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7.1.1: Origins of Antimicrobial Drugs - Biology

7.1.1: Origins of Antimicrobial Drugs - Biology


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The era of antimicrobials begins when Pasteur and Joubert discover that one type of bacteria could prevent the growth of another.

Learning Objectives

  • Recall the technical defintion of antibiotics

Key Points

  • Antibiotics are only those substances that are produced by one microorganism that kill, or prevent the growth, of another microorganism.
  • In today’s common usage, the term antibiotic is used to refer to almost any drug that attempts to rid your body of a bacterial infection.
  • The discovery of antimicrobials like penicillin and tetracycline paved the way for better health for millions around the world.

Key Terms

  • antimicrobial: An agent that destroys microbes, inhibits their growth, or prevents or counteracts their pathogenic action.
  • penicillin: Any of a group of broad-spectrum antibiotics obtained from Penicillium molds or synthesized; they have a beta-lactam structure; most are active against gram-positive bacteria and used in the treatment of various infections and diseases.

The history of antimicrobials begins with the observations of Pasteur and Koch, who discovered that one type of bacteria could prevent the growth of another. They did not know at that time that the reason one bacterium failed to grow was that the other bacterium was producing an antibiotic. Technically, antibiotics are only those substances that are produced by one microorganism that kill, or prevent the growth, of another microorganism.

The discovery of antimicrobials like penicillin by Alexander Fleming and tetracycline paved the way for better health for millions around the world. Before penicillin became a viable medical treatment in the early 1940s, no true cure for gonorrhea, strep throat, or pneumonia existed. Patients with infected wounds often had to have a wounded limb removed, or face death from infection. Now, most of these infections can be cured easily with a short course of antimicrobials.

The term antibiotic was first used in 1942 by Selman Waksman and his collaborators in journal articles to describe any substance produced by a microorganism that is antagonistic to the growth of other microorganisms in high dilution. This definition excluded substances that kill bacteria, but are not produced by microorganisms (such as gastric juices and hydrogen peroxide). It also excluded synthetic antibacterial compounds such as the sulfonamides. Many antibacterial compounds are relatively small molecules with a molecular weight of less than 2000 atomic mass units. With advances in medicinal chemistry, most of today’s antibacterials chemically are semisynthetic modifications of various natural compounds.


7.1.1: Origins of Antimicrobial Drugs - Biology

An antimicrobial is a substance that kills or inhibits the growth of microorganisms such as bacteria, fungi, or protozoans.

Learning Objectives

Recall the synthetic antimicrobial drugs that are sulfonamide and sulphonamide based

Key Takeaways

Key Points

  • The discovery of antimicrobials like penicillin and tetracycline paved the way for better health for millions around the world.
  • With the development of antimicrobials, microorganisms have adapted and become resistant to previous antimicrobial agents.
  • Synthetic agents include: sulphonamides, cotrimoxazole, quinolones, anti-virals, anti-fungals, anti-cancer drugs, anti-malarials, anti-tuberculosis drugs, anti-leprotics, and anti-protozoals.

Key Terms

  • antimicrobial: An agent that destroys microbes, inhibits their growth, or prevents or counteracts their pathogenic action.
  • microorganism: An organism that is too small to be seen by the unaided eye, especially a single-celled organism, such as a bacterium.
  • bacteria: A type, species, or strain of bacterium.

An antimicrobial is a substance that kills or inhibits the growth of microorganisms such as bacteria, fungi, or protozoans. Antimicrobial drugs either kill microbes (microbiocidal) or prevent the growth of microbes (microbiostatic). Disinfectants are antimicrobial substances used on non-living objects or outside the body.

The history of antimicrobials begins with the observations of Pasteur and Joubert, who discovered that one type of bacteria could prevent the growth of another. They did not know at that time that the reason one bacterium failed to grow was that the other bacterium was producing an antibiotic. Technically, antibiotics are only those substances that are produced by one microorganism that kill, or prevent the growth, of another microorganism. Of course, in today’s common usage, the term antibiotic is used to refer to almost any drug that attempts to rid your body of a bacterial infection. Antimicrobials include not just antibiotics, but synthetically formed compounds as well.

The discovery of antimicrobials like penicillin and tetracycline paved the way for better health for millions around the world. Before penicillin became a viable medical treatment in the early 1940s, no true cure for gonorrhea, strep throat, or pneumonia existed. Patients with infected wounds often had to have a wounded limb removed, or face death from infection. Now, most of these infections can be cured easily with a short course of antimicrobials.

However, with the development of antimicrobials, microorganisms have adapted and become resistant to previous antimicrobial agents. The old antimicrobial technology was based either on poisons or heavy metals, which may not have killed the microbe completely, allowing the microbe to survive, change, and become resistant to the poisons and/or heavy metals.

Antimicrobial nanotechnology is a recent addition to the fight against disease-causing organisms, replacing heavy metals and toxins, and may some day be used as a viable alternative.

Infections that are acquired during a hospital visit are called “hospital acquired infections” or nosocomial infections. Similarly, when the infectious disease is picked up in the non-hospital setting, it is considered “community acquired”.

Synthetic agents include: sulphonamides, cotrimoxazole, quinolones, anti-virals, anti-fungals, anti-cancer drugs, anti-malarials, anti-tuberculosis drugs, anti-leprotics, and anti-protozoals.

Sulfonamide or sulphonamide is the basis of several groups of drugs. The original antibacterial sulfonamides (sometimes called sulfa drugs or sulpha drugs) are synthetic antimicrobial agents that contain the sulfonamide group. Some sulfonamides are also devoid of antibacterial activity, e.g., the anticonvulsant sultiame. The sulfonylureas and thiazide diuretics are newer drug groups based on the antibacterial sulfonamides.

Sulfa allergies are common, and medications containing sulfonamides are prescribed carefully. It is important to make a distinction between sulfa drugs and other sulfur-containing drugs and additives, such as sulfates and sulfites, which are chemically unrelated to the sulfonamide group and do not cause the same hypersensitivity reactions seen in the sulfonamides.

In bacteria, antibacterial sulfonamides act as competitive inhibitors of the enzyme dihydropteroate synthetase (DHPS), an enzyme involved in folate synthesis. As such, the microorganism will be “starved” of folate and die.

The sulfonamide chemical moiety is also present in other medications that are not antimicrobials, including thiazide diuretics (including hydrochlorothiazide, metolazone, and indapamide, among others), loop diuretics (including furosemide, bumetanide, and torsemide), sulfonylureas (including glipizide, glyburide, among others), and some COX-2 inhibitors (e.g., celecoxib), and acetazolamide.


Antibiotic resistance: What you need to know

For the last 70 years, doctors have prescribed drugs known as antimicrobial agents to treat infectious diseases. These are diseases that occur due to microbes, such as bacteria, viruses, and parasites. Some of these diseases can be life-threatening.

However, the use of these drugs is now so common that some microbes have adapted and started to resist them. This is potentially dangerous because it could result in a lack of effective treatments for some diseases.

According to the Centers for Disease Control and Prevention (CDC), at least 2 million people become infected with antimicrobial-resistant bacteria in the United States every year. Around 23,000 people die as a result.

In addition, one out of every 25 hospital patients has a healthcare-associated infection (HAI) on any given day.

In this article, we look at the causes of antimicrobial drug resistance, some specific examples, and other treatment options.

Share on Pinterest Antibiotics and other antimicrobial drugs are crucial for fighting infection and saving lives, but they must be used correctly.

Antimicrobial resistance (AMR), or drug resistance, develops when microbes, including bacteria, fungi, parasites, and viruses, no longer respond to a drug that previously treated them effectively.

AMR can lead to the following issues:

  • some infections being harder to control and staying longer inside the body
  • longer hospital stays, increasing the economic and social costs of infection
  • a higher risk of disease spreading
  • a greater chance of fatality due to infection

A significant concern is that AMR could lead to a post-antibiotic era in which antibiotics would no longer work.

This would mean that common infections and minor injuries that became straightforward to treat in the 20th century could again become deadly.

Antibiotic versus antimicrobial resistance

Distinguishing between antibiotic and antimicrobial resistance is important.

  • Antibiotic resistance refers to bacteria resisting antibiotics.
  • Antimicrobial resistance (AMR) describes the opposition of any microbe to the drugs that scientists created to kill them.

It is possible for AMR to develop in bacteria, but it can also originate in fungi, parasites, and viruses. This resistance could affect people with Candida, malaria, HIV, and a wide range of other conditions.

Microbes can become resistant to drugs for both biological and social reasons.

Microbial behavior

As soon as scientists introduce a new antimicrobial drug, there is a good chance that it will become ineffective at some point in time.

This is due primarily to changes occurring within the microbes.

These changes can come about in different ways:

Mutation: When microbes reproduce, genetic mutations can occur. Sometimes, this will create a microbe with genes that help it survive in the face of antimicrobial agents.

Selective pressure: Microbes that carry these resistance genes survive and replicate. The newly generated resistant microbes eventually become the dominant type.

Gene transfer: Microbes can pick up genes from other microbes. Genes conferring drug resistance can easily transfer between microbes.

Phenotypic change: Microbes can change some of their characteristics to become resistant to common antimicrobial agents.

People’s behavior

The way in which people use antimicrobial drugs is a significant contributing factor. For example:

Inexact diagnosis: Doctors sometimes prescribe antimicrobials “just in case,” or they prescribe broad-spectrum antimicrobials when a specific drug would be more suitable. Using these medications in this way increases the risk of AMR.

