Antimicrobial Resistance: Causes, Effects and Remedies

Introduction to Antimicrobial Resistance  

Antimicrobials are drugs which are used to treat various cases of infectious diseases in humans, animals and plants. Antimicrobials consist of antibacterial, antivirals, antifungals and antiparasitics agents or drugs. Antimicrobial Resistance occurs when bacteria, viruses, fungi and parasites continue to grow and proliferate at therapeutically achievable antibiotic concentration or when the minimum inhibitory concentration (MIC) is higher in-vitro than the in-vivo attainable serum or tissue concentration.

Types of drug resistance

1. Natural Resistance

Some microbes have some resistance to certain antimicrobials e.g gram –ve bacilli are not responsive to penicillins G, Mycobacterium tuberculosis is not sensitive to Tetracyclines.

2. Acquired Resistance

Development of resistance by an organism (which used to be sensitive to a particular drug) due to antimicrobial use over a long
period of time. E.g staphylococcus aureus and tubercle bacilli developed resistance to penicillin (widespread use for over 50yrs)

Causes of Antimicrobial Resistance 

Antimicrobial resistance may occur as a result of mutation or gene transfer:

1. Mutation

Antimicrobial resistance developed by gene mutation is stable and a heritable genetic changes that occurs spontaneously and randomly among micro organisms (usually on plasmids). Mutation resistance may be single or multiple step. Single gene mutation may confer high degree of resistance e.g. enteroccoci to streptomycin while multiple step mutation may modify more number of gene that will decrease the sensitivity of antimicrobials to pathogens.

2. Gene Transfer

Gene transfer (infectious resistance) occurs from one organism to another through:

• Conjugation
• Transduction
• Transformation

Conjugation: Transfer of resistance gene between microorganisms via conjugation

Conjugation is a cell to cell contact during which there is transfer of chromosomal or extra chromosomal DNA from one bacterium or microorganisms to another through sex pili . The gene carrying
the resistance or the ‘R’ factor is transferred only if another “resistance transfer factor’ (RTF) is present. This will frequently occur in gram negative bacilli. This is the main mechanism for the spread of resistance.
The non pathogenic organism may transfer ‘R’ factor to pathogenic organism, which may become wide spread through food and water contamination.
The multidrug resistance has occurred through conjugation. Chloramphenicol resistance to typhoid bacilli, Penicillin resistance to haemophillus, gonococci.
streptomycin resistance to E.coli are examples of drugs resistance via conjugation.

Transduction

Transduction involves transfer of
resistance gene through bacteriophage
(bacterial virus) to another bacteria of the
same specie. e.g transmission of resistance gene between strains of staphylococci & strains of streptococci. This is a less common method of transfer.

Transformation

This involves horizontal transfer of resistance factors from a donor cell, perhaps of a different species which involves the incorporation of DNA found from environment into the bacterial genome.

Biochemical mechanisms of
resistance to antibiotics.

1. Drug inactivation or Enzymatic inactivation or destruction of agent

Examples include:

• β-lactamases for β-lactam antibiotics.
• Aminoglycosides, modifying enzymes due to acetylases, phosphorylases and adenylases and
• chromphenicol acetyl trasferases that inactivate chloramphenicol.

2. Decreased permeability or decreased concentration of drug at
the target site

This can be as a result of:

• decreased uptake or influx
• increased efflux or increased extrusion of agents from microbial cell
• alteration of the agent during passage across the microbial membrane .

Examples: This type of resistance is
common and has greatly reduced the therapeutic value of the tetracyclines in human. Also Resistance to erythromycin and the other macrolides, and to fluoroquinolones, is also brought about by energy-dependent efflux.

3. Altered target sites (Reprogramming of the Target structure).

Below are the targets that can be altered:

• Ribosomes – resistance to streptomycin
• DNA gyrase – resistance to nalidixic acid and rifampicin
• RNA polymerase – Rifampicin resistance due to change in the DNA directed RNA polymerase
• Penicillin binding proteins (PBP) – resistance to penicillins and other β-lactams.
• Metabolic by-pass or synthesis of resistant or alternative metabolic path ways – Sulphonamide resistance due to altered dihydropteroate synthetases. Dihydrofolate reductase becomes insensitive to trimethoprim.
• Failure to metabolize the drug:  Microbial cells contain a constitutive reductase enzyme which converts nitro-imidazole (nitrofurantoin, metronidazole) to the active principles responsible for their antibacterial activities. The loss of nitro reductase enzyme is associated with resistance to nitro imidazole and metronidazole compounds.

Resistance due to Human Behaviour

Lack of adherence to the guidelines for the use of some antimicrobials can make bigger the danger of antimicrobial resistance. The approaches in which antimicrobial drugs are used is a  contributor to resistance. These include:

1. Inexact or wrong diagnosis: This happens when wrong antimicrobials are prescribed for use or when broad-spectrum antimicrobials are prescribed when a precise one would be more suitable. Using these medicinal drugs in this way will increase the chance of resistance of antimicrobials in the individual.
2. Wrong use of antimicrobials: Resistance can occur when drugs are used for incorrect conditions. For example: using antibacterial for viral infections
3. Agricultural use: This includes the use of antibiotics in farm animals which can promote drug resistance.

Ways to Reduce Antimicrobial Resistance

These are some redress that can be employed to forestall or deal with antimicrobial resistance. This may include:

1. Use of combinations of exclusive medications, known as multiple-drug therapy. 
2. Use of monoclonal antibodies that can combat the consequences of the toxins that the microbes produce.
3. By vaccination to prevent infections from occurring.
4. By the usage of fecal microbiota transplant, which entails taking excellent bacteria from a healthy person’s gut and transplanting them into a recipient who is lacking the bacteria.
5. By the use of probiotics to fix the gut flora.
6. Advising clinical practitioners to prescribe antibiotics only when they are useful and necessary.
7. By advising individuals to; use antimicrobials precisely as the physician recommends, use after a whole diagnosis, use when a physician prescribes them, take the full prescribed course even if the signs and symptoms have subsided or gone, never share antimicrobials with others or use leftover tablets from previous prescriptions, do not pressurise doctors into prescribing antimicrobials when they are not necessary, observe good hygiene practices to stop the unfold of microbes, get recommended vaccinations. 
8. Antimicrobial Stewardship

This is the formal step taken in the control of antimicrobial resistance. It is described as a good selection of dosage, and duration of antimicrobial  for the cure or prevention of infection, with minimal toxicity to the patient and minimal influence on subsequent resistance. 
The purpose of antimicrobial stewardship is 3-fold:

• The first purpose is to work with health care practitioners to help every affected person get hold of a good antimicrobial with the correct dose and length (right Drug, right Dose, De-escalation to pathogen-directed therapy, and right Duration of therapy).
• The 2nd purpose is to stop antimicrobial overuse, misuse, and abuse.
• The third purpose is to limit the development of resistance.

Some strategies which are adopted in antimicrobial stewardship includes:

1. Formulary Restriction. Most hospitals have a formulary that is rather selective and does not encompass each and every handy antimicrobial. This helps to minimize the extent and kind of antimicrobials administered. 
2. Pharmacodynamic Dose Optimization
3. Pharmacy dispensary: Some hospitals adopt this to control the medications given to patients.