Antibiotic resistance

Antibiotic resistance is a type of drug resistance where a microorganism is able to survive exposure to an antibiotic. While a spontaneous or induced genetic mutation in bacteria may confer resistance to antimicrobial drugs, genes that confer resistance can be transferred between bacteria in a horizontal fashion by conjugation, transduction, or transformation. Thus a gene for antibiotic resistance which had evolved via natural selection may be shared. Evolutionary stress such as exposure to antibiotics then selects for the antibiotic resistant trait. Many antibiotic resistance genes reside on plasmids, facilitating their transfer. If a bacterium carries several resistance genes, it is called multidrug resistant (MDR) or, informally, a superbug or super bacterium.

Genes for resistance to antibiotics, like the antibiotics themselves, are ancient. [1] However, the increasing prevalence of antibiotic-resistant bacterial infections seen in clinical practice stems from antibiotic use both within human medicine and veterinary medicine. Any use of antibiotics can increase selective pressure in a population of bacteria to allow the resistant bacteria to thrive and the susceptible bacteria to die off. As resistance towards antibiotics becomes more common, a greater need for alternative treatments arises. However, despite a push for new antibiotic therapies there has been a continued decline in the number of newly approved drugs.[2][clarification needed] Antibiotic resistance therefore poses a significant problem.

Contents

Causes

The widespread use of antibiotics both inside and outside of medicine is playing a significant role in the emergence of resistant bacteria.[3] Although there were low levels of preexisting antibiotic-resistant bacteria before the widespread use of antibiotics,[4][5] evolutionary pressure from their use has played a role in the development of muiltidrug resistance varieties and the spread of resistance between bacterial species.[6] Antibiotics are often used in rearing animals for food, and this use, among others, leads to the creation of resistant strains of bacteria. In some countries, antibiotics are sold over the counter without a prescription, which also leads to the creation of resistant strains. In human medicine, the major problem of the emergence of resistant bacteria is due to misuse and overuse of antibiotics by doctors as well as patients.[7] Other practices contributing towards resistance include the addition of antibiotics to livestock feed.[8][9] Household use of antibacterials in soaps and other products, although not clearly contributing to resistance, is also discouraged (as not being effective at infection control).[10] Also unsound practices in the pharmaceutical manufacturing industry can contribute towards the likelihood of creating antibiotic-resistant strains.[11]

Certain antibiotic classes are highly associated with colonisation with superbugs compared to other antibiotic classes. The risk for colonisation increases if there is a lack of sensitivity (resistance) of the superbugs to the antibiotic used and high tissue penetration, as well as broad-spectrum activity against "good bacteria". In the case of MRSA, increased rates of MRSA infections are seen with glycopeptides, cephalosporins and especially quinolones.[12][13] In the case of colonisation with Clostridium difficile the high risk antibiotics include cephalosporins and in particular quinolones and clindamycin.[14][15]

In a paper published in the recent edition of the journal Nature, researchers at McMaster University say they have discovered that antibiotic-resistant genes existed in soil bacteria at the same time that now-extinct mammoths, early horses and bison roamed Canada's North.

In medicine

The volume of antibiotic prescribed is the major factor in increasing rates of bacterial resistance rather than compliance with antibiotics.[16] A single dose of antibiotics leads to a greater risk of resistant organisms to that antibiotic in the person for up to a year.[17]

Inappropriate prescribing of antibiotics has been attributed to a number of causes, including: people who insist on antibiotics, physicians simply prescribe them as they feel they do not have time to explain why they are not necessary, physicians who do not know when to prescribe antibiotics or else are overly cautious for medical legal reasons.[18] For example, a third of people believe that antibiotics are effective for the common cold[19] and 22% of people do not finish a course of antibiotics primarily because they feel better (varying from 10% to 44%, depending on the country).[20] Compliance with once-daily antibiotics is better than with twice-daily antibiotics.[21] Suboptimum antibiotic concentrations in critically ill people increase the frequency of antibiotic resistance organisms.[22] While taking antibiotics doses less than those recommended may increase rates of resistance, shortening the course of antibiotics may actually decrease rates of resistance.[16][23]

