Antibiotic Resistance: Origin, Causes, Mechanism and Prevention 4.75/5 (8)

Antibiotics are the main therapeutic tools to treat various bacterial infections. But today, more and more antibiotics are becoming less effective. It is because of the antibiotic resistance developed by bacteria due to the use and misuse of antibiotics.
Antibiotic resistance is the acquired ability of a bacterium to resist the effects of an antibiotic to which it is normally susceptible. It occurs when bacteria change in a way that reduces the efficacy of antibiotics. Thus, the bacteria continue to multiply in the presence of therapeutic levels of antibiotics.

Resistant bacteria destroy the antibiotic or neutralize its effects. Antibiotic resistance is encoded by bacteria at either chromosome or plasmid.

Bacteria resistant to multiple antibiotics are called multidrug resistant (MDR) bacteria or superbugs.
Every living organism makes efforts to survive. If an organism adjusts itself to a changing environment, it survives, and if not, it dies. When bacteria constantly come in contact with antibiotics, some bacteria develop a resistance mechanism. Such bacteria have a greater chance of survival than those that are susceptible. Thus, antibiotic resistance is a natural phenomenon.

Selection pressure

 

Selection Pressure (source: cdc.gov)

Suppose very few bacteria are antibiotic resistant in a large population of bacteria. The antibiotic, on its exposure, kills all the susceptible bacteria. This leads to a selective pressure for the survival of resistance bacteria. Now, the resistant bacteria are able to multiply rapidly giving rise to more number of resistant bacteria. In addition, resistant bacteria also transfer their resistant gene to susceptible bacteria. One resistant bacterium among millions of bacteria cannot cause harm. The problem arises when it transfers its resistant gene to other bacteria ultimately making resistant bacteria a majority.

Ways of gaining a resistant gene by bacteria:

Natural resistance

Some bacteria are naturally resistant to certain antibiotics. For example, antibiotics inhibiting cell wall synthesis are useless for Mycoplasma as these organisms lack cell wall. Similarly, most Gram-negative bacteria are resistant to glycopeptide antibiotics like vancomycin. It is because these antibiotics are larger in size which cannot pass through the small pores of outer membrane of the Gram-negative bacteria.
Natural resistance to a certain antibiotic is not generally considered as antibiotic resistant because the bacteria were never susceptible to that antibiotic.

Acquired resistance

If the presence of antibiotics is unfavorable, bacteria either be suppressed or develop a resistance. If bacteria are not resistant to antibiotics naturally, they may gain resistant gene from other bacteria. Bacteria can gain resistance either by mutation or gene transfer from resistant bacteria.

Mutation

Mutation is a stable heritable change of a gene of an organism. Different genetic mutation yield different types of resistance. Resistant cells can be isolated from the cultures of bacteria that were susceptible to the antibiotic. This type of resistance is usually due to the mutation in chromosomal gene.

Gene transfer

Resistant gene can be transferred from one bacterium to the other. The transmission of resistant genes occurs via vertical gene transfer or horizontal gene transfer.

Vertical gene transfer

Resistant gene is transferred from one generation to another generation by reproduction. This is called vertical gene transfer and it is a usual life process.

Horizontal gene transfer

Bacteria also transfer their resistant gene to susceptible bacteria by horizontal gene transfer. Bacteria may transfer resistant gene horizontally among the same species or even between different genus and species. It can occur through conjugation, transformation and transduction.

Conjugation

Conjugation is a mating process through which genes are transferred through the temporary fusion of the mating partners. Thus, plasmid or a portion of chromosome which bears resistant genes can be transferred.

Transformation

Another method of gene transfer is transformation. When a bacterium containing resistant genes dies, its DNA is released outside. Then another bacterium can receive that naked, “free” DNA from the environment.

Transduction

Viruses (bacteriophages) are another means for passing resistant genes between bacteria through the process called transduction. When a virus invades an antibiotic resistant bacterium, the resistant gene of the bacterium is packaged into the head portion of the virus. When virus invades another (susceptible) bacterium, it injects the resistant gene into that bacterium.

Causes and spread of antibiotic resistance

The emergence of antibiotic resistance is mainly due to misuse or overuse of antibiotics. Some of the causes are mentioned below.

Examples of How Antibiotic Resistance Spreads (source: CDC)

Indiscriminate use of antibiotics

Antibiotics are found to be used indiscriminately, like taking wrong antibiotics or inappropriate dose and for inappropriate duration; patients not taking full course of antibiotic as they stop it soon after feeling better, using antibiotics for viral diseases, etc. These types of misuses lead to the rise of antibiotic resistance.

Non-medical use of antibiotics

Antibiotics are also given to animals for disease prevention and growth promotion. Such antibiotics expose large number of animals and thus bacteria, for more extended period, and at lower doses. This leads to the evolution of resistance. Consuming the animals as food or by a close contact with such animals, humans get such resistant bacteria. Antibiotic resistant bacteria from hospital, poultry farm or any other place spread in the environment. These bacteria cause infectious diseases which are difficult to treat.

Mechanism of antibiotic resistance

Decreased permeability

Resistant bacteria make their membrane less permeable to prevent the entry of antibiotics. Example: resistance shown by some Gram negative bacteria towards beta-lactam antibiotics.

