The origin of resistant genes could be due a natural process whereby the resistant genes are maintained in nature because of the presence of antibiotics producing bacteria in soil. These antibiotics act on other bacterial species other than the producer bacteria13. There has to be a mechanism of protection in the host bacteria against the antibiotics that it produces, which could be the source of genes encoding resistance. Resistance to penicillin in S. aureus was observed just a few years after penicillin came into use14.
As the next generations of antibiotics were developed to overcome the problems of resistance against available antibiotics, bacteria developed mechanisms to resist the newer antimicrobial also. For example, the resistance to penicillin initially was due to production of an enzyme penicillinase by bacteria, antibiotics like cloxallin were developed which was resistant to penicillinase enzyme. To resist these antibiotics bacteria altered the target site for binding of b-lactam antibiotics i.e., PBPs and this led to the development of MRSA15. Simultaneously attempts were being made to develop newer generations of cephalosporins with wide range of activity and resistance to existing known b-lactamase enzymes. The3rd and 4th generations of cephalosporins were introduced which were not destroyed by the blactamases produced by the Gram negative bacteria16.
However, after the wide use, the bacteria responded by developing mechanisms producing ESBL to destroy these drugs. To overcome this problem carbapenems were introduced, which were resistant to ESBL enzymes. These agents were the best in the b-lactam group of antibiotics but no sooner have they came into use, the bacterial populations started producing carbapenemases which hydrolyze carbapenems17. Thus it is evident that though numerous b-lactam antibiotics have been developed during the last 40 yr in an attempt to circumvent the activity of b-lactamases, the prime result of this has been the selection of more diverse and potentially more deleterious enzymes hydrolyzing all b-lactams. The situation is alarming because b-lactams are otherwise the best bactericidal agents which when combined with aminoglycosides another bactericidal agent, make a synergistic combination and is an ideal choice for all types of critical infections. This is also the best choice of empirical therapy in infections in an immunocompromised host and in patients in high risk units18.
Another classical example of emergence of resistance due to abuse of antibiotics is the extensive use of vancomycin. As the infections due to MRSA in hospitals all over the world increased, vancomycin became the drug of choice to treat these infections. This led to the selection of VRE present as normal flora in the gut of the patient19, and possibly contributed to the emergence of VRE besides other factors. Various contributing factors responsible for emergence of antibiotic resistance are:
(i) Lack of education—The combination of poverty and ignorance makes the ground perfect for resistance development. Important reason for irrational therapy is inability to buy adequate quantity of antibiotics or to reach to qualified doctors due to poverty or ignorance for rational prescriptions of antibiotics20.
(ii) Hospital acquired infections—Hospitals are the places where the selective pressure of antibiotics is the highest as the hospital bacteria are mostly multi drug resistant21. The main reason for this is the increase in hospital associated infections because of the disregard to standard isolation precautions in most of the busy hospitals with limited resources22.
(iii) Use of antibiotics in agriculture or aquaculture — Antibiotics are used widely in agriculture and aquaculture for therapeutic, prophylactic and growth promoting purposes23,24. The presence of residual antibiotics in the flesh of animals may result in direct exposure of the consumers to these drugs. In addition, the presence of low levels of antibiotics may select for resistant bacteria in the intestines of animals intended for human consumption. The animals can be contaminated with facal bacteria during the slaughter process and therefore contaminate the meat reaching the consumer. Emergence of VRE is one particular example of appearance of resistant bacteria in animals that have affected susceptible human populations25. Antibiotics resistant bacteria can also be found on fruits and vegetables due to spreading of sewage sludge on farm land or use of antibiotics directly on fruit and vegetable crops23.
(iv) Environmental factors- The presence of antibiotic resistant bacteria in fresh water sources has been documented from different parts of the world24. Selection of resistant organism in nature may result from the natural production of antibiotics by soil organisms, or contamination from animal feed or crops or waste products from treated animals or humans. Resistant organisms from farming practices may be transferred into rivers and other water sourses through waste disposal system or by drainage or rain water from farm land23. All these factors contribute to the natural reservoirs of resistance genes which may provide a source of transferable genes.
(v) Use in household products—There is an increase in the use of surface antibacterial agents over the years into healthy households. The antibacterial substances added to diverse household cleaning products are similar to antibiotics in many ways26. These products can also select out resistant strains.