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Title: Beta-lactam resistance in gram-negative bacteria isolated in India
Author: Nandivada, Lakshmi Sarada
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 1990
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The most important resistance mechanism to beta-lactam antibiotics is the plasmid-mediated beta-lactamase and the common criterion for the epidemiology of these enzymes is the determination of their biochemical characteristics. Surveys of plasmid-encoded beta-lactamases of Gram-negative bacteria, used to investigate their relative clinical importance, have been poorly performed and rarely conducted outside the developed world. A survey of uropathogenic strains and of salmonellae and shigellae, isolated in south India in 1984, revealed a higher incidence of ampicillin resistance (minimum inhibitory concentration [MIC] > 10mg/1) than had ever been reported before (Enterobacteriacea 82%, salmonellae 90%, shigellae 60%). Only the enterobacterial strains showed any significant resistance to the first generation cephalosporin, cephalosporin, cephaloridine (MIC > 10mg/1). However, 66% of the salmonellae strains were cefuroxime resistant. A small proportion of all species conferred resistance to third generation cephalosporins. In the individual species, there was a very high incidence of ampicillin resistance (E. coli 76% Klebsiella spp 96%) and cephaloridine resistance (E.coli 57% Klebsiella spp 69%). Many of the ampicillin resistant strains harboured either auto-transferable or mobilisable plasmids (40%). Characterisation of the plasmid DNA from the E.coli transconjugants revealed the existence of 37 different plasmids types. The transconjugants from klebsiella, salmonella and shigella possessed fewer plasmids types than those from E. coli. Most plasmids possessed resistance genes to aminoglycosides and to six or more drugs. Beta-lactamase studies revealed that TEM-1 was the most predominant enzyme in all transconjugant strains followed by OXA-1, SHV-1, TEM-2, OXA-2 and the novel enzyme SAR-2. The SAR-2 enzyme was fully characterised and had a higher pI (8.3) than any previously characterised plasmid-mediated beta-lactamase. It had a broad-spectrum activity with the molecular weight of 36000. In addition the unusual observations of E.coli strains producing both the PSE-1 and PSE-2 beta-lactamases and strains hyperproducing the TEM-1 were made and these strains were studied further. The development and mechanisms of resistance to beta-lactam/beta-lactamase inhibitor combinations (ampicillin and clavulanic acid) have been performed with laboratory strains possessing the ampicillin resistance plasmid R1. The results show that challenge with clavulanic acid alone did not affect the expression or integrity of the beta-lactamase whereas challenge with the combination of ampicillin and clavulanic acid caused radical changes with the expression of the beta-lactamase. In some cases there were multiple copies of genes which resulted in hyperproduction of TEM-1 enzyme and this was sufficient to resist the combinations. Unfortunately, these variants also conferred resistance to second and third generation cephalosporins. Evidence of this type of resistance to clavulanic acid is now emerging in clinical practice.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available