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Interest in Staphylococcus aureus as a possible agent of disease in man and animals arose in the last quarter of the nineteenth century. At that time there were conflicting views regarding the aetiological relationship of staphylococci to the pyogenic lesions in which they were observed. The possibility that diffusible extraoellular products of bacteria might be involved in initiation of such lesions was not at first considered until Klebs (1872) postulated a general relationship between pathogenicity and toxin production in bacteria, and De Christmas (1888) demonstrated the toxicity of heated broth cultures of S. aureus. It was unfortunately soon apparent that the brilliant results obtained following bacteriological research on diphtheria and anthrax were not to be readily reproduced in the field of staphylococcal research. Pathogenic bacteria had seemed to fall into one of two groups: the first characterised by invasiveness, and the second by production of a toxin. However, S. aureus was found on occasion to possess attributes of both groups. It is now known that culture filtrates of S. aureus contain a great many toxic and enzymic factors, some of which have been fairly well characterised.

No description available.

The differentiation of strains of Staphylococcus aureus isolated from infections and elsewhere in the environment has been difficult in the past because of the lack of suitable laboratory techniques for testing easily recognised and stable strain characters. This has made the epidemiological study of staphylococcal infections unsatisfactory and the resulting lack of precise knowledge of the sources and routes and modes of spread has interfered with the development of successful preventive methods. More recently the use of techniques such as the coagulate test and bacteriophage and serological typing tests have beer, more successful in defining strains and are being used more and more to study the epidemiology of staphylococcal Infections. In recent years staphylococcal infections have received more attention than in the past, due to an apparent increase in their incidence, especially in hospital, and also because of the ability of Staphylococcus aureus to adapt itself to anti¬ bacterial agents which have been introduced for its control. There is need therefore for a detailed investigation of the sources, routes and modes of spread of staphylococcal infection and the part played by antibiotics in their epidemiology.

Cholera in one of the most important health problems of many areas of Asia. Despite extensive research, workers are still confronted with a number of unsolved problems that stand in the way of control and ultimate eradication of the disease. The immediate problems presented by cholera at this time are related to its treatment and its practical control. The clinical and biochemical abnormalities that occur in the cholera patient can be rapidly and consistently corrected by intravenous administration of fluids approximately equal in volume and electrolyte concentration to the fluids lost via the gastrointestinal route. Although treatment by rehydration is good, specific treatment must wait until we know more regarding the mechanism of pathogenicity in cholera. Alternatively, it may be that phage therapy still is worthy of consideration but this is doubtful. The control of cholera depends on several factors. (i) Improvement of sanitation, provision of safe water, satisfactory disposal of excreta and health education of the public to improve personal hygiene are essentials. (ii) Further investigation of the epidemiology of cholera and cholera like diseases will assist control. This demands more research into cholera phages and genetic mechanisms so that epidemics can be traced and understood. (iii) Finally, active immunization may achieve control of cholera, but we meanwhile require more knowledge of mechanisms of pathogenicity so that good protective antigens may be prepared. The writer has therefore investigated the 2 obviously important aspects of (A) The toxins of cholera; (B) The phage, and genetics related to cholera. These studies are reported in Sections I and II of this thesis respectively.

Although the spread of hepatitis B infection has largely been controlled through the use of sophisticated serological tests for the detection of hepatitis B surface antigen there is still comparatively little basic inf creation available on the protein, lipid and carbohydrate composition of these particles, and on the arrangement of these components into a stable quaternary structure. In the present work three separate approaches have been made to extending this information. 1. Polypeptide analysis of purified HB_Ag particles by column 0 chromatography and discontinuous or continuous polyacrylamide gel electrophoresis (PAGE) produced discrepant polypeptide profiles; in the latter system reaggregation of protein constituted a major problem, and with all techniques incomplete dissociation and/or reaggregation during handling and storage of antigen were noted. In the discontinuous PAGE system one major polypeptide of 14,000 daltons or less and one minor polypeptide of 60-70,000 daltcms 125 were consistently detected in both unlabelled and I labelled HBgAg. However, major limitations in the use of standard PAGE techniques for the analysis of HB_Ag polypeptides were clearly 0 documented, which may contribute to the present confused situation in the literature relating to the number, molecular weight and immunogenicity of these components.2. 22nm HB Ag particles were treated with a range of denaturing agents including nonionic or anionic detergents, reducing agent, or high concentrations of urea or guanidine hydrochloride. The particle displayed considerable resistance to disruption under strong denaturing conditions, in one instance only incomplete dissociation to a stable subunit of 25S being achieved after boiling with sodium dodecyl sulphate and reducing agent. However, prolonged incubation with high concentrations of Triton X-100 released a polypeptide of 70-80»000 daltons which retained both group specific a and subtype specific d activity when analysed by double antibody radioimmunopreoipitation using monospecific antisera. 3. Examination of HBaAg particles by electron microscopy following treatment with denaturing agents revealed a number of stages in the breakdown of these structures. The smallest detectable morphological structures were ring shaped units of 4-6nm diameter; a model for the assembly of these units into the complete 22nm HB_Ag particle is proposed.

