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Chapter: Medical Microbiology: An Introduction to Infectious Diseases: Antimicrobial Resistance

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Epidemiology of Resistance - Bacterial Resistance to Antimicrobics

The laws of evolution dictate that sooner or later microorganisms will develop resistance to any antimicrobic to which they are exposed.

Epidemiology of Resistance

The laws of evolution dictate that sooner or later microorganisms will develop resistance to any antimicrobic to which they are exposed. Since the start of the “antibiotic era,” each new antimicrobic has tended to go through a remarkably similar sequence. When an agent is first introduced, its spectrum of activity seems almost completely predictable; some species are naturally resistant, and others are susceptible, with few exceptions. With clini-cal use, resistant strains of previously susceptible species begin to appear and become in-creasingly common.

In some situations, resistance develops rapidly; in other cases it takes years, even decades. For example, when penicillin was first introduced in 1944, all strains of S. au-reus appeared to be fully susceptible to this antimicrobic. By 1950, less than one third ofisolates remained susceptible. Currently, that figure has now declined below 15%. On the other hand, the discovery of Haemophilus in uenzae strains resistant to ampicillin did not occur until ampicillin had been used heavily for more than a decade. Penicillin was the primary treatment for pneumonia and meningitis caused by S. pneumoniae for 30 years before resistance emerged. Enteric Gram-negative rods rapidly developed resistance to antimicrobics such as ampicillin, cephalosporins, tetracycline, chloramphenicol, and aminoglycosides, with many strains becoming resistant to as many as 15 agents. Fortu-nately, these developments have not been universal. The spirochete of syphilis and the group A streptococcus have thus far retained their susceptibility to penicillin.

Origin of Resistant Strains

Resistant strains may exist prior to the introduction of an antimicrobic but at a frequency so small they are unlikely to be detected. For example, penicillinase-producing S. aureus have been found in culture collections that proceeded the development and use of this an-tibiotic. Under the selective pressure provided by use of any antimicrobic, preexisting re-sistant clones are likely to increase and, if they are virulent, spread.

The origin of plasmid-carried determinants of resistance remains somewhat obscure. Some may have played a role in nature by protecting the organism from antimicrobics produced by another organism or even for protection of the cell from its own antibiotic. Plasmids and transposons carrying resistance genes have little, if any, adverse influence on the capacity of most organisms to survive, infect, and spread.

Enhancement and Spread of Resistance

The central factors involved in the increasing incidence of resistance are the selective ef-fect of the use of antimicrobics, the spread of infection in human populations, and the ability of plasmids to cross species and even generic lines. Therapeutic or prophylactic use of antimicrobics, particularly those with a broad spectrum of activity, produces a rela-tive ecologic vacuum in sites with a normal flora or on lesions prone to infection and al-lows resistant organisms to colonize or infect with less competition from others. Treat-ment with a single antimicrobic may select for strains that are also resistant to many other agents. Thus, chemotherapy can both enhance the opportunity for acquiring resistant strains from other sources and increase their numbers in the body. The amplifying effect of antimicrobial therapy on resistance is also apparent with the transfer of resistance plas-mids to previously susceptible strains. This effect has been most clearly demonstrated in the lower intestinal tract, where the antimicrobic may reduce the flora and also produce an increased oxidation – reduction potential that favors plasmid transfer.

As an example, consider a male patient harboring a strain of E. coli carrying a plas-mid with genes encoding resistance to tetracycline, ampicillin, chloramphenicol, and the sulfonamides as a very small part of his facultative intestinal flora. He develops an infec-tion with Shigella dysenteriae that is susceptible to all of these antimicrobics and is treated with tetracycline. Most of the normal flora and the Shigella are inhibited, but the resistant E. coli increases because its multiplication is not impeded and competition is removed. Plasmid transfer occurs between the resistant E. coli and some surviving Shigella, which then multiply, causing a relapse of the disease with a strain that is nowmultiresistant. Any endemic or epidemic spread of dysentery from this patient to others will now be with the multiresistant Shigella strain, and its ability to infect will be en-hanced if the recipient is on prophylaxis or therapy with any of the four antimicrobics to which it is resistant.

The use of antimicrobics added to animal feeds for their growth-promoting effects represents a major source of resistant strains. Cattle or poultry that consume feed supple-mented with antimicrobics rapidly develop a resistant enteric flora that spreads through-out the herd. Resistance is largely plasmid determined and has been shown capable of spreading to the flora of those living in close proximity to cattle-rearing farms. The links to human disease have been established, particularly for bacteria where these animals are the direct reservoir for human infection. For example, the techniques of molecular epi-demiology have allowed the tracing of resistance plasmids involved in outbreaks of Sal-monella gastroenteritis from the contaminated food back to the food processing plant andthen to the originating farm. As a consequence, many countries have banned or controlled addition to animal feeds of antimicrobics that are useful for systemic therapy in humans. The United States has not yet taken any action because of opposition by business forces in the animal husbandry industry that fear lost profits.

Control of Resistance

In the past, numerous examples in the literature showed that the extent of resistance in a hospital directly reflects the extent of usage of an antimicrobic, and that withdrawal or control can lead to rapid reduction of the incidence of resistance. Although this is more difficult to demonstrate in the community setting, experience and our understanding of the mechanisms and spread of resistance indicate that certain principles can help keep the problem under control:

1.     Use antimicrobics conservatively and specifically in therapy.


2.     Use an adequate dosage and duration of therapy to eliminate the infecting organism and reduce the risk of selecting resistant variants.


3.     Select antimicrobics according to the proved or anticipated known susceptibility of the infecting strain whenever possible.


4.     Use narrow-spectrum rather than broad-spectrum antimicrobics when the specific eti-ology of an infection is known, if possible.


5.     Use antimicrobic combinations when they are known to prevent emergence of resis-tant mutants.


6.     Use antimicrobics prophylactically only in situations in which it has been proven valuable and for the shortest possible time to avoid selection of a resistant flora.


7.     Avoid environmental contamination with antimicrobics.


8.     Rigidly apply careful, aseptic and handwashing procedures to help prevent spread of resistant organisms.


9.     Use containment isolation procedures for patients infected with resistant organisms that pose a threat to others, and use protective precautions for those who are highly susceptible.


10.            Epidemiologically monitor resistant organisms or resistance determinants in an instituteion and apply enhanced control measures if a problem develops.


11.            Restrict the use of therapeutically valuable antimicrobics for nonmedical purposes.

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