Efflux pump

In some bacteria, efflux pump is developed when antibiotic enters the cell, which throws out the antibiotics outside the cell. This type of resistance is seen in tetracycline resistant bacteria.

Altered target

Some bacteria become resistant by modifying the target on which antibiotics bind and act. For example, when the structure of penicillin binding protein (PBP) in bacteria is altered, penicillin can no longer bind to that protein. This makes penicillin ineffective.

Inactivation of antibiotics

Some bacteria produce enzymes which damage the structure of an antibiotic so that it cannot work. For example, bacteria producing beta lactamase enzyme inactivate beta lactam antibiotic such as penicillin.
Alteration of metabolic pathway
Bacteria change some of the metabolic processes and become resistant to the antibiotics which act on such processes. For example, sulfonamide resistant bacteria do not require PABA to synthesize folic acid. Like mammalian cells they directly use preformed folic acid.

Origin of antibiotic resistance and present status

We know microorganisms produce antibiotics. In order to survive these organisms naturally bear resistant gene against their own antibiotics. The genes can be transferred between and among microorganisms by genetic exchange.
Resistant genes in bacteria to certain antibiotics were found even prior to the discovery of those antibiotics. Non-pathogenic soil bacteria were found to have resistance gene even before the discovery of antibiotics. It may be because, antibiotic producing fungi, like Penicillium, Streptomyces present in soil induce the development of such strains of bacteria.
Antibiotic resistance gene in intestinal pathogens has been found to be transferred from E. coli which dwells in intestine.In such cases, resistant gene has been transferred by horizontal gene transfer; mainly by conjugation.

The problem of antibiotic resistant was infrequent soon after the discovery of antibiotics by Alexander Fleming. However, Fleming warned that misuse of the antibiotics could result in selection for resistant bacteria. The development of resistance was seen few decades after the discovery of antibiotic.
Now, the rapid emergence and spread of resistant bacteria is occurring worldwide. And it is a major serious problem. The first discovered, efficient antibiotic, penicillin is now ineffective for most of the bacteria. Even those which are sensitive require high dose of penicillin. Penicillin resistance led to produce semi synthetic penicillins like ampicillin, methicillin, amoxycillin etc. which are widely used nowadays as bacteria show less resistance against these antibiotics. Other newer antibiotics and alternative therapies are also being practiced. The bacteria isolated from hospital-acquired infection are more likely to be resistant to antibiotics. It is because of the excessive exposure of antibiotics.
Today’s major threats are methicillin resistant Staphylococus aureus (MRSA), Vancomycin resistant enterococci (VRE), multi-drug resistant Mycobacterium tuberculosis (MDR-TB), etc. These bacteria are resistant to most of the commonly used antibiotics.

Antibiotic Sensitivity test: Multidrug resistant E. coli on Mueller Hinton Agar isolated from urine sample (1=Amoxycillin, 2=Norfloxacin, 3=Ciprofloxacin, 4=Cefixime, 5=Gentamicin, 6=Nitrofurantoin). No clear zone (and very small clear zone) was seen around different antibiotic discs; this means the bacterial cells are not inhibited by multiple antibiotics.

Prevention for antibiotic resistance

Each and every strain of bacteria isolated from clinical sample must be tested for minimum inhibiting concentration (MIC) and antibiotic sensitivity test (AST). This helps clinicians to choose correct antibiotic with correct dose and it reduces the chance of resistance.
Combination of different nature of antibiotics helps to work against resistant bacteria. As these antibiotics act on different sites of bacteria, the bacteria are less likely to develop resistance. However, this may not be effective against MDR bacteria.

Some of the preventive ways are as follows:

Prevent infection

Infection can be prevented by immunization. Vaccines increase body’s immune system and decrease resistant pathogens. Less use of IV line and catheter also helps to prevent infection in hospitals.

Diagnose and treat effectively

Patient’s sample should be cultured in lab to isolate and identify the causative organism. Proper antibiotic should be prescribed. It is better to prefer narrow spectrum antibiotics which only target pathogenic bacteria.

Use antibiotic wisely

Patients should be given the right dose of antibiotics for right duration. Patients should be informed why full course of antibiotic is necessary. Focus should be given to treat the infection not the contamination.

Stop antibiotic therapy when unnecessary

If an antibiotic in use is found to be ineffective against the causative organism, it should be stopped. Sometimes antibiotics are prescribed prior to the culture reports; after finding negative result for bacteria the antibiotic should be stopped as infection may be caused by a virus.

Prevent transmission of pathogen

Patient should maintain proper hygiene and sanitization; hand washing should be promoted, direct contact with the patient should be avoided to prevent the spread of communicable disease.

References

1. Madigan MT, Martinko JM (2006). Brock Biology of Microorganisms. 11th edn. Pearson Educational International. pp. 692-698.
2. https://en.wikipedia.org/wiki/Antimicrobial_resistance
3. Pelczar MJ, Chan ECS, Krieg NR (2007). Microbiology. 5th edn. Tata McGraw-Hill. pp. 531-532.
4. Hugo WB and Russel AD (2004). Pharmaceutical Microbiology. 7th edn. Blackwell Scientific Publications, UK. pp. 220-232.
5. http://www.who.int/mediacentre/factsheets/fs194/en/
6. http://emerald.tufts.edu/med/apua/about_issue/about_antibioticres.shtml

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