Inappropriate use: If a person does not complete a course of antimicrobial drugs, some microbes may survive and develop resistance to the drug.

Resistance can also develop if people use drugs for conditions that they cannot treat. For example, people sometimes take an antibiotic for a viral infection.

Agricultural use: Using antibiotics in farm animals can promote drug resistance. Scientists have found drug-resistant bacteria in meat and food crops that have exposure to fertilizers or contaminated water. In this way, diseases that affect animals can pass to humans.

Hospital use: People who are critically ill often receive high doses of antimicrobials. This encourages the spread of AMR microbes, particularly in an environment where various diseases are present.

The United States Food and Drug Administration (FDA) point out that doctors often give antibiotics as a treatment for a sore throat. However, only 15 percent of sore throats are due to streptococcal bacteria. In many cases, antibiotics cannot cure a sore throat.

The FDA add that doctors write “tens of millions” of prescriptions for antibiotics that offer no benefit each year.

People who use these drugs are at risk of allowing AMR to develop. This could make them more likely to have a health problem in the future that will not respond to antibiotics.

Antimicrobial resistance can occur in bacteria, viruses, fungi, and parasites.

Tuberculosis (TB): This airborne lung disease results from a bacterial infection. TB was a major killer before antibiotics became available. More recently, drug-resistant forms of TB have emerged worldwide. Standard antibiotic treatments will not work against these forms of the disease.

A person who has TB that is not drug-resistant will require daily treatment with several drugs for 6 to 9 months .

Drug-resistant TB is more complex to treat. The person will need to take the drugs for a longer time, and they will need close supervision. Poor management can result in fatalities.

Methicillin-resistant Staphylococcus aureus (MRSA): This is a bacterial infection that can be fatal. People usually get MRSA when they are staying in a hospital.

In the past, it was a well-controlled infection, but now the CDC see it as a major public health concern due to antibiotic resistance.

Gonorrhea: Gonorrhea is a sexually transmitted bacterial infection that is common in the U.S. and elsewhere. Cases of drug-resistant gonorrhea have started to occur.

Now, there is only one type of drug that is still effective against the drug-resistant form of this disease.

The CDC describe drug-resistant gonorrhea as an “urgent public health threat.”

Escherichia coli (E. coli): This bacterium is a common cause of food-borne disease and urinary tract infections. The rate of antibiotic resistance in E. coli is increasing quickly.

HIV: Effective antiviral treatment for HIV can now prevent this condition from becoming more severe. The treatment can make the levels of the virus undetectable, meaning that it is not transmissible.

The World Health Organization (WHO) note that if people are unable to take the drugs as they should, perhaps due to medical costs, new drug-resistant strains of the virus may appear.

Fungal infections: Candida, Aspergillus, and other fungi can lead to a range of severe infections. Candida albicans (C. albicans) is responsible for thrush, a common vaginal infection. Aspergillus can cause or worsen aspergillosis, a lung condition.

Some of these infections can have fatal consequences. There is concern that fungi are becoming increasingly resistant to antimicrobial treatments.

Malaria: Mosquitoes spread this parasitic disease, which killed around 445,000 people worldwide in 2016. In many parts of the world, drug-resistant parasites have evolved so that certain antimalarial drugs are now ineffective.

As infections stop responding to current drugs, there is an urgent need to find alternatives.

In some cases, this means using combinations of different medications, known as multiple-drug therapy.

Scientists are also looking for new forms of treatment, including different types of antibiotics and other alternatives.

What are the alternatives?

Scientists have proposed some novel ways of combating bacteria.

These include the following techniques, which researchers are investigating for the treatment of Clostridium difficile (C. difficile):

  • using a virus that consumes bacteria, known as a bacteriophage, in drug form
  • using monoclonal antibodies that can combat the effects of the toxins that the microbes produce
  • developing vaccines to prevent infection from occurring
  • fecal microbiota transplant, which involves taking good bacteria from a healthy person’s gut and transplanting them into a recipient who is lacking them
  • the use of probiotics to restore the gut flora

More research into these treatments is necessary to confirm their effectiveness.


Contents

The WHO defines antimicrobial resistance as a microorganism's resistance to an antimicrobial drug that was once able to treat an infection by that microorganism. [2] A person cannot become resistant to antibiotics. Resistance is a property of the microbe, not a person or other organism infected by a microbe. [22]

Antibiotic resistance is a subset of antimicrobial resistance. This more specified resistance is linked to pathogenic bacteria and thus broken down into two further subsets, microbiological and clinical. Resistance linked microbiologically is the most common and occurs from genes, mutated or inherited, that allow the bacteria to resist the mechanism associated with certain antibiotics. Clinical resistance is shown through the failure of many therapeutic techniques where the bacteria that are normally susceptible to a treatment become resistant after surviving the outcome of the treatment. In both cases of acquired resistance, the bacteria can pass the genetic catalyst for resistance through conjugation, transduction, or transformation. This allows the resistance to spread across the same pathogen or even similar bacterial pathogens. [23]

WHO report released April 2014 stated, "this serious threat is no longer a prediction for the future, it is happening right now in every region of the world and has the potential to affect anyone, of any age, in any country. Antibiotic resistance—when bacteria change so antibiotics no longer work in people who need them to treat infections—is now a major threat to public health." [24] In 2018, WHO considered antibiotic resistance to be one of the biggest threats to global health, food security and development. [25] The European Centre for Disease Prevention and Control calculated that in 2015 there were 671,689 infections in the EU and European Economic Area caused by antibiotic-resistant bacteria, resulting in 33,110 deaths. Most were acquired in healthcare settings. [26]

Antimicrobial resistance is mainly caused by the overuse of antimicrobials. This leads to microbes either evolving a defense against drugs used to treat them, or certain strains of microbes that have a natural resistance to antimicrobials becoming much more prevalent than the ones that are easily defeated with medication. [27] While antimicrobial resistance does occur naturally over time, the use of antimicrobial agents in a variety of settings both within the healthcare industry and outside of has led to antimicrobial resistance becoming increasingly more prevalent. [28]

Natural occurrence Edit

Antimicrobial resistance can evolve naturally due to continued exposure to antimicrobials. Natural selection means that organisms that are able to adapt to their environment survive and continue to produce offspring. [29] As a result, the types of microorganisms that are able to survive over time with continued attack by certain antimicrobial agents will naturally become more prevalent in the environment, and those without this resistance will become obsolete. [28] Over time most of the strains of bacteria and infections present will be the type resistant to the antimicrobial agent being used to treat them, making this agent now ineffective to defeat most microbes. With the increased use of antimicrobial agents, there is a speeding up of this natural process. [30]

Self medication Edit

Self medication by consumers is defined as "the taking of medicines on one's own initiative or on another person's suggestion, who is not a certified medical professional", and it has been identified as one of the primary reasons for the evolution of antimicrobial resistance. [31] In an effort to manage their own illness, patients take the advice of false media sources, friends, and family causing them to take antimicrobials unnecessarily or in excess. Many people resort to this out of necessity, when they have a limited amount of money to see a doctor, or in many developing countries a poorly developed economy and lack of doctors are the cause of self-medication. In these developing countries, governments resort to allowing the sale of antimicrobials as over the counter medications so people could have access to them without having to find or pay to see a medical professional. [32] This increased access makes it extremely easy to obtain antimicrobials without the advice of a physician, and as a result many antimicrobials are taken incorrectly leading to resistant microbial strains. One major example of a place that faces these challenges is India, where in the state of Punjab 73% of the population resorted to treating their minor health issues and chronic illnesses through self-medication. [31]

The major issue with self-medication is the lack of knowledge of the public on the dangerous effects of antimicrobial resistance, and how they can contribute to it through mistreating or misdiagnosing themselves. In order to determine the public's knowledge and preconceived notions on antibiotic resistance, a major type of antimicrobial resistance, a screening of 3537 articles published in Europe, Asia, and North America was done. Of the 55,225 total people surveyed, 70% had heard of antibiotic resistance previously, but 88% of those people thought it referred to some type of physical change in the body. [31] With so many people around the world with the ability to self-medicate using antibiotics, and a vast majority unaware of what antimicrobial resistance is, it makes the increase of antimicrobial resistance much more likely.

Clinical misuse Edit

Clinical misuse by healthcare professionals is another cause leading to increased antimicrobial resistance. Studies done by the CDC show that the indication for treatment of antibiotics, choice of the agent used, and the duration of therapy was incorrect in up to 50% of the cases studied. In another study done in an intensive care unit in a major hospital in France, it was shown that 30% to 60% of prescribed antibiotics were unnecessary. [33] These inappropriate uses of antimicrobial agents promote the evolution of antimicrobial resistance by supporting the bacteria in developing genetic alterations that lead to resistance. [34] In a study done by the American Journal of Infection Control aimed to evaluate physicians’ attitudes and knowledge on antimicrobial resistance in ambulatory settings, only 63% of those surveyed reported antibiotic resistance as a problem in their local practices, while 23% reported the aggressive prescription of antibiotics as necessary to avoid failing to provide adequate care. [35] This demonstrates how a majority of doctors underestimate the impact that their own prescribing habits have on antimicrobial resistance as a whole. It also confirms that some physicians may be overly cautious when it comes to prescribing antibiotics for both medical or legal reasons, even when indication for use for these medications is not always confirmed. This can lead to unnecessary antimicrobial use.

Studies have shown that common misconceptions about the effectiveness and necessity of antibiotics to treat common mild illnesses contribute to their overuse. [36] [37]

Environmental pollution Edit

Untreated effluents from pharmaceutical manufacturing industries, [38] hospitals and clinics, and inappropriate disposal of unused or expired medication can expose microbes in the environment to antibiotics and trigger the evolution of resistance.

