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Title: Microbiological studies in mice of intestinal decontamination regimens
Author: Ameen, Abdulmajeed Saif M.
Awarding Body: University of Glasgow
Current Institution: University of Glasgow
Date of Award: 1993
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Selective decontamination of the digestive tract (SDD) uses orally administered antibiotics to eliminate or markedly reduce the number of aerobic gram-negative bacilli colonizing the digestive tract, thus preventing endogenous infection with these organisms. The selective activity of the drugs used allows retention of the normally predominant anaerobic flora of the tract, thus preventing overgrowth or colonization with organisms resistant to the decontaminating agents; this phenomenon is termed "colonization resistance" (CR). SDD has been increasingly applied to medico-surgical intensive care patients, a procedure that remains highly contentious. The concept of colonization resistance is central to the use of SDD. However, the mechanisms underlying this phenomenon are both complex and disputed. Further, the experimental basis for the clinical use of SDD is dependent to a surprising degree on a restricted series of studies involving total decontamination of the digestive tract of mice carried out by van der Waaij and colleagues between 1971 and 1974. This thesis described studies in two areas. First, repetition of the total decontamination studies of van der Waaij et al., (1971) in order to verify or modify their conclusions concerning colonization resistance. Second, the application of the same mouse model to the SDD regimen most commonly used in clinical ITU practice: orally administered mixture of polymyxin E, tobramycin, and amphotericin B (PTA) with or without the addition of systemically administered cefotaxime. Treated and untreated Balb / c mice were subjected to direct oral challenge with bacteria resistant to the decontaminating agents, together with detailed microbiological monitoring of the aerobic and anaerobic faecal flora. Throughout these studies the results were greatly influenced by the details of the technique employed. Untreated, control mice showed a very high CR. A challenge dose of 108-10 cfu of E. coli S-R21 was required to achieve colonization in 50% of mice, and 6 other challenge strains (Klebsiella pneumoniae S-R10, Pseudomonas aeruginosa S-R321, Proteus mirabiiis s-R9, Pseudomonas cepacia S-R13, Providencia stuartii s-R7 and Candida albicans s-R5) failed to colonize the control mice at a maximum test dose of 108-10cfu. TDD rapidly reduced the aerobic faecal flora to undetectable levels. A marked reduction in the numbers and diversity of anaerobic flora was also seen, but this effect was more variable and often incomplete. These changes were associated with a striking reduction in the CR for E.coli S-R21. Values of < 2 were obtained, together with extensive multiplication of the challenge in the gut of mice. However, there was a marked variation in the CR results with different challenge organisms. SDD rapidly eliminated indigenous E.coli from the faeces, but had little effect on the levels of enterococci. Effects on anaerobic flora were limited to some simplification in flora diversity. A small reduction in CR was noted in these mice, but this was much less than that seen with TDD and multiplication of the challenge organisms within the gut was not observed. Treatment with systemic cefotaxime alone was associated with elimination of faecal E.coli and overgrowth with enterococci. There was also a major reduction in the diversity of anaerobic flora, although the total viable count was unchanged. These changes were not associated with a significant reduction in CR. However, SDD supplemented with systemic cefotaxime produced striking and surprising results. As previously, E.coli was rapidly eliminated, but this was accopanied by a marked overgrowth with enterococci. In addition, there was either apparent elimination of anaerobic flora or a marked reduction in both the numbers and the diversity of these organisms. These changes were associated with a marked reduction in CR (to value < 4, the smallest challenge tested). These results are surprising in view of the clinical experience with this widely used regimen. They also give rise to clinical concern and they warrant further investigation.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available