A. Introduction

A drug is designed to affect a pathogen for reducing its effectiveness and to cure a disease, but when the effectiveness of a drug in curing a disease or in improving patient's symptoms decreases then the pathogen is said to be drug-resistant to that particular drug. A pathogen/organism is said to multidrug resistant when it is resistant to more than one drug. In other words, multidrug resistance (MDR) is typically defined as the ability of a living cell to show resistance to a wide variety of structurally and functionally unrelated compounds.Drug resistance occurs in several pathogen classes such as Bacteria, Endoparasites, Virus, Fungi and Cancer. Among these the most prominent is antibiotic resistance (the one due to bacteria).

B. The acquisition of antibiotic resistance in bacteria

Bacteria become drug resistant in several different ways. But it must be noted at the beginning that a particular type of resistance mechanism is not confined to a single class of drugs. Two bacteria may use different resistance mechanisms to withstand the same chemotherapeutic agent. Furthermore, resistant mutants arise spontaneously and are then selected. Mutants are not created directly by exposure to a drug. Mechanisms by which bacteria can become drug resistant are -

i) Preventing entrance of drugs:- bacteria can be resistant to an antibiotic by preventing its entrance in its cell, e.g. Gram (-) bacteria which doesn't allow some drugs to permeate through their cell wall (due to presence of outer membrane). Thus some Gram (+) bacteria which are affected by these drugs can change their cell wall structure and prevent the entrance of the antibiotics.

ii) Increasing active efflux:- A second resistance strategy is to pump the drug out of the cell after it has entered. Some pathogens have plasma membrane translocases, often called efflux pumps that expel drugs. Because they are relatively non-specific and can pump many different drugs, these transport proteins often are called multidrug-resistance pumps. Exact mechanism of efflux pump is not known and there is no idea that how a bacterial cell recognizes the foreign particle. It is assumed that the ability of pumps to recognize the substrate is based on physio-chemical properties such as hydrophobicity, aromaticity and ionizable character rather than defined chemical properties. As most of the antibiotics are amphilic molecule (possessing both hydrophilic and hydrophobic characters) they are easily recognized by efflux pumps.

iii) Drug modification:- Many bacterial pathogens resist attack by inactivating drugs through chemical modification. The best-known example is the hydrolysis of the B-lactam ring of many types of penicillin by the enzyme penicillinase. Drugs also are inactivated by the addition of groups. Resistant organisms may phosphorylate or acetylate aminoglycosides and acetylate chloramphenicol.

iv) Alteration of target sites: - Because each chemotherapeutic agent acts on a specific target, resistance arises when the target enzyme or organelle is modified so that it is no longer susceptible to the drug. For example, the affinity of ribosomes for erythromycin and chloramphenicol can be decreased by a change in the 23S rRNA to which they bind.

v) Use of alternate pathways:- Resistant bacteria may either use an alternate pathway to bypass the sequence inhibited by the agent or increase the production of the target metabolite. For example, some bacteria are resistant to sulfonamides simply because they use preformed folic acid (Folate, anion of folic acid, is necessary for the production and maintenance of new cells. It is also needed for DNA replication and thus folate deficiency hinders DNA synthesis & cell division) from their surroundings rather than synthesize it themselves. Other strains increase their rate of folic acid production and thus counteract sulfonamide inhibition.

C. The spread of antibiotic resistance in bacteria

The genes for drug resistance are present on both the bacterial chromosome and plasmids, small DNA molecules that can exist separate from the chromosome or be integrated in it. A bacterial pathogen is drug resistant because it has a plasmid bearing one or more resistance genes; such plasmids are called R plasmids (resistance plasmids). Plasmid resistance genes often code for enzymes that destroy or modify drugs. Once a bacterial cell possesses an R plasmid, the plasmid may be transferred to other cells quite rapidly through following gene exchange processes: -

i) Conjugation- It involves transfer of genetic material from one bacterium to another through the sex pilus.
ii) Transformation- process of transfer of naked DNA material from environment (released from dead bacterium) to a bacterial cell.
iii) Transduction- process of transfer of genetic material from a bacteriophage to a bacterial cell.

D. Factors that encourage the spread of resistance

i) Patient-related factors- Many patients believe that new and expensive medications are more efficacious than older agents. This perception encourages the selection of re­sistance to these newer agents as well as to older agents in their class.

ii) Self-medication with antimicrobials- It is another major factor contributing to resistance. Self-medicated antimicrobials may be unnecessary, are often inadequately dosed, or may not contain adequate amounts of active drug, especially if they are counterfeit drugs.

iii) The combination of highly sus­ceptible patients, intensive and prolonged antimicrobial use, and cross-infection have resulted in nosocomial infections with highly resistant bacterial pathogens.

iv) Patient compliance with recommended treatment is another major problem. Patients forget to take medication, interrupt their treatment when they begin to feel better, or may be unable to afford a full course, thereby creating the ideal environment for microbes to adapt rather than be killed.

v) Veterinary prescription of antimicrobials- it also contributes to the problem of resistance. The largest quantities are used as regular supplements for prophylaxis or growth promotion, thus exposing a large number of animals, irrespective of their health status, to frequently sub therapeutic concentrations of antimicrobials. Such wide­spread use of antimicrobials for disease control and growth promotion in animals has been paralleled by an increase in resistance in those bacteria.

E. Precautions required to reduce the factors that spread resistance

i) Patients should not take antibiotics for which there is no medical value.
ii) Patients should adhere to appropriate prescribing guidelines and take antibiotics until they have finished.
iii) Patients should be give combination of antibiotics, when necessary, to minimize the development of resistance to a single antibiotic.
iv) Patients need to be given another antibiotic or combination of antibiotics if the first is not working.

F. The medical problem of bacterial drug resistance

We are only now able to examine patterns of susceptibility and resistance to antibiotics among new pathogens that cause these diseases. Broad patterns of resistance exist in these pathogens, and it seems likely that we will soon need new antibiotics to replace the handful that are effective now against these bacteria, especially as resistance begins to emerge among them in the selective environment antibiotic chemotherapy.

G. Appendix

It is argued that government legislation will aid in educating the public on the importance of restrictive use of antibiotics, not only for human clinical use but also for treating animals raised for human consumption. Efforts to develop new antibiotics by the pharmaceutical industry by large-scale screens of chemical libraries which inhibit bacterial growth have largely failed, and new tetracycline and sulfanilamide analogs will likely engender resistance and will quickly be rendered useless. Not only is there a problem in finding new antibiotics to fight old diseases (because resistant strains of bacteria have emerged), there is a parallel problem to find new antibiotics to fight new diseases. In the past three decades, many "new" bacterial diseases have been discovered (E. coli O157:H7 gastric ulcers, Lyme disease, toxic shock syndrome, "skin-eating" streptococci).The resistance problem is compounded further by indiscriminate and inappropriate use of antibiotics and anti-viral compounds without compliance measures or public health policies to reduce disease burden. Finally, with current legislative restrictions, the very high costs associated with clinical trials (e.g. ~$400M to bring new tetracyclines to market for an expected revenue of ~$100M), the failure to control generic sales, and the capacity to generate substantial revenues from medications for chronic illnesses, there is little if any financial incentive for big pharmaceutical companies to even develop new antibiotics, and small biotech companies simply do not have the resources. One positive development has been vaccines, which are promising for some bacterial and viral illnesses. But vaccines are not successful in all cases (e.g. in young children), and adequate resources have not been made available.

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