Food production Edit

Livestock Edit

The antimicrobial resistance crisis also extends to the food industry, specifically with food producing animals. Antibiotics are fed to livestock to act as growth supplements, and a preventative measure to decrease the likelihood of infections. This results in the transfer of resistant bacterial strains into the food that humans eat, causing potentially fatal transfer of disease. While this practice does result in better yields and meat products, it is a major issue in terms of preventing antimicrobial resistance. [39] Though the evidence linking antimicrobial usage in livestock to antimicrobial resistance is limited, the World Health Organization Advisory Group on Integrated Surveillance of Antimicrobial Resistance strongly recommended the reduction of use of medically important antimicrobials in livestock. Additionally, the Advisory Group stated that such antimicrobials should be expressly prohibited for both growth promotion and disease prevention. [40]

In a study published by the National Academy of Sciences mapping antimicrobial consumption in livestock globally, it was predicted that in the 228 countries studied, there would be a total 67% increase in consumption of antibiotics by livestock by 2030. In some countries such as Brazil, Russia, India, China, and South Africa it is predicted that a 99% increase will occur. [30] Several countries have restricted the use of antibiotics in livestock, including Canada, China, Japan, and the US. These restrictions are sometimes associated with a reduction of the prevalence of antimicrobial resistance in humans. [40]

Pesticides Edit

Most pesticides protect crops against insects and plants, but in some cases antimicrobial pesticides are used to protect against various microorganisms such as bacteria, viruses, fungi, algae, and protozoa. The overuse of many pesticides in an effort to have a higher yield of crops has resulted in many of these microbes evolving a tolerance against these antimicrobial agents. Currently there are over 4000 antimicrobial pesticides registered with the EPA and sold to market, showing the widespread use of these agents. [41] It is estimated that for every single meal a person consumes, 0.3 g of pesticides is used, as 90% of all pesticide use is used on agriculture. A majority of these products are used to help defend against the spread of infectious diseases, and hopefully protect public health. But out of the large amount of pesticides used, it is also estimated that less than 0.1% of those antimicrobial agents, actually reach their targets. That leaves over 99% of all pesticides used available to contaminate other resources. [42] In soil, air, and water these antimicrobial agents are able to spread, coming in contact with more microorganisms and leading to these microbes evolving mechanisms to tolerate and further resist pesticides.

There have been increasing public calls for global collective action to address the threat, including a proposal for international treaty on antimicrobial resistance. Further detail and attention is still needed in order to recognize and measure trends in resistance on the international level the idea of a global tracking system has been suggested but implementation has yet to occur. A system of this nature would provide insight to areas of high resistance as well as information necessary for evaluating programs and other changes made to fight or reverse antibiotic resistance.

Duration of antibiotics Edit

Antibiotic treatment duration should be based on the infection and other health problems a person may have. [7] For many infections once a person has improved there is little evidence that stopping treatment causes more resistance. [7] Some therefore feel that stopping early may be reasonable in some cases. [7] Other infections, however, do require long courses regardless of whether a person feels better. [7]

Monitoring and mapping Edit

ResistanceOpen is an online global map of antimicrobial resistance developed by HealthMap which displays aggregated data on antimicrobial resistance from publicly available and user submitted data. [44] [45] The website can display data for a 25-mile radius from a location. Users may submit data from antibiograms for individual hospitals or laboratories. European data is from the EARS-Net (European Antimicrobial Resistance Surveillance Network), part of the ECDC.

ResistanceMap is a website by the Center for Disease Dynamics, Economics & Policy and provides data on antimicrobial resistance on a global level. [46]

Limiting antibiotic use Edit

Antibiotic stewardship programmes appear useful in reducing rates of antibiotic resistance. [47] The antibiotic stewardship program will also provide pharmacists with the knowledge to educate patients that antibiotics will not work for a virus. [48]

Excessive antibiotic use has become one of the top contributors to the evolution of antibiotic resistance. Since the beginning of the antibiotic era, antibiotics have been used to treat a wide range of disease. [49] Overuse of antibiotics has become the primary cause of rising levels of antibiotic resistance. The main problem is that doctors are willing to prescribe antibiotics to ill-informed individuals who believe that antibiotics can cure nearly all illnesses, including viral infections like the common cold. In an analysis of drug prescriptions, 36% of individuals with a cold or an upper respiratory infection (both viral in origin) were given prescriptions for antibiotics. [50] These prescriptions accomplished nothing other than increasing the risk of further evolution of antibiotic resistant bacteria. [51]

At the hospital level Edit

Antimicrobial stewardship teams in hospitals are encouraging optimal use of antimicrobials. [52] The goals of antimicrobial stewardship are to help practitioners pick the right drug at the right dose and duration of therapy while preventing misuse and minimizing the development of resistance. Stewardship may reduce the length of stay by an average of slightly over 1 day while not increasing the risk of death. [53]

At the farming level Edit

It is established that the use of antibiotics in animal husbandry can give rise to AMR resistances in bacteria found in food animals to the antibiotics being administered (through injections or medicated feeds). [54] For this reason only antimicrobials that are deemed "not-clinically relevant" are used in these practices.

Recent studies have shown that the prophylactic use of "non-priority" or "non-clinically relevant" antimicrobials in feeds can potentially, under certain conditions, lead to co-selection of environmental AMR bacteria with resistance to medically important antibiotics. [55] The possibility for co-selection of AMR resistances in the food chain pipeline may have far-reaching implications for human health. [55] [56]

At the level of GP Edit

Given the volume of care provided in primary care (General Practice), recent strategies have focused on reducing unnecessary antibiotic prescribing in this setting. Simple interventions, such as written information explaining the futility of antibiotics for common infections such as upper respiratory tract infections, have been shown to reduce antibiotic prescribing. [57]

The prescriber should closely adhere to the five rights of drug administration: the right patient, the right drug, the right dose, the right route, and the right time. [58]

Cultures should be taken before treatment when indicated and treatment potentially changed based on the susceptibility report. [9] [59]

About a third of antibiotic prescriptions written in outpatient settings in the United States were not appropriate in 2010 and 2011. Doctors in the U.S. wrote 506 annual antibiotic scripts for every 1,000 people, with 353 being medically necessary. [60]

Health workers and pharmacists can help tackle resistance by: enhancing infection prevention and control only prescribing and dispensing antibiotics when they are truly needed prescribing and dispensing the right antibiotic(s) to treat the illness. [24]

At the individual level Edit

People can help tackle resistance by using antibiotics only when prescribed by a doctor completing the full prescription, even if they feel better never sharing antibiotics with others or using leftover prescriptions. [24]

Country examples Edit

  • The Netherlands has the lowest rate of antibiotic prescribing in the OECD, at a rate of 11.4 defined daily doses (DDD) per 1,000 people per day in 2011. and Sweden also have lower prescribing rates, with Sweden's rate having been declining since 2007. , France and Belgium have high prescribing rates of more than 28 DDD. [61]

Water, sanitation, hygiene Edit

Infectious disease control through improved water, sanitation and hygiene (WASH) infrastructure needs to be included in the antimicrobial resistance (AMR) agenda. The "Interagency Coordination Group on Antimicrobial Resistance" stated in 2018 that "the spread of pathogens through unsafe water results in a high burden of gastrointestinal disease, increasing even further the need for antibiotic treatment." [62] This is particularly a problem in developing countries where the spread of infectious diseases caused by inadequate WASH standards is a major driver of antibiotic demand. [63] Growing usage of antibiotics together with persistent infectious disease levels have led to a dangerous cycle in which reliance on antimicrobials increases while the efficacy of drugs diminishes. [63] The proper use of infrastructure for water, sanitation and hygiene (WASH) can result in a 47–72 percent decrease of diarrhea cases treated with antibiotics depending on the type of intervention and its effectiveness. [63] A reduction of the diarrhea disease burden through improved infrastructure would result in large decreases in the number of diarrhea cases treated with antibiotics. This was estimated as ranging from 5 million in Brazil to up to 590 million in India by the year 2030. [63] The strong link between increased consumption and resistance indicates that this will directly mitigate the accelerating spread of AMR. [63] Sanitation and water for all by 2030 is Goal Number 6 of the Sustainable Development Goals.

An increase in hand washing compliance by hospital staff results in decreased rates of resistant organisms. [64]

Water supply and sanitation infrastructure in health facilities offer significant co-benefits for combatting AMR, and investment should be increased. [62] There is much room for improvement: WHO and UNICEF estimated in 2015 that globally 38% of health facilities did not have a source of water, nearly 19% had no toilets and 35% had no water and soap or alcohol-based hand rub for handwashing. [65]

Industrial wastewater treatment Edit

Manufacturers of antimicrobials need to improve the treatment of their wastewater (by using industrial wastewater treatment processes) to reduce the release of residues into the environment. [62]

Management in animal use Edit

Europe Edit

In 1997, European Union health ministers voted to ban avoparcin and four additional antibiotics used to promote animal growth in 1999. [66] In 2006 a ban on the use of antibiotics in European feed, with the exception of two antibiotics in poultry feeds, became effective. [67] In Scandinavia, there is evidence that the ban has led to a lower prevalence of antibiotic resistance in (nonhazardous) animal bacterial populations. [68] As of 2004, several European countries established a decline of antimicrobial resistance in humans through limiting the use of antimicrobials in agriculture and food industries without jeopardizing animal health or economic cost. [69]

United States Edit

The United States Department of Agriculture (USDA) and the Food and Drug Administration (FDA) collect data on antibiotic use in humans and in a more limited fashion in animals. [70] The FDA first determined in 1977 that there is evidence of emergence of antibiotic-resistant bacterial strains in livestock. The long-established practice of permitting OTC sales of antibiotics (including penicillin and other drugs) to lay animal owners for administration to their own animals nonetheless continued in all states. In 2000, the 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. Legal challenges from the food animal and pharmaceutical industries delayed the final decision to do so until 2006. [71] Fluroquinolones have been banned from extra-label use in food animals in the USA since 2007. However, they remain widely used in companion and exotic animals.

