Antimicrobial Resistance

Antimicrobial resistance or Antibiotic resistance is the ability of a microorganism to withstand the effects of an antibiotic. Antibiotic resistance can develop naturally via natural selection through random mutation. SOS response of low-fidelity polymerases can also cause mutation via a process known as programmed evolution. Once such a gene is generated, bacteria can then transfer the genetic information in a horizontal fashion (between individuals) by plasmid exchange. If a bacterium carries several resistance genes, it is called multiresistant or, informally, a superbug.

Antibiotic resistance can also be introduced artificially into a microorganism through transformation protocols. This can be a useful way of implanting artificial genes into the microorganism.

Causes
Antibiotic resistance is a consequence of evolution via natural selection or programmed evolution. The antibiotic action is an environmental pressure; those bacteria which have a mutation allowing them to survive will live on to reproduce. They will then pass this trait to their offspring, which will be a fully resistant generation.

Several studies have demonstrated that patterns of antibiotic usage greatly affect the number of resistant organisms which develop. Overuse of broad-spectrum antibiotics, such as second- and third-generation cephalosporins, greatly hastens the development of methicillin resistance, even in organisms that have never been exposed to the selective pressure of methicillin per se. [Thus the resistance was already present.] Other factors contributing towards resistance include incorrect diagnosis, unnecessary prescriptions, improper use of antibiotics by patients, and the use of antibiotics as livestock food additives for growth promotion.

Mechanisms of antibiotic resistance
The four main mechanisms by which microorganisms exhibit resistance to antimicrobials are:
 * 1) Drug inactivation or modification: e.g. enzymatic deactivation of Penicillin G in some penicillin-resistant bacteria through the production of β-lactamases.
 * 2) Alteration of target site : e.g. alteration of PBP - the binding target site of penicillins - in MRSA and  other penicillin-resistant bacteria.
 * 3) Alteration of metabolic pathway: e.g. some sulfonamide-resistant bacteria do not require para-aminobenzoic acid (PABA) - an important precursor for the synthesis of folic acid and nucleic acids in bacteria inhibited by sulfonamides. Instead, like mammalian cells, they turn to utilizing preformed folic acid.
 * 4) Reduced  drug accumulation: by decreasing drug permeability and/or increasing active efflux.

Resistant pathogens
Staphylococcus aureus (colloquially known as "Staph aureus") is one of the major resistant pathogens. Found on the mucous membranes and the skin of around a third of the population, it is extremely adaptable to antibiotic pressure. It was the first bacterium in which penicillin resistance was found -- in 1947, just four years after the drug started being mass-produced. Methicillin was then the antibiotic of choice. MRSA (methicillin-resistant Staphylococcus aureus) was first detected in Britain in 1961 and is now "quite common" in hospitals. MRSA was responsible for 37% of fatal cases of blood poisoning in the UK in 1999, up from 4% in 1991. Half of all S. aureus infections in the US are resistant to penicillin, methicillin, tetracycline and erythromycin.

This left vancomycin as the only effective agent available at the time. However, VRSA (Vancomycin-resistant Staphylococcus aureus) was first identified in Japan in 1997, and has since been found in hospitals in England, France and the US. VRSA is also termed GISA (glycopeptide intermediate Staphylococcus aureus) or VISA (vancomycin insensitive Staphylococcus aureus), indicating resistance to all glycopeptide antibiotics.

A new class of antibiotics, oxazolidinones, became available in the 1990s, and the first commercially available oxazolidinone, linezolid, is comparable to vancomycin in effectiveness against MRSA. Linezolid-resistance in Staphylococcus aureus was reported in 2003.

Enterococcus faecium is another superbug found in hospitals. Penicillin-Resistant Enterococcus was seen in 1983, Vancomycin-Resistant Enterococcus (VRE) in 1987, and Linezolid-Resistant Enterococcus (LRE) in the late 1990s.

Penicillin-resistant pneumonia (or pneumococcus, caused by Streptococcus pneumoniae) was first detected in 1967, as was penicillin-resistant gonorrhea. Resistance to penicillin substitutes is also known beyond S. aureus. By 1993 Escherichia coli was resistant to five fluoroquinolone variants. Mycobacterium tuberculosis is commonly resistant to isoniazid and rifampin and sometimes universally resistant to the common treatments. Other pathogens showing some resistance include Salmonella, Campylobacter, and Streptococci.

In November, 2004, the Centers for Disease Control and Prevention (CDC) reported an increasing number of Acinetobacter baumannii bloodstream infections in patients at military medical facilities in which service members injured in the Iraq/Kuwait region during Operation Iraqi Freedom and in Afghanistan during Operation Enduring Freedom were treated. Most of these showed multidrug resistance (MRAB), with a few isolates resistant to all drugs tested. 