Poor hand hygiene by hospital staff has been associated with the spread of resistant organisms[24] and an increase in hand washing compliance results in decreased rates of these organisms.[25]

Role of other animals

Drugs are used in animals that are used as human food, such as cattle, pigs, chickens, fish, etc., and these drugs can affect the safety of the meat, milk, and eggs produced from those animals and can be the source of superbugs. For example, farm animals, particularly pigs, are believed to be able to infect people with MRSA.[26] The resistant bacteria in animals due to antibiotic exposure can be transmitted to humans via three pathways, those being through the consumption of meat, from close or direct contact with animals, or through the environment.[27]

The World Health Organization concluded antibiotics as growth promoters in animal feeds should be prohibited in the absence of risk assessments. In 1998, European Union health ministers voted to ban four antibiotics widely used to promote animal growth (despite their scientific panel's recommendations). Regulation banning the use of antibiotics in European feed, with the exception of two antibiotics in poultry feeds, became effective in 2006.[28] In Scandinavia, there is evidence that the ban has led to a lower prevalence of antimicrobial resistance in (nonhazardous) animal bacterial populations.[29] In the USA, federal agencies do not collect data on antibiotic use in animals, but animal-to-human spread of drug-resistant organisms has been demonstrated in research studies. Antibiotics are still used in U.S. animal feed, along with other ingredients which have safety concerns.[9][30]

Growing U.S. consumer concern about using antibiotics in animal feed has led to a niche market of "antibiotic-free" animal products, but this small market is unlikely to change entrenched, industry-wide practices.[31]

In 2001, the Union of Concerned Scientists estimated that greater than 70% of the antibiotics used in the US are given to food animals (for example, chickens, pigs and cattle) in the absence of disease.[32] In 2000, the US Food and Drug Administration (FDA) announced their intention to revoke approval of fluoroquinolone use in poultry production because of substantial evidence linking it to the emergence of fluoroquinolone-resistant Campylobacter infections in humans. The final decision to ban fluoroquinolones from use in poultry production was not made until five years later because of challenges from the food animal and pharmaceutical industries.[33] During 2007, two federal bills (S. 549[34] and H.R. 962[35]) aim at phasing out "nontherapeutic" antibiotics in US food animal production.

Mechanisms

Schematic representation of how antibiotic resistance evolves via natural selection. The top section represents a population of bacteria before exposure to an antibiotic. The middle section shows the population directly after exposure, the phase in which selection took place. The last section shows the distribution of resistance in a new generation of bacteria. The legend indicates the resistance levels of individuals.
Diagram depicting antibiotic resistance through alteration of the antibiotic's target site, modeled after MRSA's resistance to penicillin. Beta-lactam antibiotics permanently inactivate PBP enzymes, which are essential for bacterial life, by permanently binding to their active sites. MRSA, however, expresses a PBP that will not allow the antibiotic into its active site.

Antibiotic resistance can be a result of horizontal gene transfer,[36] and also of unlinked point mutations in the pathogen genome at a rate of about 1 in 108 per chromosomal replication. The antibiotic action against the pathogen can be seen as 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 result in the evolution of a fully resistant colony.

The four main mechanisms by which microorganisms exhibit resistance to antimicrobials are:

  1. Drug inactivation or modification: for example, enzymatic deactivation of penicillin G in some penicillin-resistant bacteria through the production of β-lactamases
  2. Alteration of target site: for example, alteration of PBP—the binding target site of penicillins—in MRSA and other penicillin-resistant bacteria
  3. Alteration of metabolic pathway: for example, 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 using preformed folic acid.
  4. Reduced drug accumulation: by decreasing drug permeability and/or increasing active efflux (pumping out) of the drugs across the cell surface[37]