Global action plans and awareness Edit

The increasing interconnectedness of the world and the fact that new classes of antibiotics have not been developed and approved for more than 25 years highlight the extent to which antimicrobial resistance is a global health challenge. [72] A global action plan to tackle the growing problem of resistance to antibiotics and other antimicrobial medicines was endorsed at the Sixty-eighth World Health Assembly in May 2015. [73] One of the key objectives of the plan is to improve awareness and understanding of antimicrobial resistance through effective communication, education and training. This global action plan developed by the World Health Organization was created to combat the issue of antimicrobial resistance and was guided by the advice of countries and key stakeholders. The WHO's global action plan is composed of five key objectives that can be targeted through different means, and represents countries coming together to solve a major problem that can have future health consequences. [30] These objectives are as follows:

  • improve awareness and understanding of antimicrobial resistance through effective communication, education and training.
  • strengthen the knowledge and evidence base through surveillance and research.
  • reduce the incidence of infection through effective sanitation, hygiene and infection prevention measures.
  • optimize the use of antimicrobial medicines in human and animal health.
  • develop the economic case for sustainable investment that takes account of the needs of all countries and to increase investment in new medicines, diagnostic tools, vaccines and other interventions.

Steps towards progress

  • React based in Sweden has produced informative material on AMR for the general public. [74]
  • Videos are being produced for the general public to generate interest and awareness. [75][76]
  • The Irish Department of Health published a National Action Plan on Antimicrobial Resistance in October 2017. [77] The Strategy for the Control of Antimicrobial Resistance in Ireland (SARI), Iaunched in 2001 developed Guidelines for Antimicrobial Stewardship in Hospitals in Ireland [78] in conjunction with the Health Protection Surveillance Centre, these were published in 2009. Following their publication a public information campaign 'Action on Antibiotics [79] ' was launched to highlight the need for a change in antibiotic prescribing. Despite this, antibiotic prescribing remains high with variance in adherence to guidelines. [80]

Antibiotic Awareness Week Edit

The World Health Organization has promoted the first World Antibiotic Awareness Week running from 16 to 22 November 2015. The aim of the week is to increase global awareness of antibiotic resistance. It also wants to promote the correct usage of antibiotics across all fields in order to prevent further instances of antibiotic resistance. [81]

World Antibiotic Awareness Week has been held every November since 2015. For 2017, the Food and Agriculture Organization of the United Nations (FAO), the World Health Organization (WHO) and the World Organisation for Animal Health (OIE) are together calling for responsible use of antibiotics in humans and animals to reduce the emergence of antibiotic resistance. [82]

In 2016 the Secretary-General of the United Nations convened the Interagency Coordination Group (IACG) on Antimicrobial Resistance. [83] The IACG worked with international organizations and experts in human, animal, and plant health to create a plan to fight antimicrobial resistance. [83] Their report released in April 2019 highlights the seriousness of antimicrobial resistance and the threat it poses to world health. It suggests five recommendations for member states to follow in order to tackle this increasing threat. The IACG recommendations are as follows:

  • Accelerate progress in countries
  • Innovate to secure the future
  • Collaborate for more effective action
  • Invest for a sustainable response
  • Strengthen accountability and global governance

Bacteria Edit

The five main mechanisms by which bacteria exhibit resistance to antibiotics are:

  1. Drug inactivation or modification: for example, enzymatic deactivation of penicillin G in some penicillin-resistant bacteria through the production of β-lactamases. Most commonly, the protective enzymes produced by the bacterial cell will add an acetyl or phosphate group to a specific site on the antibiotic, which will reduce its ability to bind to the bacterial ribosomes and disrupt protein synthesis. [84]
  2. Alteration of target- or binding site: for example, alteration of PBP—the binding target site of penicillins—in MRSA and other penicillin-resistant bacteria. Another protective mechanism found among bacterial species is ribosomal protection proteins. These proteins protect the bacterial cell from antibiotics that target the cell's ribosomes to inhibit protein synthesis. The mechanism involves the binding of the ribosomal protection proteins to the ribosomes of the bacterial cell, which in turn changes its conformational shape. This allows the ribosomes to continue synthesizing proteins essential to the cell while preventing antibiotics from binding to the ribosome to inhibit protein synthesis. [85]
  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. [86]
  4. Reduced drug accumulation: by decreasing drug permeability or increasing active efflux (pumping out) of the drugs across the cell surface [87] These pumps within the cellular membrane of certain bacterial species are used to pump antibiotics out of the cell before they are able to do any damage. They are often activated by a specific substrate associated with an antibiotic, [88] as in fluoroquinolone resistance. [89]
  5. Ribosome splitting and recycling: for example, drug-mediated stalling of the ribosome by lincomycin and erythromycin unstalled by a heat shock protein found in Listeria monocytogenes, which is a homologue of HflX from other bacteria. Liberation of the ribosome from the drug allows further translation and consequent resistance to the drug. [90]

There are several different types of germs that have developed a resistance over time. For example, Penicillinase-producing Neisseria gonorrhoeae developed a resistance to penicillin in 1976. Another example is Azithromycin-resistant Neisseria gonorrhoeae, which developed a resistance to azithromycin in 2011. [91]

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. [92]

Some bacteria are naturally resistant to certain antibiotics for example, gram-negative bacteria are resistant to most β-lactam antibiotics due to the presence of β-lactamase. Antibiotic resistance can also be acquired as a result of either genetic mutation or horizontal gene transfer. [93] Although mutations are rare, with spontaneous mutations in the pathogen genome occurring at a rate of about 1 in 10 5 to 1 in 10 8 per chromosomal replication, [94] the fact that bacteria reproduce at a high rate allows for the effect to be significant. Given that lifespans and production of new generations can be on a timescale of mere hours, a new (de novo) mutation in a parent cell can quickly become an inherited mutation of widespread prevalence, resulting in the microevolution of a fully resistant colony. However, chromosomal mutations also confer a cost of fitness. For example, a ribosomal mutation may protect a bacterial cell by changing the binding site of an antibiotic but will also slow protein synthesis. [84] manifesting, in slower growth rate. [95] Moreover, some adaptive mutations can propagate not only through inheritance but also through horizontal gene transfer. The most common mechanism of horizontal gene transfer is the transferring of plasmids carrying antibiotic resistance genes between bacteria of the same or different species via conjugation. However, bacteria can also acquire resistance through transformation, as in Streptococcus pneumoniae uptaking of naked fragments of extracellular DNA that contain antibiotic resistance genes to streptomycin, [96] through transduction, as in the bacteriophage-mediated transfer of tetracycline resistance genes between strains of S. pyogenes, [97] or through gene transfer agents, which are particles produced by the host cell that resemble bacteriophage structures and are capable of transferring DNA. [98]

Antibiotic resistance can 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. [99]

Recent findings show no necessity of large populations of bacteria for the appearance of antibiotic resistance. Small populations of Escherichia coli in an antibiotic gradient can become resistant. Any heterogeneous environment with respect to nutrient and antibiotic gradients may facilitate antibiotic resistance in small bacterial populations. Researchers hypothesize that the mechanism of resistance evolution is based on four SNP mutations in the genome of E. coli produced by the gradient of antibiotic. [100]

In one study, which has implications for space microbiology, a non-pathogenic strain E. coli MG1655 was exposed to trace levels of the broad spectrum antibiotic chloramphenicol, under simulated microgravity (LSMMG, or, Low Shear Modeled Microgravity) over 1000 generations. The adapted strain acquired resistance to not only chloramphenicol, but also cross-resistance to other antibiotics [101] this was in contrast to the observation on the same strain, which was adapted to over 1000 generations under LSMMG, but without any antibiotic exposure the strain in this case did not acquire any such resistance. [102] Thus, irrespective of where they are used, the use of an antibiotic would likely result in persistent resistance to that antibiotic, as well as cross-resistance to other antimicrobials.

In recent years, the emergence and spread of β-lactamases called carbapenemases has become a major health crisis. [103] One such carbapenemase is New Delhi metallo-beta-lactamase 1 (NDM-1), [104] an enzyme that makes bacteria resistant to a broad range of beta-lactam antibiotics. The most common bacteria that make this enzyme are gram-negative such as E. coli and Klebsiella pneumoniae, but the gene for NDM-1 can spread from one strain of bacteria to another by horizontal gene transfer. [105]

Viruses Edit

Specific antiviral drugs are used to treat some viral infections. These drugs prevent viruses from reproducing by inhibiting essential stages of the virus's replication cycle in infected cells. Antivirals are used to treat HIV, hepatitis B, hepatitis C, influenza, herpes viruses including varicella zoster virus, cytomegalovirus and Epstein-Barr virus. With each virus, some strains have become resistant to the administered drugs. [106]

Antiviral drugs typically target key components of viral reproduction for example, oseltamivir targets influenza neuraminidase, while guanosine analogs inhibit viral DNA polymerase. Resistance to antivirals is thus acquired through mutations in the genes that encode the protein targets of the drugs.