Antibiotic resistance and the role of animals
MRSA is acknowledged to be a human commensal and pathogen. MRSA has been found in cats, dogs and horses, where it can cause the same problems as it does in humans. Owners can transfer the organism to their pets and vice-versa, and MRSA in animals is generally believe to be derived from humans.

This is not the case for other pathogens, however. There are concerns that some antibiotic resistant organisms may derive from the use of antibiotics in food animals. 15% of all antibiotics manufactured in Europe are used on animals. For precisely this reason, in many countries, antibiotics that are licensed for human use are banned from use in animals. However, related antibiotics are often used as growth promoters (particularly in poultry) and have been associated with the development of resistant strains.

The US Food and Drug Administration banned enrofloxacin from use in poultry in July 2005. Campylobacter is an avian gut commensal, and Campylobacter gastroenteritis in humans is associated with the consumption of undercooked chicken. Campylobacter resistance is up to 20% in parts of the developed world. Enrofloxacin is a fluoroquinolone whose mechanism of action is very similar to ciprofloxacin; it is used in veterinary practice to treat respiratory infections of poultry, when it is added to water or to the feed and may be used to medicate a whole flock. Farmers lobby groups often agitate that there is no evidence of the transfer of antibiotic resistance in food animals to humans, but given Campylobacter does not naturally occur in humans and that ciprofloxacin resistance is increasing, it is difficult not to draw the conclusion that ciprofloxacin-resistant Campylobacter in humans arises from eating enrofloxacin-resistant Campylobacter in chickens, hence the FDA ban on enrofloxacin.

The illegal use of amantadine to medicate poultry in the South of China and other parts of southeast Asia, means that although the H5N1 strain that appear in Hong Kong in 1997 was amantadine sensitive, the more recent strains have all been amantadine resistant. This seriously reduces the treatment options available to doctors in the event of an influenza pandemic.

Eighteen UK organisations banded together in November 1997 to set guidelines on the use of antibiotics in farm animals, in order to address the concerns of the larger public. The consortium is called RUMA (Responsible use of Medicine in Agriculture Alliance) Members of this consortium include the British Poultry Council and various industry and pharmaceutical firms. The European Union has banned the use of all antibiotics as growth promoters since 1 January 2006.

Prevention
Wash hands properly to reduce the chance of getting sick and spreading infection. Wash fruits and vegetables thoroughly. Avoid raw eggs and undercooked meat, especially in ground form.

Do not demand antibiotics from your physician; if antibiotics are not prescribed, there is a reason.

When given antibiotics, take them exactly as prescribed, and complete the full course of treatment; do not hoard pills for later use, or share leftover antibiotics.

Vaccines
Vaccines do not suffer the problem of resistance because a vaccine enhances the body's natural defenses, while an antibiotic operates separately from the body's normal defenses. Nevertheless, new strains may evolve that escape immunity induced by vaccines.

While theoretically promising, anti-staphylococcal vaccines have shown limited efficacy, because of immunological variation between Staphylococcus species, and the limited duration of effectiveness of the antibodies produced. Development and testing of more effective vaccines is under way.

Phage therapy
Phage therapy is a more recent alternative that can cope with the problem of resistance.

Development of newer antibiotics
The resistance problem demands that a renewed effort be made to seek antibacterial agents effective against pathogenic bacteria resistant to current antibiotics. One of the possible strategies towards this objective is the rational localization of bioactive phytochemicals. Plants have an almost limitless ability to synthesize aromatic substances, most of which are phenols or their oxygen-substituted derivatives such as tannins. Most are secondary metabolites, of which at least 12,000 have been isolated, a number estimated to be less than 10% of the total. In many cases, these substances serve as plant defense mechanisms against predation by microorganisms, insects, and herbivores. Many of the herbs and spices used by humans to season food yield useful medicinal compounds including those having antibacterial activity.

Traditional healers have long used plants to prevent or cure infectious conditions. Many of these plants have been investigated scientifically for antimicrobial activity and a large number of plant products have been shown to inhibit growth of pathogenic bacteria. A number of these agents appear to have structures and modes of action that are distinct from those of the antibiotics in current use, suggesting that cross-resistance with agents already in use may be minimal.

Applications
Antibiotic resistance is an important tool for genetic engineering. By constructing a plasmid which contains an antibiotic resistance gene as well as the gene being engineered or expressed, a researcher can ensure that when bacteria replicate, only the copies which carry along the plasmid survive. This ensures that the gene being manipulated passes along when the bacteria replicates.

The most commonly used antibiotics in genetic engineering are generally "older" antibiotics which have largely fallen out of use in clinical practice. These include:


 * ampicillin
 * kanamycin
 * tetracycline
 * chloramphenicol

Industrially the use of antibiotic resistance is disfavored since maintaining bacterial cultures would require feeding them large quantities of antibiotics. Instead, the use of auxotrophic bacterial strains (and function-replacement plasmids) is preferred.