There are three known mechanisms of fluoroquinolone resistance. Some types of efflux pumps can act to decrease intracellular quinolone concentration.[38] In Gram-negative bacteria, plasmid-mediated resistance genes produce proteins that can bind to DNA gyrase, protecting it from the action of quinolones. Finally, mutations at key sites in DNA gyrase or topoisomerase IV can decrease their binding affinity to quinolones, decreasing the drug's effectiveness.[39] Research has shown the bacterial protein LexA may play a key role in the acquisition of bacterial mutations giving resistance to quinolones and rifampicin.[40]

Antibiotic resistance can also be introduced artificially into a microorganism through laboratory protocols, sometimes used as a selectable marker to examine the mechanisms of gene transfer or to identify individuals that absorbed a piece of DNA that included the resistance gene and another gene of interest. A recent study demonstrated the extent of horizontal gene transfer among Staphylococcus to be much greater than one previously expected, and encompasses genes with functions beyond antibiotic resistance and virulence, and beyond genes residing within the mobile genetic elements.[41]

Resistant pathogens

Staphylococcus aureus

Staphylococcus aureus (colloquially known as "Staph aureus" or a "Staph infection") is one of the major resistant pathogens. Found on the mucous membranes and the human skin of around a third of the population, it is extremely adaptable to antibiotic pressure. It was one of the earlier bacteria 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, but has since been replaced by oxacillin due to significant kidney toxicity. Methicillin-resistant Staphylococcus aureus (MRSA) was first detected in Britain in 1961, and is now "quite common" in hospitals. MRSA was responsible for 37% of fatal cases of sepsis 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, strains with intermediate (4-8 μg/ml) levels of resistance, termed glycopeptide-intermediate Staphylococcus aureus (GISA) or vancomycin-intermediate Staphylococcus aureus (VISA), began appearing in the late 1990s. The first identified case was in Japan in 1996, and strains have since been found in hospitals in England, France and the US. The first documented strain with complete (>16 μg/ml) resistance to vancomycin, termed vancomycin-resistant Staphylococcus aureus (VRSA) appeared in the United States in 2002.[42]

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 S. aureus was reported in 2003.[citation needed]

Community-acquired MRSA (CA-MRSA)has now emerged as an epidemic that is responsible for rapidly progressive, fatal diseases, including necrotizing pneumonia, severe sepsis and necrotizing fasciitis.[43] MRSA is the most frequently identified antimicrobial drug-resistant pathogen in US hospitals. The epidemiology of infections caused by MRSA is rapidly changing. In the past 10 years, infections caused by this organism have emerged in the community. The two MRSA clones in the United States most closely associated with community outbreaks, USA400 (MW2 strain, ST1 lineage) and USA300, often contain Panton-Valentine leukocidin (PVL) genes and, more frequently, have been associated with skin and soft tissue infections. Outbreaks of CA-MRSA infections have been reported in correctional facilities, among athletic teams, among military recruits, in newborn nurseries, and among men who have sex with men. CA-MRSA infections now appear to be endemic in many urban regions and cause most CA-S. aureus infections.[44]

Streptococcus and Enterococcus

Streptococcus pyogenes (Group A Streptococcus: GAS) infections can usually be treated with many different antibiotics. Early treatment may reduce the risk of death from invasive group A streptococcal disease. However, even the best medical care does not prevent death in every case. For those with very severe illness, supportive care in an intensive care unit may be needed. For persons with necrotizing fasciitis, surgery often is needed to remove damaged tissue.[45] Strains of S. pyogenes resistant to macrolide antibiotics have emerged; however, all strains remain uniformly sensitive to penicillin.[46]

Resistance of Streptococcus pneumoniae to penicillin and other beta-lactams is increasing worldwide. The major mechanism of resistance involves the introduction of mutations in genes encoding penicillin-binding proteins. Selective pressure is thought to play an important role, and use of beta-lactam antibiotics has been implicated as a risk factor for infection and colonization. S. pneumoniae is responsible for pneumonia, bacteremia, otitis media, meningitis, sinusitis, peritonitis and arthritis.[46]