Resistance to HIV antivirals is problematic, and even multi-drug resistant strains have evolved. [107] One source of resistance is that many current HIV drugs, including NRTIs and NNRTIs, target reverse transcriptase however, HIV-1 reverse transcriptase is highly error prone and thus mutations conferring resistance arise rapidly. [108] Resistant strains of the HIV virus emerge rapidly if only one antiviral drug is used. [109] Using three or more drugs together, termed combination therapy, has helped to control this problem, but new drugs are needed because of the continuing emergence of drug-resistant HIV strains. [110]

Fungi Edit

Infections by fungi are a cause of high morbidity and mortality in immunocompromised persons, such as those with HIV/AIDS, tuberculosis or receiving chemotherapy. [111] The fungi candida, Cryptococcus neoformans and Aspergillus fumigatus cause most of these infections and antifungal resistance occurs in all of them. [112] Multidrug resistance in fungi is increasing because of the widespread use of antifungal drugs to treat infections in immunocompromised individuals. [113]

Of particular note, Fluconazole-resistant Candida species have been highlighted as a growing problem by the CDC. [43] More than 20 species of Candida can cause Candidiasis infection, the most common of which is Candida albicans. Candida yeasts normally inhabit the skin and mucous membranes without causing infection. However, overgrowth of Candida can lead to Candidiasis. Some Candida strains are becoming resistant to first-line and second-line antifungal agents such as azoles and echinocandins. [43]

Parasites Edit

The protozoan parasites that cause the diseases malaria, trypanosomiasis, toxoplasmosis, cryptosporidiosis and leishmaniasis are important human pathogens. [114]

Malarial parasites that are resistant to the drugs that are currently available to infections are common and this has led to increased efforts to develop new drugs. [115] Resistance to recently developed drugs such as artemisinin has also been reported. The problem of drug resistance in malaria has driven efforts to develop vaccines. [116]

Trypanosomes are parasitic protozoa that cause African trypanosomiasis and Chagas disease (American trypanosomiasis). [117] [118] There are no vaccines to prevent these infections so drugs such as pentamidine and suramin, benznidazole and nifurtimox are used to treat infections. These drugs are effective but infections caused by resistant parasites have been reported. [114]

Leishmaniasis is caused by protozoa and is an important public health problem worldwide, especially in sub-tropical and tropical countries. Drug resistance has "become a major concern". [119]

The 1950s to 1970s represented the golden age of antibiotic discovery, where countless new classes of antibiotics were discovered to treat previously incurable diseases such as tuberculosis and syphilis. [120] However, since that time the discovery of new classes of antibiotics has been almost nonexistent, and represents a situation that is especially problematic considering the resiliency of bacteria [121] shown over time and the continued misuse and overuse of antibiotics in treatment. [122]

The phenomenon of antimicrobial resistance caused by overuse of antibiotics was predicted as early as 1945 by Alexander Fleming who said "The time may come when penicillin can be bought by anyone in the shops. Then there is the danger that the ignorant man may easily under-dose himself and by exposing his microbes to nonlethal quantities of the drug make them resistant." [123] [124] Without the creation of new and stronger antibiotics an era where common infections and minor injuries can kill, and where complex procedures such as surgery and chemotherapy become too risky, is a very real possibility. [125] Antimicrobial resistance threatens the world as we know it, and can lead to epidemics of enormous proportions if preventive actions are not taken. In this day and age current antimicrobial resistance leads to longer hospital stays, higher medical costs, and increased mortality. [122]

Since the mid-1980s pharmaceutical companies have invested in medications for cancer or chronic disease that have greater potential to make money and have "de-emphasized or dropped development of antibiotics". [126] On 20 January 2016 at the World Economic Forum in Davos, Switzerland, more than "80 pharmaceutical and diagnostic companies" from around the world called for "transformational commercial models" at a global level to spur research and development on antibiotics and on the "enhanced use of diagnostic tests that can rapidly identify the infecting organism". [126]

Legal frameworks Edit

Some global health scholars have argued that a global, legal framework is needed to prevent and control antimicrobial resistance. [127] [128] [20] [129] For instance, binding global policies could be used to create antimicrobial use standards, regulate antibiotic marketing, and strengthen global surveillance systems. [20] [127] Ensuring compliance of involved parties is a challenge. [20] Global antimicrobial resistance policies could take lessons from the environmental sector by adopting strategies that have made international environmental agreements successful in the past such as: sanctions for non-compliance, assistance for implementation, majority vote decision-making rules, an independent scientific panel, and specific commitments. [130]

United States Edit

For the United States 2016 budget, U.S. president Barack Obama proposed to nearly double the amount of federal funding to "combat and prevent" antibiotic resistance to more than $1.2 billion. [131] Many international funding agencies like USAID, DFID, SIDA and Bill & Melinda Gates Foundation have pledged money for developing strategies to counter antimicrobial resistance.

On 27 March 2015, the White House released a comprehensive plan to address the increasing need for agencies to combat the rise of antibiotic-resistant bacteria. The Task Force for Combating Antibiotic-Resistant Bacteria developed The National Action Plan for Combating Antibiotic-Resistant Bacteria with the intent of providing a roadmap to guide the US in the antibiotic resistance challenge and with hopes of saving many lives. This plan outlines steps taken by the Federal government over the next five years needed in order to prevent and contain outbreaks of antibiotic-resistant infections maintain the efficacy of antibiotics already on the market and to help to develop future diagnostics, antibiotics, and vaccines. [132]

The Action Plan was developed around five goals with focuses on strengthening health care, public health veterinary medicine, agriculture, food safety and research, and manufacturing. These goals, as listed by the White House, are as follows:

  • Slow the Emergence of Resistant Bacteria and Prevent the Spread of Resistant Infections
  • Strengthen National One-Health Surveillance Efforts to Combat Resistance
  • Advance Development and use of Rapid and Innovative Diagnostic Tests for Identification and Characterization of Resistant Bacteria
  • Accelerate Basic and Applied Research and Development for New Antibiotics, Other Therapeutics, and Vaccines
  • Improve International Collaboration and Capacities for Antibiotic Resistance Prevention, Surveillance, Control and Antibiotic Research and Development

The following are goals set to meet by 2020: [132]

  • Establishment of antimicrobial programs within acute care hospital settings
  • Reduction of inappropriate antibiotic prescription and use by at least 50% in outpatient settings and 20% inpatient settings
  • Establishment of State Antibiotic Resistance (AR) Prevention Programs in all 50 states
  • Elimination of the use of medically important antibiotics for growth promotion in food-producing animals.

United Kingdom Edit

Public Health England reported that the total number of antibiotic resistant infections in England rose by 9% from 55,812 in 2017 to 60,788 in 2018, but antibiotic consumption had fallen by 9% from 20.0 to 18.2 defined daily doses per 1,000 inhabitants per day between 2014 and 2018. [133]

Policies Edit

According to World Health Organization, policymakers can help tackle resistance by strengthening resistance-tracking and laboratory capacity and by regulating and promoting the appropriate use of medicines. [24] Policymakers and industry can help tackle resistance by: fostering innovation and research and development of new tools and promoting cooperation and information sharing among all stakeholders. [24]

Rapid viral testing Edit

Clinical investigation to rule out bacterial infections are often done for patients with pediatric acute respiratory infections. Currently it is unclear if rapid viral testing affects antibiotic use in children. [134]

Vaccines Edit

Microorganisms do not develop resistance to vaccines because a vaccine enhances the body's immune system, whereas an antibiotic operates separately from the body's normal defenses. Furthermore, if the use of vaccines increases, there is evidence that antibiotic resistant strains of pathogens will decrease the need for antibiotics will naturally decrease as vaccines prevent infection before it occurs. [135] However, new strains that escape immunity induced by vaccines may evolve for example, an updated 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 underway. [136]

Two registrational trials have evaluated vaccine candidates in active immunization strategies against S. aureus infection. In a phase II trial, a bivalent vaccine of capsulat protein 5 & 8 was tested in 1804 hemodialysis patients with a primary fistula or synthetic graft vascular access. After 40 weeks following vaccination a protective effect was seen against S. aureus bacteremia, but not at 54 weeks following vaccination. [137] Based on these results, a second trial was conducted which failed to show efficacy. [138]

Merck tested V710, a vaccine targeting IsdB, in a blinded randomized trial in patients undergoing median sternotomy. The trial was terminated after a higher rate of multiorgan system failure–related deaths was found in the V710 recipients. Vaccine recipients who developed S. aureus infection were 5 times more likely to die than control recipients who developed S. aureus infection. [139]

Numerous investigators have suggested that a multiple-antigen vaccine would be more effective, but a lack of biomarkers defining human protective immunity keep these proposals in the logical, but strictly hypothetical arena. [138]

Alternating therapy Edit

Alternating therapy is a proposed method in which two or three antibiotics are taken in a rotation versus taking just one antibiotic such that bacteria resistant to one antibiotic are killed when the next antibiotic is taken. Studies have found that this method reduces the rate at which antibiotic resistant bacteria emerge in vitro relative to a single drug for the entire duration. [140]

Studies have found that bacteria that evolve antibiotic resistance towards one group of antibiotic may become more sensitive to others. [141] This phenomenon can be used to select against resistant bacteria using an approach termed collateral sensitivity cycling, [142] which has recently been found to be relevant in developing treatment strategies for chronic infections caused by Pseudomonas aeruginosa. [143]

Development of new drugs Edit

Since the discovery of antibiotics, research and development (R&D) efforts have provided new drugs in time to treat bacteria that became resistant to older antibiotics, but in the 2000s there has been concern that development has slowed enough that seriously ill people may run out of treatment options. [144] [145] Another concern is that doctors may become reluctant to perform routine surgeries because of the increased risk of harmful infection. [146] Backup treatments can have serious side-effects for example, treatment of multi-drug-resistant tuberculosis can cause deafness or psychological disability. [147] The potential crisis at hand is the result of a marked decrease in industry R&D. [148] Poor financial investment in antibiotic research has exacerbated the situation. [149] [148] The pharmaceutical industry has little incentive to invest in antibiotics because of the high risk and because the potential financial returns are less likely to cover the cost of development than for other pharmaceuticals. [150] In 2011, Pfizer, one of the last major pharmaceutical companies developing new antibiotics, shut down its primary research effort, citing poor shareholder returns relative to drugs for chronic illnesses. [151] However, small and medium-sized pharmaceutical companies are still active in antibiotic drug research.

