secondgeneration cephalosporin antibiotic, Loracarbef. A 56-year old white female developed acute severe thrombocytopenia associated with acute respiratory symptoms following administration of Loracarbef. She responded to Loracarbef withdrawal and systemic corticosteroid administration. Loracarbef-dependent platelet-reactive antibodies were demonstrable in her serum by flow cytometry.