Multidrug-resistant Enterococcus faecalis and Enterococcus faecium are associated with nosocomial infections.[47] Among these strains, penicillin-resistant Enterococcus was seen in 1983, vancomycin-resistant Enterococcus in 1987, and linezolid-resistant Enterococcus in the late 1990s.[citation needed]

Pseudomonas aeruginosa

Pseudomonas aeruginosa is a highly prevalent opportunistic pathogen. One of the most worrisome characteristics of P. aeruginosa is its low antibiotic susceptibility, which is is attributable to a concerted action of multidrug efflux pumps with chromosomally encoded antibiotic resistance genes (for example, mexAB-oprM, mexXY, etc.) and the low permeability of the bacterial cellular envelopes.[48] Besides intrinsic resistance, P. aeruginosa easily evolves specific resistance either by mutation in chromosomally-encoded genes, or by the horizontal gene transfer of antibiotic resistance determinants. Evolution of multidrug resistance by P. aeruginosa isolates requires several genetic events that include acquisition of different mutations and/or horizontal transfer of antibiotic resistance genes. Hypermutation favours the selection of mutation-driven antibiotic resistance in P. aeruginosa strains, producing chronic infections, whereas the clustering of several different antibiotic resistance genes in integrons favours the concerted acquisition of antibiotic resistance determinants. Some recent studies have shown phenotypic resistance associated with biofilm formation or the emergence of small-colony-variants may be important in the response of P. aeruginosa populations to antibiotics treatment.[49][50]

Clostridium difficile

Clostridium difficile is a nosocomial pathogen that causes diarrheal disease in hospitals world wide.[51][52] Clindamycin-resistant C. difficile was reported as the causative agent of large outbreaks of diarrheal disease in hospitals in New York, Arizona, Florida and Massachusetts between 1989 and 1992.[53] Geographically dispersed outbreaks of C. difficile strains resistant to fluoroquinolone antibiotics, such as ciprofloxacin and levofloxacin, were also reported in North America in 2005.[54]

Salmonella and E. coli

Escherichia coli and Salmonella come directly from contaminated food. When both bacteria are spread, serious health conditions arise. Many people are hospitalized each year after becoming infected, with some dying as a result. By 1993, E. coli resistant to multiple fluoroquinolone variants was documented.[citation needed]

Acinetobacter baumannii

On November 5, 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.[55][56]

Mycobacterium tuberculosis

Resistance of Mycobacterium tuberculosis to isoniazid, rifampin, and other common treatments has become an increasingly relevant clinical challenge.

Alternatives

Prevention

Rational use of antibiotics may reduce the chances of development of opportunistic infection by antibiotic-resistant bacteria due to dysbacteriosis. In one study, the use of fluoroquinolones is clearly associated with Clostridium difficile infection, which is a leading cause of nosocomial diarrhea in the United States,[57] and a major cause of death, worldwide.[58]

There is clinical evidence that topical dermatological preparations, such as those containing tea tree oil and thyme oil, may be effective in preventing transmittal of CA-MRSA.[59] In addition, other phytotherapeutic medicines, too, can reduce the use of antibiotics or eliminate their use entirely.[60]

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; for example an update influenza vaccine is needed each year.

While theoretically promising, antistaphylococcal 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.[citation needed]

The Australian Commonwealth Scientific and Industrial Research Organization (CSIRO), realizing the need for the reduction of antibiotic use, has been working on two alternatives. One alternative is to prevent diseases by adding cytokines instead of antibiotics to animal feed.[citation needed] These proteins are made in the animal body "naturally" after a disease and are not antibiotics, so they do not contribute to the antibiotic resistance problem. Furthermore, studies on using cytokines have shown they also enhance the growth of animals like the antibiotics now used, but without the drawbacks of nontherapeutic antibiotic use. Cytokines have the potential to achieve the animal growth rates traditionally sought by the use of antibiotics without the contribution of antibiotic resistance associated with the widespread nontherapeutic uses of antibiotics currently used in the food animal production industries. Additionally, CSIRO is working on vaccines for diseases.[citation needed]

