The Effects on Human Health of Subtherapeutic Use of Antimicrobials in Animal Feeds (1980) / Chapter Skim
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Appendix I: Infectious Disease: Effect of Antimicrobials on Bacterial Populations
Appendix I: Infectious Disease: Effect of Antimicrobials on Bacterial Populations
Pages 275-300
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From page 275... ...
The last discovery of an antibiotic with a truly new target site may have been rifampicin, which was first marketed 15 years ago (Hartmann _ al., 1967~. Most of the newer antibiotics circumvent resistance mechanisms to reach old target sites (Christensen et al., 1979~.
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From page 276... ...
These resistance mechanisms force us to use succeeding waves of newer antibiotics that are expensive to develop and promote. These costly products now account for most of the antibiotic dollar volume which is, in turn, a large part of the pharmaceutical dollar volume.
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From page 277... ...
The 6-lactamases could have evolved if the active sites of transpeptidases of the bacterial cell wall, which selectively bind but do not hydrolyze penicillins, had begun to acquire a hydrolytic function (Crosa et al., 1977; Tipper and Strominger, 1965~. Techniques for characterizing products of resistance genes are so new, and surveillance so sketchy, that there has been little opportunity to distinguish evolution of a new gene from dissemination of a previously rare one.
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From page 278... ...
The ultimate dissemination and persistence of a plasmidborne resistance gene also depends on the other types of genes that are on the same plasmid. Many of the plasmids bearing resistance genes are large and have space for many other genes.
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From page 279... ...
Genes coding for resistance to a number of commonly used antibiotics have been found on transposons (Campbell et al., 1977~. A resistance gene can be limited in its distribution by its position on the chromosome of, or on a nonconjugative plasmid in, a poorly colonizing strain; on a plasmid of limited host range; or on a plasmid carrying few other genes with survival advantages.
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From page 280... ...
If the only mechanism available is a gene coding for an enzyme with a narrow specificity including only that antibiotic and if that gene is the only resistance gene on the chromosome of a bacterial species with poor colonizing and competing abilities, the ensuing resistance would be directed only against the antibiotic used and would be unlikely to persist. However, resistance would become widespread and persistent if the population contains a resistance mechanism consisting of a gene coding for an enzyme with a broad substrate range and if the gene is located on a transposon in a plasmid with a broad host range and is rich with closely linked genes for resistance to other antibiotics and for other survival advantages.
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From page 281... ...
In this population, the prevalence of resistance after exposure would be diminished primarily by the segregation rates of the resistance mechanism from each of the strains, which may also be a variable characteristic of the resistance mechanism (Levin, in press) or, possibly, the normal influx of new strains colonizing and displacing the older members, although these new strains could also be susceptible to infection by a mobile plasmid widely resident in the population.
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From page 282... ...
All of these considerations lead to one essential question: What is the source of the more efficient and more efficiently distributing resistance mechanisms? Everything suggests that the mechanisms themselves are the ultimate evolutionary products of the cumulative application of antibiotic selection pressures to bacterial populations.
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From page 283... ...
If A had 100% resistance and B by itself would have had only 10% resistance, yet 1Z of B's strains actually came from A, then they would add 1% resistance for a total of 11% resistance in B If there are qualitative differences among resistance mechanisms, as discussed in the preceding section, then the influence of resistance in one compartment on that of another may be quite out of proportion to the circulation between them.
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From page 284... ...
The 2 -aminoglycoside nucleotidyl transferase (AND 2 ~ and the 3-aminoglycoside acetyl transferase (AAC-3) were known to be widely distributed in nosocomial strains.
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From page 285... ...
This experience illustrates that if there are qualitative r differences between resistance mechanisms, the influence of resistance in one bacterial flora compartment on that of another may be completely out of proportion to the rate of interchange between them. The compartment in which this particular complex mechanism had evolved could not have had great interchange with the compartment of flora in humans in the United States because only traces of it could be found there prior to the outbreak.
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From page 286... ...
The exchange of antibiotic-treated flora between animals in a feedlot, all of whom may be receiving antibiotics, would appear to be of great magnitude. Recycling of large numbers of the same strains of bacteria through successive rounds of exposure to antibiotics would also seem to favor reassociation of antibiotic resistance genes and other genes towards the development of more efficient resistance mechanisms and more efficient distribution (Threlfall et al., 1978~.
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From page 287... ...
. The foregoing discussions have emphasized dissemination and entrenchment of antibiotic resistance in bacterial populations as implied by studies of the resistance mechanisms themselves.
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From page 288... ...
Upper let t is the collection of veterinary i solaces ~ upper right those from a hospital in the United States, and the lower two are from hospitals outs ide the United States. Figure provided by the International Survey of Ant ibiot ic Res istance Group .
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From page 289... ...
They may transpose from one plasmid to another within a bacterial cell, transfer on a plasmid from one bacterial cell to another, or be carried in a bacterial cell that leaves one patient or animal and colonizes another. Antibiotic usage exerts selection pressure at each level, concentrating resistance genes on transposons, transposons on plasmids, plasmids in bacterial cells, and resistant cells at the expense of their susceptible counterparts.
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From page 290... ...
With regard to the dissemination of antibiotic resistance, it seems likely that only the tip of the iceberg has been observed. A corrolary to this is that improved discrimination of any component in this system -- levels of antibiotic resistance, identification of inactivating enzymes, identification of specific transposons or plasmids, or identification of specific biotypes or serotypes of host bacteria -- will greatly increase our ability to find distinctive combinations that can be traced through bacterial populations.
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From page 291... ...
Previously noted incursions of this kind, e.g., penicillinase-producing gonococci from the Far East, have been observed, usually because they were extremely conspicuous. The more sensitive and selective are one's techniques for identifying resistance mechanisms, the greater is one's ability to detect incursion of more subtly distinctive groups from the flora of humans in the United States or from the flora of animals.
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From page 293... ...
I On ~ ~ ~ ~ ~o ~ 'a rl I ~ 0.)
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From page 294... ...
The prevalence of various resistance mechanisms in the flora of humans from these different countries are presumably largely the consequences of these practices. Observation of these results could, therefore, be an indispensable guide to the development of optimal antibiotic usage policy.
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From page 295... ...
This could represent fortuitous linkages of the streptomycin resistance gene, as discussed previously, but it might also reflect continuing use of streptomycin in livestock in the United States. The second resource for improved future observation of the antibiotic resistance system is the newer techniques for characterizing resistance mechanisms, ranging from the detailed characterization of inactivating enzymes to analyses conducted by incubating the plasmid~s)
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From page 296... ...
1973. R-factors of Escherichia cold frog dressed beef and humans.
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From page 297... ...
1979. Nosocomial multiply resistant Klebsiella pneumonias: Epidemiology of an outbreak of apparent index case origin.
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From page 298... ...
1979. The conditions for the existence of plasmids in bacterial populations.
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From page 299... ...
1979. Persistence of plasmid-carrying tetracycline-resistant Escherichia cold in a married couple, one of whom was receiving antibiotics.
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From page 300... ...
1970. Animal sources of common serotypes of Escherichia cold in the food of hospital patients.
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