In the United States, drug companies and the administration of President Barack Obama had been proposing changing the standards by which the FDA approves antibiotics targeted at resistant organisms. [146] [152]

On 18 September 2014 Obama signed an executive order [153] to implement the recommendations proposed in a report [154] by the President's Council of Advisors on Science and Technology (PCAST) which outlines strategies to stream-line clinical trials and speed up the R&D of new antibiotics. Among the proposals:

  • Create a 'robust, standing national clinical trials network for antibiotic testing' which will promptly enroll patients once identified to be suffering from dangerous bacterial infections. The network will allow testing multiple new agents from different companies simultaneously for their safety and efficacy.
  • Establish a 'Special Medical Use (SMU)' pathway for FDA to approve new antimicrobial agents for use in limited patient populations, shorten the approval timeline for new drug so patients with severe infections could benefit as quickly as possible.
  • Provide economic incentives, especially for development of new classes of antibiotics, to offset the steep R&D costs which drive away the industry to develop antibiotics.

Biomaterials Edit

Using antibiotic-free alternatives in bone infection treatment may help decrease the use of antibiotics and thus antimicrobial resistance. [155] The bone regeneration material bioactive glass S53P4 has shown to effectively inhibit the bacterial growth of up to 50 clinically relevant bacteria including MRSA and MRSE. [156] [157] [158]

During the last decades, copper and silver nanomaterials have demonstrated appealing features for the development of a new family of antimicrobial agents. [159]

Rediscovery of ancient treatments Edit

Similar to the situation in malaria therapy, where successful treatments based on ancient recipes have been found, [160] there has already been some success in finding and testing ancient drugs and other treatments that are effective against AMR bacteria. [161]

Rapid diagnostics Edit

Distinguishing infections requiring antibiotics from self-limiting ones is clinically challenging. In order to guide appropriate use of antibiotics and prevent the evolution and spread of antimicrobial resistance, diagnostic tests that provide clinicians with timely, actionable results are needed.

Acute febrile illness is a common reason for seeking medical care worldwide and a major cause of morbidity and mortality. In areas with decreasing malaria incidence, many febrile patients are inappropriately treated for malaria, and in the absence of a simple diagnostic test to identify alternative causes of fever, clinicians presume that a non-malarial febrile illness is most likely a bacterial infection, leading to inappropriate use of antibiotics. Multiple studies have shown that the use of malaria rapid diagnostic tests without reliable tools to distinguish other fever causes has resulted in increased antibiotic use. [162]

Antimicrobial susceptibility testing (AST) can help practitioners avoid prescribing unnecessary antibiotics in the style of precision medicine, [163] and help them prescribe effective antibiotics, but with the traditional approach it could take 12 to 48 hours. [164] Rapid testing, possible from molecular diagnostics innovations, is defined as "being feasible within an 8-h working shift". [164] Progress has been slow due to a range of reasons including cost and regulation. [165]

Phage therapy Edit

Phage therapy is the therapeutic use of bacteriophages to treat pathogenic bacterial infections. [166] Phage therapy has many potential applications in human medicine as well as dentistry, veterinary science, and agriculture. [167]

Phage therapy relies on the use of naturally-occurring bacteriophages to infect and lyse bacteria at the site of infection in a host. Due to current advances in genetics and biotechnology these bacteriophages can possibly be manufactured to treat specific infections. [168] Phages can be bioengineered to target multidrug-resistant bacterial infections, and their use involves the added benefit of preventing the elimination of beneficial bacteria in the human body. [31] Phages destroy bacterial cell walls and membrane through the use of lytic proteins which kill bacteria by making many holes from the inside out. [169] Bacteriophages can even possess the ability to digest the biofilm that many bacteria develop that protect them from antibiotics in order to effectively infect and kill bacteria. Bioengineering can play a role in creating successful bacteriophages. [169]

Understanding the mutual interactions and evolutions of bacterial and phage populations in the environment of a human or animal body is essential for rational phage therapy. [170]

Bacteriophagics are used against antibiotic resistant bacteria in Georgia (George Eliava Institute) and in one institute in Wrocław, Poland. [171] [172] Bacteriophage cocktails are common drugs sold over the counter in pharmacies in eastern countries. [173] [174] In Belgium, four patients with severe musculoskeletal infections received bacteriophage therapy with concomitant antibiotics. After a single course of phage therapy, no recurrence of infection occurred and no severe side-effects related to the therapy were detected. [175]


Journal of Antimicrobial Agents

An antimicrobial is an agent that kills or inhibits the growth of microorganisms. The microbial agent may be a chemical compounds and physical agents. These agents interfere with the growth and reproduction of causative organisms like bacteria, fungi, parasites, virus etc. The journal of Antimicrobial Agents stocks up information about antibacterial, antifungal, antiviral, Anti protozoal, anti-algal agents and their methods of detection, different therapies and advanced treatments to overcome diseases.

Journal of Antimicrobial Agents is an open access peer reviewed journal that includes a wide range of fields on areas and creates a platform for the authors to make their contribution towards the journal and the editorial office promises a peer review process for the submitted manuscripts for the quality of publishing.

Journal of Antimicrobial Agents serves to be one of the best open access journal that aims to publish the most complete and reliable source of information on discoveries and current developments in field in the mode of original articles, review articles, case reports, short communications, etc. and provide free access through online without any restrictions or any other subscriptions to researchers worldwide.

The journal is using Editorial manager for quality in peer review process. Editorial manager is an online manuscript submission, review and tracking systems. Review processing is performed by the editorial board members of Journal of Antimicrobial Agents or outside experts at least two reviewers approval followed by editor approval is required for acceptance of any citable manuscript. Authors may submit manuscripts and track their progress through the system, hopefully to publication. Reviewers can download manuscripts and submit their opinions to the editor. Editors can manage the whole submission/review/revise/publish process.


Background

Antimicrobial use and resistance in animal agriculture

Antimicrobial resistance is a global public health threat, reflected in at least 2 million resistant infections and at least 23,000 deaths in the United States each year [1]. Antimicrobial drug use is considered to be the single most important factor leading to resistance [1]. However, effective policy interventions are hindered by the fact that the emergence and spread of antimicrobial resistance is complex and the underlying dynamics incompletely understood [2, 3]. Antimicrobial drugs are used in a variety of settings including hospitals, outpatient clinics, and long-term care facilities as well as animal-associated settings such as veterinary clinics, farms, and feedlots. There is general scientific consensus that antimicrobial drug use in a variety of settings contributes to the burden of antimicrobial resistance [2, 3]. However, the relative contribution of different antimicrobial uses to the overall burden has so far remained unclear. Moreover, despite decades of research and a considerable body of scientific evidence, the link between antimicrobial drug use on farms and antimicrobial resistant infections in humans remains contested by critics, primarily in the U.S. [3]. This dispute is disruptive to the debate around judicious use of antimicrobial drugs in animal agriculture, and has the potential to slow the implementation of policies aimed at assuring the responsible and prudent use of antibiotics in animal agriculture. Notably, various organizations including the World Health Organization for Animals (OIE), U.S. Food and Drug Administration, and the British and American Veterinary Medical Associations, have defined the concept of responsible, prudent or judicious antimicrobial use in animal agriculture. Optimizing therapeutic efficacy and minimizing antimicrobial resistance are key objectives underpinning all of these definitions, despite some definitional differences. For the purposes of this study, judicious antimicrobial use shall be equivalent to OIE’s ‘responsible and prudent use’ definition of ‘improv[ing]animal health and animal welfare while preventing or reducing the selection, emergence and spread of antimicrobial-resistant bacteria in animals and humans.’

Policy solutions to ensure judicious antimicrobial use in animal agriculture

Around the world, policy efforts to ensure judicious antimicrobial use in animal agriculture have generally, as a first step, focused on restricting the use of those antimicrobial drugs important for human medicine for ‘growth promotion’ purposes. For the purposes of this article, the Codex Alimentarius definition of growth promotion shall be used, where ‘growth promotion refers to the use of antimicrobial substances to increase the rate of weight gain and/or the efficiency of feed utilization in animals by other than purely nutritional means’ and antimicrobials are thus administered to healthy animals with the primary goal of increasing growth rates and enhancing feed conversion efficiency [4].