Phage therapy

Phage therapy, an approach that has been extensively researched and used as a therapeutic agent for over 60 years, especially in the Soviet Union, is an alternative that might help with the problem of resistance. Phage therapy was widely used in the United States until the discovery of antibiotics, in the early 1940s. Bacteriophages or "phages" are viruses that invade bacterial cells and, in the case of lytic phages, disrupt bacterial metabolism and cause the bacterium to lyse. Phage therapy is the therapeutic use of lytic bacteriophages to treat pathogenic bacterial infections.[61][62][63]

Bacteriophage therapy is an important alternative to antibiotics in the current era of multidrug resistant pathogens. A review of studies that dealt with the therapeutic use of phages from 1966–1996 and few latest ongoing phage therapy projects via internet showed: phages were used topically, orally or systemically in Polish and Soviet studies. The success rate found in these studies was 80–95% with few gastrointestinal or allergic side effects. British studies also demonstrated significant efficacy of phages against Escherichia coli, Acinetobacter spp., Pseudomonas spp. and Staphylococcus aureus. US studies dealt with improving the bioavailability of phage. Phage therapy may prove as an important alternative to antibiotics for treating multidrug resistant pathogens.[64][65]

Research

New medications

Until recently, research and development (R&D) efforts have provided new drugs in time to treat bacteria that became resistant to older antibiotics. That is no longer the case.[citation needed] The potential crisis at hand is the result of a marked decrease in industry R&D, and the increasing prevalence of resistant bacteria. Infectious disease physicians are alarmed by the prospect that effective antibiotics may not be available to treat seriously ill patients in the near future[citation needed].

As bacterial antibiotic resistance continues to exhaust the supply of effective antibiotics, a global public health disaster appears likely[citation needed]. Poor financial investment in antibiotic research has exacerbated the situation[citation needed]. A call to arms raised by several prestigious scientific organisations a few years ago rallied the scientific community, and now the scope of antibacterial research has broadened considerably.[66]

The pipeline of new antibiotics is drying up.[citation needed]Major pharmaceutical companies are losing interest in the antibiotics market because these drugs may not be as profitable as drugs that treat chronic (long-term) conditions and lifestyle issues.[67]

Archaeocins is the name given to a new class of potentially useful antibiotics that are derived from the Archaea group of organisms. Eight archaeocins have been partially or fully characterized, but hundreds are believed to exist, especially within the haloarchaea. The prevalence of archaeocins is unknown simply because no one has looked for them. The discovery of new archaeocins hinges on recovery and cultivation of archaeal organisms from the environment. For example, samples from a novel hypersaline field site, Wilson Hot Springs, recovered 350 halophilic organisms; preliminary analysis of 75 isolates showed that 48 were archaeal and 27 were bacterial.[68]

In research published on October 17, 2008 in Cell, a team of scientists pinpointed the place on bacteria where the antibiotic myxopyronin launches its attack, and why that attack is successful. The myxopyronin binds to and inhibits the crucial bacterial enzyme, RNA polymerase. The myxopyronin changes the structure of the switch-2 segment of the enzyme, inhibiting its function of reading and transmitting DNA code. This prevents RNA polymerase from delivering genetic information to the ribosomes, causing the bacteria to die.[69]

One of the major causes of antibiotic resistance is the decrease of effective drug concentrations at their target place, due to the increased action of ABC transporters. Since ABC transporter blockers can be used in combination with current drugs to increase their effective intracellular concentration, the possible impact of ABC transporter inhibitors is of great clinical interest. ABC transporter blockers that may be useful to increase the efficacy of current drugs have entered clinical trials and are available to be used in therapeutic regimens.[70]

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:

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.

See also

References

Footnotes

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