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 usually is 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 an effort to survive. If an organism adjusts to a changing environment, it survives; 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.
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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 selective pressure for the survival of resistant bacteria. The resistant bacteria can multiply rapidly, giving rise to more resistant bacteria. For example, the bacteria isolated from hospital-acquired infections are more likely to be antibiotic-resistant. It is because of excessive exposure to antibiotics.
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.
Today’s significant 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.
Some bacteria are naturally resistant to certain antibiotics. For example, antibiotics inhibiting cell wall synthesis are useless for Mycoplasma as these organisms lack a cell wall. Similarly, most Gram-negative bacteria are resistant to glycopeptide antibiotics like vancomycin. These antibiotics are larger and cannot pass through the tiny pores of the Gram-negative bacteria’s outer membrane.
Natural resistance to a certain antibiotic is not generally considered antibiotic-resistant because the bacteria were never susceptible to that antibiotic.
If antibiotics are unfavorable, bacterial growth either suppresses or develop resistance. If bacteria are not resistant to antibiotics naturally, they may gain resistant genes from other bacteria. Bacteria can gain resistance either by mutation or a gene transfer from resistant bacteria.
The mutation is a stable, heritable change of an organism’s gene. Different genetic mutations yield different types of resistance. Isolation of resistant cells can be from the cultures of bacteria that were susceptible to the antibiotic. This type of resistance is usually due to a mutation in a chromosomal gene.
Resistant genes 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, a usual life process.
Horizontal gene transfer
Bacteria also transfer their resistant gene to susceptible bacteria by horizontal gene transfer. Bacteria may transfer resistant genes horizontally among the same species or even between different genera 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, a plasmid or a portion of a chromosome that bears resistant genes can be shared. For example, the transfer of antibiotic-resistance genes in intestinal pathogens from E. coli.
- Transformation: Another method of gene transfer is transformation. When a bacterium containing resistant genes dies, its DNA releases outside. Then another bacterium can uptake that “free” DNA from the environment.
- Transduction: Viruses (bacteriophages) are another means for passing resistant genes between bacteria through transduction. When a bacteriophage invades an antibiotic-resistant bacterium, the resistant gene of the bacterium is packaged into the head portion of the phage. When that phage invades another (susceptible) bacterium, it injects the resistant gene into it.
Causes and spread of antibiotic resistance
Antibiotic resistance is driven by various factors, ranging from contaminated bodies of water to misuse of antibiotics in food production and human medicine.
Indiscriminate use of antibiotics
Antibiotics are used indiscriminately, like taking the wrong antibiotics or inappropriate doses and for the inappropriate duration; patients not taking an entire course of antibiotics as they stop it soon after feeling better, using antibiotics for viral diseases, etc. These types of misuse lead to the rise of antibiotic resistance.
Non-medical use of antibiotics
Antibiotics are also given to farm animals for disease prevention and growth promotion. Such antibiotics expose many animals and, thus, bacteria for a more extended period and at lower doses. This leads to the evolution of resistance. Consuming animals as food or by close contact with such animals, humans get such resistant bacteria. Antibiotic-resistant bacteria from hospitals, poultry farms, or any other place spread in the environment. These bacteria cause infectious diseases which are difficult to treat.
Mechanism of antibiotic resistance
Changes in the number and characters of porin channels through which beta-lactam and aminoglycosides cross the outer membrane to reach penicillin-binding proteins (PBPs) of gram-negative bacteria substantially reduce the uptake of beta-lactam agents.
Resistance shown by some Gram-negative bacteria towards beta-lactam antibiotics (e.g., P. aeruginosa resistance to imipenem) and aminoglycoside resistance in various gram-negative bacteria are some of the important examples.
In some bacteria, an development of efflux pump occurs. When an antibiotic enters the cell, the efflux pump throws the antibiotics outside the cell. This type of resistance is seen in tetracycline-resistant bacteria.
The efflux mechanism in various streptococci and staphylococci pumps macrolides out of the cell before target binding.
Some bacteria become resistant by modifying the target on which antibiotics bind and act. For example, when the structure of a penicillin-binding protein (PBP) in bacteria alters, penicillin can no longer bind to that protein. This makes penicillin ineffective.
|Examples of Resistance
|Mechanism of Resistance
|Staphylococcal resistance to methicillin and other available beta-lactams. Penicillin and cephalosporin resistance in S. pneumoniae and viridans streptococci.
|Mutational changes in original penicillin-binding proteins (PBPs) or acquisition of different PBPs that do not bind beta-lactams sufficiently to inhibit cell wall synthesis.
|Enterococcal and Staphylococcus aureus resistance to vancomycin.
|Alteration in the molecular structure of cell wall precursor components decreases the binding of vancomycin, allowing cell wall synthesis to continue.
|Enterococcal resistance to streptomycin
|Mutational changes in ribosomal binding sites diminish the ability of aminoglycoside to bind sufficiently and halt protein synthesis. This resistance may also be mediated by enzymatic modification.
|Gram-negative and gram-positive bacteria resistance to various quinolones
|Changes in DNA gyrase subunits decrease the ability of quinolones to bind this enzyme and interfere with DNA synthesis.
|Resistance of various streptococci and staphylococci to macrolides (erythromycin, azithromycin, clarithromycin)
|Enzymatic alteration of ribosomal target reduces drug binding.
Enzymatic Inactivation of antibiotics
Some bacteria produce enzymes that damage the structure of an antibiotic so that it cannot work. For example, bacteria producing beta-lactamase enzymes inactivate beta-lactam antibiotics such as penicillin.
|Examples of Resistance
|Mechanism of Resistance
|Staphylococcal resistance to penicillin. Enterobacteriaceae and P. aeruginosa resistant to penicillin, cephalosporin, and aztreonam
|Beta-lactamase enzymes destroy the beta-lactam ring. Thus, antibiotics cannot bind to penicillin-binding protein (PBP) and interfere with cell wall synthesis.
|Gram-positive and gram-negative resistance to aminoglycosides
|Modifying enzymes alter various sites on the aminoglycoside molecule; thus, the ability of the drug to bind to ribosome and halt protein synthesis is greatly reduced or lost.
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.
Prevention for antibiotic resistance
Every strain of bacteria isolated from the clinical sample must be tested for minimum inhibiting concentration (MIC) and antibiotic sensitivity test (AST). This helps clinicians choose the correct antibiotic with the right dose and reduces the chance of resistance.
A combination of different natures 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:
Infection can be prevented by immunization. Vaccines increase the body’s immune system and decrease resistant pathogens. Fewer IV lines and catheter use also help prevent infection in hospitals.
Diagnose and treat effectively
Patient’s sample should be cultured in a lab to isolate and identify the causative organism. Proper antibiotics should be prescribed. It is better to prefer narrow-spectrum antibiotics which only target pathogenic bacteria.
Use antibiotic wisely
Patients should be given the correct dose of antibiotics for a suitable duration. Patients should be informed why the full course of antibiotics is necessary. The focus should be given to treating 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 before the culture reports; after finding negative results for bacteria, the antibiotic should be stopped as infection may be caused by a virus.
Prevent transmission of the pathogen
The patient should maintain proper hygiene and sanitization; hand washing should be promoted, and direct contact with the patient should be avoided to prevent the spreading of communicable diseases.
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