As early as 1969, a report by the U.K. Joint Committee on the Use of Antibiotics in Animal Husbandry, known as the ‘Swann Report’, motivated by concerns about the emergence of antimicrobial resistance, called for the ban of medically important (i.e., shared between humans and animals) antimicrobials for growth promotion purposes [3]. However, it took nearly another two decades before governments took concrete action and individual countries differ drastically in their responsiveness on the issue [3]. Sweden outlawed the use of all antimicrobial drugs for growth promotion in 1986 and Denmark banned the use of the two medically important antimicrobials, avoparcin and virginiamycin, as growth promoters in 1995 [5]. Avoparcin was banned for growth promoting purposes across the European Union in 1997 and growth promotion uses of the remaining four medically important antibiotics (as defined by the World Health Organization [6]) bacitracin, spiramycin, tylosin and virginiamycin were banned in 1999 [5]. Following the precautionary principle, the use of any antimicrobial drug for growth promotion, including antimicrobial drug classes not used in human medicine, has been banned in Europe since 2006 [7]. In the U.S., the use of medically important antimicrobial drugs (as defined by the U.S. Food and Drug Administration [8]) for growth promotion was phased out on January 1, 2017. In fact, according to data collected by the OIE for 2015, more than 70% of member countries that responded to the survey did not authorize antimicrobial drugs for growth promotion purposes [9]. However, outlawing the use of medically important antimicrobial drugs for growth promotion is only the first step towards assuring their judicious use in animal agriculture. Several European countries have taken concrete next steps towards curtailing the emergence and spread of antimicrobial resistance by assuring antimicrobial drugs are used judiciously and only when necessary to ensure the health and well-being of the animal, and the U.S. Food and Drug Administration has recently announced plans to examine potential actions to that effect [10].

The dynamics of antimicrobial resistance and their relevance for this study

For the purpose of this study, antimicrobial resistance is defined as ‘microbiological resistance’ and refers to the increased resistance of a bacterium in vitro compared to a population of wild-type bacteria which can be expressed, for instance, as an increase in minimal inhibitory concentration (MIC). Infections with bacteria that meet this definition of resistance may in fact on occasion still respond to treatments with the antimicrobial drug. In this respect, microbiological resistance is different from the concept of ‘clinical resistance’, which is focused on treatment failures and considers clinical factors such as the therapeutic concentration that can be reached at the site of infection. To evaluate clinical resistance, MIC values can be compared to clinical breakpoints, which should be specific to the animal species and site of infection [11]. However, for many situations encountered in veterinary medicine specific breakpoints have not been established and extrapolations from existing breakpoints can be challenging.

This study focuses on the emergence and spread of acquired antimicrobial resistance. This resistance can emerge through point mutations, usually associated with a progression from low-level to high-level resistance as sequential mutations occur [12], or through horizontal gene transfer (HGT), which usually shows immediate high-level resistance as resistance genes are shared among bacteria [12]. HGT can occur through several mechanisms [12] for instance, plasmids that carry resistance genes can be shared among bacterial strains, bacteriophages can transfer resistance genes from one bacterium to another, and bacteria can take up naked DNA (e.g., genes originating from dead bacteria). Notably, the relative importance of each resistance pathway appears to at least partially depend on the bacterial species [12]. Acquired resistance has to be distinguished from inherent resistance. Some bacteria are inherently resistant to a drug because the bacterium is outside of the drug’s spectrum of action, for example because the bacterium lacks the drug target. In addition, some bacteria can be transiently resistant to a drug without a corresponding genetic change, probably because of a transient dormant state in which the bacterium’s metabolism is lowered to a point where it virtually ceases to function. These resistance types are generally believed not to be affected by antimicrobial use and will not be considered here.

The analysis of the link between antibiotic use on farms and human health risk is complicated by the fact that the evolutionary dynamics of antimicrobial resistance do not followed a simple ‘necessary and sufficient’ [13] model of epidemiological causation, where the presence of antimicrobial drug use would be both necessary and sufficient for the emergence of resistance. In many cases, the same acquired antimicrobial resistance type or trait can be encoded by more than one genetic mechanism. Resistance traits often, although not always, carry a fitness cost, at least in in vitro experimental systems, and fitness costs may differ for the same resistance trait based on the determining genetic changes [12]. If there is a fitness cost associated with a resistance trait, resistant strains are selected against in antimicrobial-free environments and selected for in the presence of antimicrobials. The fitness cost may be higher for chromosomally-mediated than plasmid-mediated mutations, may differ by resistance mechanism (e.g., whether resistance is conferred by modification of a metabolic pathway, alteration of a target site, or upregulation of membrane channels), and may increase with the number of point mutations required to express the trait [12]. In some cases, however, the fitness cost is very low. Moreover, compensatory mutations that correct the fitness loss brought about by the resistance-conferring mutations are possible. It is unknown how closely fitness costs under in vitro conditions track those experienced in vivo – for instance, multi-drug resistance may be associated with a lower fitness cost in vivo than predicted based on in vitro data [14].

Antimicrobial resistance is not a new phenomenon. There is strong scientific evidence for the pre-existence of some antimicrobial resistance genes (e.g., beta-lactamase genes) in the absence of any antimicrobial use [14]. In fact, many antimicrobial drugs are naturally produced by fungi or bacteria to stave off competition from other bacteria some resistance genes are necessary to allow these antimicrobial-producing microbes to survive, and others have emerged as an adaptation to the natural presence of these antimicrobial compounds in the environment, primarily in soil [15]. The term ‘resistome’ has been proposed to describe the ecology of resistance genes, broadly encompassing all resistance genes circulating in pathogenic and non-pathogenic bacteria, be they from soil, animals, humans, or other sources [15]. A comprehensive knowledge of the resistome and adequate phylogenetic analysis is necessary to determine whether a newly-detected resistance gene truly emerged recently, has been present for a while but recently became more prevalent, or simply has not been detected previously.

The evolutionary dynamics of antimicrobial resistance are further complicated by the potential for cross-resistance (the simultaneous resistance to multiple related drugs that share a drug target) and co-resistance (where several genes are transferred together, for instance on one plasmid, and selection for one of the genes indirectly selects for the others as well). Moreover, antimicrobial resistance to a given drug can be mediated by multiple genetic changes, with potentially different evolutionary dynamics, and bacterial mutation rates vary, potentially pre-disposing some bacteria (i.e., ‘hypermutators’) to the more rapid emergence of resistance-conferring mutations than others.

For all of these reasons, the exact dynamics between antimicrobial use and resistance development may differ by bacterial species, drug or drug target, and resistance-conferring mutation, and may be influenced by external factors such as the selection pressures exerted by the use of related drugs. Even if antimicrobial use decreases or ceases, this may not necessarily translate into a direct, measurable drop in antimicrobial resistance, and the impact of introducing, restraining or eliminating antimicrobial use may vary by bacterial strain, bacterial target and environment (e.g., as a result of different resistance mechanisms with different evolutionary and ecological properties). Perhaps most importantly, resistance may not in all cases be reversible by discontinuing antimicrobial use alone. As is also clear from this discussion, there are many aspects about the emergence, ecology and evolution of antimicrobial resistance genes that are not yet fully understood. For these reasons it is difficult to extrapolate from individual research studies to other settings, and to adequately evaluate all direct and indirect impacts of antimicrobial use on the emergence of resistance.

Because antimicrobial drug use and the emergence of resistance may not follow a direct cause and effect relationship, it can be very difficult to establish causality outside of tightly controlled experimental settings. However, many chronic diseases also do not follow a direct cause and effect relationship and research methods developed to address these challenges may be applicable to antimicrobial resistance. One widely used epidemiological model of causation that fits these chronic diseases and antimicrobial resistance is that of ‘sufficient-component causes,’ first articulated by Rothman [16]. According to this model, a sufficient cause can be made up of multiple components, each of which needs to occur in order for the sufficient condition to occur. For example, in order for a certain bacterium in a certain environment and with a given genetic make-up to acquire antimicrobial resistance both exposure to an antimicrobial drug and external factors such as contact with bacteria carrying a plasmid with resistance against the antimicrobial drug have to occur. In addition, there can be more than one sufficient condition for a cause. For example, another bacterium with a different genetic predisposition or exposed to other environmental conditions may not require exposure to the antimicrobial drug to develop resistance, for instance because of co-selection for heavy-metal resistance. While antimicrobial exposure may be a necessary condition for resistance in one situation, it may not be necessary in all situations, depending on the genetic predisposition and external factors. This model of causation, which is widely accepted by epidemiologists, will be used here. It provides a useful framework for the assessment of causality, including in instances with seemingly contradictory study findings. Moreover, it demonstrates the challenge associated with quantifying the proportion of antimicrobial resistant bacteria associated with different causes: if each cause in fact consists of multiple component causes each occurrence of antimicrobial resistant bacteria could be attributed to each of the component causes.

Study aims and objectives

The goal of this review is to provide an objective methodical summary of the available scientific evidence for or against a relationship between antimicrobial drug use on farms and antimicrobial resistant human infections. Because this nexus remains contested by some groups, particularly in the U.S., relevant antibiotic use policies and restrictions in the U.S. are highlighted where relevant. To achieve this, we review the scientific evidence supporting or refuting each step in the causal pathways from on-farm antimicrobial use to human public health risk, placing particular emphasis on the strengths and limitations of the available scientific evidence. Breaking down the exceedingly complex pathway from farm to public health risk into discrete intermediary steps considerably reduces complexity and allows for a hypothesis-driven approach. The goal of this study is to characterize the link between antimicrobial use on farms and human infections with resistant bacteria, rather than quantifying the relative importance of this link compared to antimicrobial drug use in other settings even though that quantification will ultimately be important to guide public health policy and data gaps that complicate or prevent quantification are highlighted. Similarly, quantifying the relative importance of different transmission routes from farm to humans is important but beyond the scope of this study.

