It was long ago in 1929, when Alexander Fleming revolutionised how infections could be treated with his wonder drug discovery “penicillin”. In his Nobel Prize speech in 1945, he had warned about the development of resistance to this class of drugs popularly known as antibiotics. Indeed how true!  It took less than twenty years for bacteria to show resistance with the first strain of Staphylococcus aureus being resistant in 1950. Today, this bacterium is practically resistant to each and every antibiotic available on the planet. It was the first bacterium in which penicillin resistance was found in 1947, just four years after the drug started being mass-produced. Through the years and after development of at least 150 more antibiotics, we still grapple with the same problem, only that this time around the problem has assumed gigantic proportions. No sooner does an antibiotic show some positive treatment signs and resistance comes around.

So the history of antibiotics started from the 1st generation or class of antibiotics i.e. Penicillin. Today, we are using 4th generation or class of antibiotics due to ineffectiveness of previous classes of antibiotics. The sole reason of development in journey of antibiotics is due to the gain in resistance and surviving ability of existing bacteria against the earlier classes of antibiotics. Now, we have XDR, (extensively drug resistant tuberculosis) MDR-TB (multi drug resistant tuberculosis) and MRSA (methicillin resistant Staphylococcus aureus), these are the various classes of resistant bacteria we see nowadays. The most important reason cited for development of resistance is the indiscriminate use of different classes of antibiotics.

In fact, today the pipeline for development of new antibacterial drugs is virtually empty, particularly for the treatment of gram negative bacteria and research on treatments for replacement of antibacterial drugs is still in the early stages. Progress in modern medicine is at risk hence, since most of the bacteria have got resistant to most drugs. Some of the serious areas for concern are:

• Common community acquired infections such as pneumonia which used to be treatable earlier with simple antibiotics are more difficult to treat with increasing development of resistance.
• Common infections in neonatal and intensive care are becoming more difficult and sometimes impossible to treat.
• Patients receiving cancer treatment, organ transplants and other advanced treatments are particularly vulnerable to infection. In such cases, if treatment of an infection fails, it can become life threatening and hence fatal for such patients.
• Antibacterial drugs used to treat post-operative surgical site infections have become less effective or rather ineffective.

Mechanism of drug resistance
Antibiotic resistance is a specific type of drug resistance, which is a consequence of evolution via natural selection. Antibiotic resistance is the ability of bacteria and microbes to gain resistance over a period of time due to overuse and misuse. In order to fight and survive against the drugs and antibiotics, bacteria make some cellular and genetics changes by making modifications in its genome and in this way existing line of antibiotics  lose their potency because they are made to act on cell and genome of bacteria.

Resistance to antibiotics needs to be understood in context to a particular patient. This is so because any bacterium is susceptible to a very high concentration of an antibiotic, however one has to consider the condition of the patient during treatment. Factors such as type of bacterium, its location in the body, distribution of antibiotic in the body, its concentration at the site of infection and immune status of the patient are all important when determining resistance. This is why a complex concept of clinical resistance has emerged in recent times which is dependent on the outcome of treatment. The complexity is due to the fact that all the above listed factors interact at an individual level thus affecting resistance.

Resistance occurs by one of four different mechanisms in bacteria, it is possible that more than one mechanism can occur at a type in a particular bacterium. Antibiotic modification is most common in which resistant bacteria retain the same sensitive target as antibiotic sensitive strains but the antibiotic is prevented from reaching it. Example: B-lactamases.  In the second type, the antibiotic resistant bacteria prevent the antibiotic from flowing into the cell, rather entering into the cell, example would be low level resistance as seen with aminoglycosides and fluoroquinolones. The third mechanism is by alterations in the primary site of action – which necessarily means that the antibiotic penetrates the cell and reaches the target site but is unable to act because of structural changes in the molecule. Example is enterococci being resistant to cephalosporins. The final mechanism is one in which the bacteria produce an alternative target which is usually an enzyme that is resistant to inhibition while also continuing to produce the original sensitive target. A good example of this is the development of alternative penicillin binding protein in MRSA (methicillin resistant Staphylococcus aureus).

There are two types of resistance seen in bacteria: Intrinsic and acquired. In the intrinsic type, resistance develops due to the biology of the microorganism, example vancomycin resistance in E.coli. Acquired resistance occurs when a bacterium was earlier sensitive to antibiotics but now develops resistance either due to mutation or acquisition of new DNA.

Resistance mechanism could have probably evolved from genes present in bacteria producing antibiotics and these are present in common commensals too, to which we are continually exposed and which are found in food, environment and animals. Once this gene is generated, bacteria can transfer the genetic information by plasmid exchange. When a bacterium carries many such resistance genes it is called as multi resistant or in other words, a “super bug”.

Among the other factors that contribute towards resistance are incorrect diagnosis, unnecessary prescriptions and improper use of antibiotics by patients. When we first began our fight against bacteria we thought we had conquered them all. In time, we have realized that we cannot completely destroy the microbial world, resistance is a double edged sword, it has the antibiotic which is the selective factor that helps to propagate organisms with the second factor, the resistance gene. After all, it is a fight for survival.