Bacteria, resistance to antibiotics

Ken Alibek, interview, November 6,1998. The Soviet defector,Vladimir Pasechnik, was the first to tell the West that the Soviets had developed plague bacteria resistant to antibiotics. See Richard Preston, The Bioweaponeers, The NewYorker (March 9,1998) p. 58. 

The development of strains of bacteria resistant to antibiotics (e.g.. Staphylococcus aureus) has received much attention in the popular press and the public is generally aware of this phenomenon and its attendant health risk. However, the mechanisms by which microbes exhibit this resistance are even more complex and varied than the modes by which biocides and antibiotics suppress microbial growth or destroy them. As noted in the excellent review on biocides, it has only been in the past 10 to 20 years that we have acquired some understanding on how bacteria and other microorganisms exhibit resistance to antimicrobial agents [16]. 

Resistance to antimicrobial agents is of concern as it is well known that bacterial resistance to antibiotics can develop. Many bacteria already derive some nonspecific resistance to biocides through morphological features such as thek cell wall. Bacterial populations present as part of a biofilm have achieved additional resistance owkig to the more complex and thicker nature of the biofilm. A system contaminated with a biofilm population can requke several orders of magnitude more chlorine to achieve control than unassociated bacteria of the same species. A second type of resistance is attributed to chemical deactivation of the biocide. This deactivation resistance to the strong oxidising biocides probably will not occur (27). 

Acylation of 7-ACA with 2-thienylacetylchloride gives the amide cephalothin (43). Displacement of the allylic acetyl group by pyridine affords the corresponding pyridinium salt cephalori-dine (44). Both these compounds constitute useful injectable antibiotics with some activity against bacteria resistant to penicillin by reason of penicillinase production. 

Bacterial resistance to antibiotics has been recognized since the first drugs were introduced for clinical use. The sulphonamides were introduced in 1935 and approximately 10 years later 20% of clinical isolates of Neisseria gonorrhoeae had become resistant. Similar increases in sulphonamide resistance were found in streptococci, coliforms and other bacteria. Penicillin was first used in 1941, when less than 1 % of Staphylococcus aureus strains were resistant to its action. By 1947,3 8% of hospital strains had acquired resistance and currently over 90% of Staph, aureus isolates are resistant to penicillin. Increasing resistance to antibiotics is a consequence of selective pressure, but the actual incidence of resistance varies between different bacterial species. For example, ampicillin resistance inEscherichia coli, presumably under similar selective pressure as Staph, aureus with penicillin, has remained at a level of 30-40% for mai years with a slow rate of increase. Streptococcus pyogenes, another major pathogen, has remained susceptible to penicillin since its introduction, with no reports of resistance in the scientific literature. Equally, it is well recognized that certain bacteria are unaffected by specific antibiotics. In other words, these bacteria have always been antibiotic-resistant. 

It has been shown (Smith et al. 1978) that in enteric bacteria carrying thermosensitive plasmids coding for the utilization of citrate and for resistance to antibiotics, rates of transmission were negligible at 37°C but appreciable at 23°C—a temperature more closely approaching that which prevails in natural ecosystems. 

Another problem is bacterial resistance to antibiotics. As doctors have treated people with the available antibiotics that medicinal chemistry devised in the past, they have selected for strains of bacteria that are resistant to those antibiotics. There is now a race against time by medicinal chemists to devise new antibiotics that will work against the resistant organisms. If we do not succeed, many bacterial infections that we thought had been cured will emerge again as major threats to our health and life. 

Resistance to antibiotics has a close parallel that has become equally familiar over the past fifty years. On repeated exposure, agricultural pests typically become tolerant of a pesticide that is used to control them. Farmers know that the amount of pesticide required to achieve control increases from year to year. Insect pests develop resistance through evolution in the same way that bacteria do. One or two serious pests are now essentially immune to all available pesticides, and many others are moving in that direction. 

Some of the reasons for the return are as follows (i) new breeding grounds for the insects that are vectors for some pathogens (ii) antigenic drift in viruses and bacteria (iii) resistance to antibiotics (iv) a decrease in the effectiveness of the immune system due to the presence of other more chronic infections, poor nutrition or stress (v) expansion of air travel. 

Since 1969, the Food and Drug Administration s Center for Veterinary Medicine (formerly the Bureau of Veterinary Medicine) has had cause for concern that the subtherapeutic use of antibiotics in animal feeds may cause bacteria in animals to become resistant to antibiotics. This resistance to antibiotics is said by many knowledgeable scientists to be transferred to bacteria in humans, thus making these antibiotics ineffective in treating human bacterial infections due to compromise of therapy. For this reason, FDA proposed in 1977 to withdraw the use of penicillin in animal feed and restrict the use of the tetracyclines (chlortetracycline and oxytetracycline) to certain uses in animal feed. This talk will focus on FDA s efforts to finalize its review of the issue and present an update on the current status of the 1977 proposals. 

R-plasmids can be transferred from normally nonpathogenic E. coli to certain pathogenic strains of bacteria with which they may come in contact in man or animals. Since R-plasmids carry drug resistance, this transfer can result in the creation of pathogenic strains of bacteria which are resistant to antibiotic therapy. 

Approximately 19 million pounds of antibiotics are used each year in U.S. cattle, hogs, poultry, and other food animals this is over 40% of the antibiotics sold in the U.S. (17). The routine use of antibiotics on farms to accelerate growth and prevent diseases has been speculated to have created strains of disease-causing bacteria that are resistant to antibiotics, which in turn infect more human beings every year (18). Because of the widespread use of antibiotics in livestock production, it would not be surprising to see antibiotic contamination of the aquatic environments situated near animal feedlots and confinements. The presence of antibiotics in water resources is suspected to contribute to the proliferation of resistant microorganisms, ft is not clear how much of these chemicals finds its way into the surface water near livestock operations. 

Chopra, I. et al. (1997). The search for anti-microbial agents effective against bacteria resistant to multiple antibiotics. 

Kiicken D., H-H. Feucht, and P-M. Kaulfers (2000). Association of qacE and qacEAl with multiple resistance to antibiotics and antiseptics in clinical isolates of gram-negative bacteria. FEMS Microbiology Letters 183 95-98. 

Bacteria have two classes of transposons. Insertion sequences (simple transposons) contain only the sequences required for transposition and the genes for proteins (transposases) that promote the process. Complex transposons contain one or more genes in addition to those needed for transposition. These extra genes might, for example, confer resistance to antibiotics and thus enhance the survival chances of the host cell. The spread of antibiotic-resistance elements among disease-causing bacterial populations that is rendering some antibiotics ineffectual (pp. 925-926) is mediated in part by transposition. 

As antibiotics came into widespread use, an unanticipated problem arose in the rapid development of resistance by bacteria. The problem was made acute by the fact that resistance genes are easily transferred from one bacterium to another by the infectious R-factor plasmids.a-d Since resistance genes for many different antibiotics may be carried on the same plasmid, "super bacteria," resistant to a large variety of antibiotics, have developed, often in hospitals. 

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