Antimicrobial Drug Resistance

First of all we must know certain basic definitions to differentiate most interchangeably used terms like chemotherapy, antibiotic, and 

antibacterial/antimicrobial agent.

Chemotherapy

‘It is treatment of infections with specific drugs that selectively suppress the infecting microorganism without significantly affecting the patient.’

For example: 

If the patient is suffering from throat infection (due to gram positive bacteria), patient is treated with medication which will harm/kill the bacteria present in throat, but will produce less or no harm to the patient.

The same thing occurs in therapy of cancer, where medications are given to patient which harm/stop growth of “Tumer Cells”, with less or no harm to patient.

Hence the cancer therapy is known as chemotherapy.

Note that treating any infection with antimicrobial drug can be considered as chemotherapy.

Antibiotics

These are substances produced by microorganisms, which selectively suppress the growth of or kill other microorganisms at very low concentrations.

For example, throat infection due to gram positive bacteria can be treated with penicillin (a substance produced by another group of bacteria, Penicillin Notatum)

Both antibiotics and chemotherapeutic agents are commonly known as AntiMicrobial Agents (AMA).

Resistance

     

It refers to unresponsiveness of a microorganism to an Antimicrobial agents, and is similar to the phenomenon of tolerance seen in human.

There are two types of resistance.
1. Natural,
2. Aquired

Some microbes have always been resistant to certain antimicrobial agents which is known as Natural resistance.

They lack the metabolic process or the target site which is affected by the particular drug.

                       

This is generally a group or species characteristic,

E.g. Gram-negative bacilli (a type of bacteria causing food poisoning, gastroenteritis, urinary tract infection and many more)  are normally unaffected by penicillin G. 

This type of resistance does not pose a significant clinical problem.

Some microbes develop the resistance  (which was sensitive before)due to the use of an AMA over a period of time known as Acquired resistance.  

                    

This can happen with any microbe and is a major clinical problem.

However, development of resistance is dependent on the microorganism as well as the drug. 

Some bacteria are notorious as they rapid acquit resistance

e.g. tubercle bacilli (The reason for long term therapy of Tuberculosis). 

Others like spirochetes (Present in teeth) have not developed significant resistance to penicillin despite its widespread use for > 50
years.

Resistance may be developed by mutation or gene transfer.

Mutation

It is a stable and heritable genetic change that occurs spontaneously and randomly among microorganisms.

It is not induced by the AMA. 

Any sensitive population of a microbe contains a few genetically modified cells which require higher concentration of the AMA for inhibition. 

These are selectively preserved and get a chance to proliferate when the sensitive cells are eliminated by the AMA. 

Thus, in time it would appear that a sensitive strain has been replaced by a resistant one.

E.g. When a single antitubercular drug is used. 
As Tubercular bacterium easily acquires resistance, hence multi drug therapy for long period (3-8 months) are given. 
If single drug treatment would be done it would easily develop resistance against that drug.

                             Elaboration of mechanism of Mutation

Suppose a patient has infection of gram positive bacteria. He is prescribed Penicillin G for 5 days, daily once.

For first three days patient takes it regularly which destroys 80% of bacteria, now patient has stopped taking the drug.

The drug concentration will become low in body and remaining 20% bacteria will get chance to survive.

Now these 20% bacteria has altered their genes and are resisted to penicillin G.

These 20 % bacteria will grow, are now they are more power full with altered gene structure, requiring new way to be killed. 

Mutation may be:

(i) Single step: A single gene mutation may confer high degree of resistance; emerges rapidly,

e.g. E. coli (bacteria) to rifampin (first line drug of TB).

(ii) Multistep: A number of gene modifications are involved; sensitivity decreases gradually in a stepwise manner.

Resistance to erythromycin (Drug used against gram positive bacteria, for throat infection)

Sometimes mutational changes in bacteria may decrease their severity to produce damage.

Gene transfer (infectious resistance) from one organism to another can occur by:

(i) Conjugation

Sexual contact through the formation of a bridge or sex pilus is common among gram-negative bacilli of the same or another species. 

This may involve chromosomal or extrachromosomal (plasmid) DNA. 

The gene carrying the ‘resistance’ or ‘R’ factor is transferred only if another ‘resistance transfer factor’ (RTF) is also present. 

                                

Conjugation frequently occurs in the colon where a large variety of gram-negative bacilli come in close contact. 

Even nonpathogenic organisms may transfer R factor to pathogenic organisms, which may become widespread by contamination of food or water. 

Chloramphenicol resistance of typhoid bacilli.

(ii) Transduction

It is the transfer of gene carrying resistance through the agency of a bacteriophage. 

                      

The R factor is taken up by the phage and delivered to another bacterium which it infects. 

Many Staph. aureus strains have acquired resistance by transduction.

(iii) Transformation

A resistant bacterium may release the resistance carrying DNA into the medium and this may be imbibed by another sensitive organism—becoming unresponsive to the drug. 

Resistance once acquired by any of the above mechanisms becomes prevalent due to the selection pressure of a widely used AMA,

i.e. presence of the AMA provides opportunity for the resistant subpopulation to thrive in preference to the sensitive population.

Resistant organisms can broadly be of the following three types:

(a) Drug tolerant

Loss of affinity of the target biomolecule of the microorganism for a particular AMA, 
e.g. resistant Staph. aureus and E. coli develop a RNA polymerase that does not bind rifampin,  

Another mechanism is acquisition of an alternative metabolic pathway, 
e.g. certain sulfonamide resistant bacteria switch over to utilizing preformed folic acid in place of synthesizing it from PABA taken up from the medium.

(b) Drug destroying

The resistant microbe elaborates an enzyme which inactivates the drug,

e.g. β-lactamases are produced by staphylococci, Haemophilus, gonococci, etc. which inactivate penicillin G.

(c) Drug impermeable

Many hydrophilic antibiotics gain access into the bacterial cell through specific channels formed by proteins called ‘porins’, or need specific transport mechanisms.

These may be lost by the resistant strains, so drug can not enter in to bacterial cell. 

Chloroquine-resistant P. falciparum accumulates less chloroquine. 

Cross resistance
 

Acquisition of resistance to one antimicrobial agent (AMA) conferring resistance to another AMA, to which the organism has not been exposed, is called cross resistance. 

This is more commonly seen between chemically or mechanistically related drugs, 
e.g. resistance to one sulfonamide means resistance to all other drugs of this class. 

Such cross resistance is often complete. However, resistance to one aminoglycoside may not extend to another, e.g. gentamicin-resistant strains may respond to amikacin. 

Sometimes unrelated drugs show partial cross resistance, e.g. between tetracyclines and chloramphenicol, between erythromycin and lincomycin.

Cross resistance may be 
two-way,  E.g. between erythromycin and clindamycin and vice versa, 
                                                          or 
one-way, E.g. development of neomycin resistance by entero-bacteriaceae makes them insensitive to streptomycin but many streptomycin-resistant organisms remain susceptible to neomycin.