The main objects of this study were: a. To compare virulent and non-viralent strains of leptospirae, by a wide range of techniques, in the hope of detecting differences which could be correlated with their infectivity and virulence. b. To extend the search for leptospiral toxins and aggressins.

The aim of this investigation was to study the interaction of different kinds of pyocine with a single sensitive indicator strain of Pseudomonas aeruginosa, and to examine the possible therapeutic applications of these pyocines to infections caused by the indicator strain. After surveying the literature concerning Is. aeruginosa. with particular emphasis on the pathogenicity of the organism, the past and present therapy of Ps. aeruginosa infections was discussed. The literature on the pyooines was reviewed and it wa3 clear that two train groups of pyocines were distinguishable; the high and low molecular weight groups, and within the high molecular weight pyooines, two structural types were defined; contraotile and filamentous. Members of the low molecular weight group were referred to as small pyocines. Ninety-four strains of Ps. aeruginosa were examined for pyocine production against two selected indicator strains, Ps. aeruginosa 6a and P14. Thirteen strains which produced pyocines with properties characteristic of each of the three types of pyocine were selected and examined in greater detail. The inducibility of the strains was examined and the effects of heat, trypsin and ultracentrifugation on the extraoted pyocinea were investigated. Eleotronmicroscopy was used to oonfirm the classifioation of the pyocines. 6. Three pyocinogenic strains were selected for further investigation! one (5893) which produced contractile pyocines, another (5882) which produced filamentous pyocines, and a third (H108) whioh produced small pyocines. These pyocinogenic strains were defined with respect to their pyocine activity against indioator strain P14 only and this indicator strain alone was used throughout the remainder of the study. The pyooines were numbered according to their producer strain, e.g. pyocine 5893 was the pyocine produced by strain 5893 and inhibitory to indicator strain P14. 7. Various methods for purifying and concentrating the pyocine preparations were examined and precipitation of the proteins with ammonium sulphate proved the most satisfactory. 8. Mouse toxicity testing of pyocine preparations at various degrees of purity revealed that in some forma, certain pyocine preparations caused adverse effects. Uninduced, low activity preparations of the pyocine were more lethal, suggesting that factors other than pyocine were responsible for toxicity, but examination of fractions of an induced preparation in vivo favoured the pyocine itself as the toxic agent. In view of the toxicity problems, another pyocinogenic strain (1577), which produced contractile pyocines inhibitory to indicator strain HL4, replaced the tacie pyocine (5893). 10, An extended pyocine purification scheme was devised that included ion-exchange chromatography. The method gave satisfactory results with the high molecular weight pyocines but the small pyocine proved more problematic. 11, The interactions between the pyooines and cultures of strain P14 were examined in vitro and the effects of dosage and incubation time on the survival of P14 cells were studied. 12, The pyocines were examined in mic^ alone, and in the presence of infections caused by strain P14. When the pyocines were injected into mice by various routes, inhibitory activity against strain P14 could be identified in tie serum for several hours. 13, High molecular weight pyooines given intraperitoneally in the presence of a lethal dose of strain P14 administered by the same route, were unable to prevent the fatal outcone of the infection unless they were given before or simultaneously with the bacteria. The 3mall pyocine preparation had no protective effect. 14, Infection of experimentally-induced burns with strain P14 was examined; although colonisation of the burn was easily established, lethal infections were more difficult to achieve. The effects of topical application of the high moleoular weight pyocines on infected burns were examined and it was eonoluded that the pyocines did not improve the ohanoes of survival of burned, infected aioe, 15, Despite the problems of pyocine resistance of strain P14 recognised in vitro, this did not appear to be the cause of failure of pyocine therapy in vivo. 16, A single, intraperitoneal dose of pyocine was sufficient to cause the production of pyocine-neutralising antibody, but topically-applied pyooine did not elicit an antibody response. 17, The future of pyocine therapy was discussed.

In the first part of this thesis an attempt has been made to provide a concise account of the history of hospital infection. Neglected early contributions, particularly from the eighteenth and nineteenth centuries, are reviewed; and the survey is continued up to 1966. It is hoped that this section, together with the subsequent discussions, may usefully supplement the review by Williams et al. (1960) which deals almost exclusively with the literature from the end of the Second World War until 1960. The investigations embodied in the second and third parts of the thesis began in 1960. During the first year of the work, a study was made of all clinically-apparent infections which developed in the maternity department and in the majority of medical and surgical wards of a general hospital. To the broad picture of hospital infection which emerged, were added the results of a systematic bacteriological examination of the hospital environment. Following this general study, a detailed enquiry was made into the mechanism of cross-infection in a dermatology department. The conditions encountered in such a department offered unique opportunities for the study of the bacteriological interaction of patients and environment. This investigation occupied a period of four years. It was mainly concerned with the dispersal of pathogenic bacteria by patients, and with the effects of specific counter-measures on both the incidence of cross infection and of bacterial contamination of the environment.

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