Pathways from antimicrobial drug use on farms to resistant infections in humans

There are different pathways that can lead from antimicrobial use on farms to a public health risk, including foodborne and non-foodborne routes. (Drug residues are a separate public health concern not considered in this study.) Regardless of pathway, four distinct factors have to be understood to characterize the public health risk associated with antimicrobial drug use in animal agriculture.

Antimicrobial drug use on farms and feedlots

How antimicrobial drugs are used on farms and feedlots is central to understanding the emergence of antimicrobial resistance. Unfortunately, the amount of information available on actual antimicrobial drug use on farms and feedlots differs considerably across countries and is in many cases insufficient for understanding antimicrobial exposures.

Risk of resistance emergence as a result of antimicrobial exposure on farms and feedlots

This question concerns foodborne and zoonotic pathogens as well animal pathogens and commensal bacteria (i.e., the very large number of naturally occurring microorganisms that usually inhabit the body surfaces of humans and animals [17]). Resistance in commensal or animal pathogens poses a human health risk only if the resistance genes can be transferred to human pathogens this is regardless of whether the transfer occurs in the gut of farm animals, in the environment – be that on farms or off - or within the human gut. Horizontal gene transfer between human commensals and human pathogens has been widely demonstrated [18]. Therefore, evidence of resistance gene transfer from animal-associated bacteria to human commensals can be regarded as indirect evidence for a potential transmission to human pathogens and therefore a public health risk.

Risk of infection due to resistant bacteria that emerged on the farm

Bacteria, including foodborne or zoonotic pathogens, can be transferred from food producing animals to humans through direct contact, or indirectly through food or the environment. In addition to contact with the environment in which the animals are raised, indirect transmission may also include exposure to agricultural operations through manure run-offs, airborne particles, or other environmental exposures, even though these transmission routes are considerably less well understood and documented than the other possible transmission routes [19,20,21]. Some evidence further suggests that humans can transmit bacteria that originated on farms to other humans through direct contact, food contamination during processing, or contamination of shared environments, but, again, the evidence is limited and often circumstantial, the underlying dynamics are not well understood, and at least some animal-associated bacteria may be poorly equipped to be transmitted from human to human [22,23,24].

In some cases (e.g., foodborne outbreaks) the directionality of infection is quite obvious, but this is not always true. The question of directionality has to be considered in evaluations of the available scientific evidence. However, even if directionality may not always be clear, such studies imply a shared host range, which makes cross-species transmissions likely.

Excess morbidity and mortality caused by antimicrobial resistance traits that emerged on farms

Several specific mechanisms by which antimicrobial resistance can have adverse human health impacts have been identified in the literature, of which at least three are directly relevant to resistance that emerged in animal agriculture [25]:

Linkage of virulence and resistance traits, leading to drug-resistant strains with increased virulence

Treatment delay because initial treatments are ineffective

Necessity to choose less desirable treatment options because of resistance to more desirable antimicrobial drugs

Observational studies on the topic can be complicated by the presence of potential confounders such as differences in age or underlying disease among patient groups [26, 27] the choice of reference group can also have significant impacts on study findings [28] in addition, bacterial strains can differ in the severity of associated health outcomes independent of antimicrobial resistance [29], thus potentially introducing another source of confounding.

Given the vast amount of literature published on the subject, this review does not strive to be comprehensive in reviewing the available literature associated with the topic. Rather, for each step in the pathway a selected number of studies that exemplify each relevant study type are discussed together with a general discussion of the strength and limitations of the available evidence. Unanswered questions and areas requiring further study are clearly highlighted. Therefore, this study documents the current scientific understanding about the link between antimicrobial drug use on farms and human health risks associated with antimicrobial resistant infections, highlighting what is known and what remains to be determined.


Antimicrobial (Drug) Resistance

Scanning electron micrograph of methicillin-resistant Staphylococcus aureus (MRSA, brown) surrounded by cellular debris.

Scanning electron micrograph of methicillin-resistant Staphylococcus aureus (MRSA, brown) surrounded by cellular debris.

Bacteria, fungi, and other microbes evolve over time and can develop resistance to antimicrobial drugs. Microbes naturally develop resistance however, using antibiotics too often in humans and animals and in cases where antibiotics are not an appropriate treatment can make resistance develop more quickly.


Introduction

Antimicrobial resistance (AMR) is recognized as one of the greatest threats to human health worldwide. Just one organism, methicillin-resistant Staphylococcus aureus (MRSA), kills more Americans every year than emphysema, HIV/AIDS, Parkinson’s disease and homicide combined [Infectious Diseases Society of America et al. 2011]. Globally, 3.7% of new cases and 20% of previously treated cases of tuberculosis are estimated to be caused by strains that are resistant to isoniazid and rifampicin. For decades, these antituberculosis agents have been effective against tuberculosis, but today the effect is insufficient. Nowadays, only one-half of multidrug-resistant tuberculosis is effectively treated with the existing drugs [World Health Organization, 2014]. Extensively drug-resistant tuberculosis (defined as multidrug-resistant tuberculosis plus resistance to any fluoroquinolone and any second-line injectable drug) has been identified in 84 countries globally [World Health Organization, 2013]. Carbapenem-resistant Enterobacteriaceae spp. and extended-spectrum beta-lactamase-producing Enterobacteriaceae have been isolated in recent years [Nordmann et al. 2009 Ho et al. 2010 Oteo et al. 2010 Society for Healthcare Epidemiology of America, Infectious Diseases Society of America, and Pediatric Infectious Diseases Society, 2012]. There is a striking lack of development of new drugs active against these multidrug-resistant Gram-negative bacteria, particularly those producing carbapenemases [Boucher et al. 2013], and none of the antibiotics currently available are now effective [Falagas et al. 2008 Chen et al. 2009 Society for Healthcare Epidemiology of America, Infectious Diseases Society of America, and Pediatric Infectious Diseases Society, 2012].

While antibiotic resistance has predominantly been a clinical problem in hospital settings, recent data show resistant organisms have also been detected in patients in primary care [National Collaborating Centre for Infectious Diseases, 2010]. A recent report from the World Health Organization (WHO) clearly states that this is not a phenomenon occurring in just poor or developing countries the problem of AMR is now found throughout the world [World Health Organization, 2014]. Diseases associated with AMR in primary care include tuberculosis, gonorrhoea (specifically Neisseria gonorrhoeae), typhoid fever and Group B streptococcus [Centers for Disease Control and Prevention, 2012]. Community-acquired AMR is of particular concern, as these infections can be common and easily transmitted. The most recent data from the European Antibiotic Surveillance Reports found that antibiotic resistance rates of Escherichia coli and/or Klebsiella pneumoniae vary markedly between countries. Rates of resistant E. coli varied 18-fold between Sweden (1.0%) and Greece (18.2%) and for K. pneumoniae the differences were even more pronounced, ranging from 0.7% in Sweden to 64.1% in Greece [European Centre for Disease Prevention and Control, 2011]. However, antibiotic resistance of E. coli and Klebsiella spp. is highest in Asia (�%), with rates of 10�% in Southern Europe, and 5�% in Northern Europe, Australasia and North America [Livermore, 2012]. European data from 2011 demonstrate an alarming increase in the resistance of these organisms, with around a third of European countries showing a rise in combined resistance to third-generation cephalosporins, fluoroquinolones and aminoglycosides over the previous 4 years [European Centre for Disease Prevention and Control, 2011]. Some of these types of antibiotics are considered by the WHO as 𠆌ritically important antimicrobials’ in medicine [World Health Organization, 2009], and these broad-spectrum antibiotics should be avoided when narrow-spectrum antibiotics remain effective, as they also increase the risk of Clostridium difficile infection, MRSA and resistant urinary tract infections [Public Health England, 2013]. The problem of resistance not only involves the community, it also affects the individual. A recent review describing patients with bacterial urinary tract and respiratory tract infections treated with antibiotics reported that individual resistance may persist for up to 12 months post-treatment, thereby creating situations with the need of requiring second-line antibiotics [Costelloe et al. 2010].

Infection with antibiotic-resistant bacteria may cause severe illness, increased mortality rates, and an increased risk of complications and admission to hospital [Kollef, 2008 Paul et al. 2010 Livermore, 2012]. According to the European Centre for Disease Prevention and Control, 25,000 people in Europe die each year as a direct result of resistant infection [European Centre for Disease Prevention and Control, 2011]. Antibiotic resistance leads to an increased amount of healthcare costs. It is estimated that complications associated with antibiotic resistance cost 𠫉 billion annually in Europe [Oxford and Kozlov, 2013]. A recent review demonstrated that the additional cost of resistance could be of ꌠ,000 per patient episode in hospital [Smith and Coast, 2013].

In the context of few innovative or new antibiotics in the drug development pipeline, the WHO describes a future of a post-antibiotic world and warns that not only will this eliminate the advances in healthcare made over the past 100 years, which have ensured longer life in most parts of the developed and developing worlds, but it may also result in simple infections becoming unmanageable and potentially fatal [World Health Organization, 2012a, 2012b]. The United Kingdom Chief Medical Officer has highlighted the need for clinicians to preserve the effectiveness of antibiotics by giving clear evidence-based guidance on their appropriate use [Department of Health, 2012] and has stated that we are losing the battle against infectious diseases, and antibiotics may no longer be effective in the long term [Davies et al. 2013].

Most of the antibiotics used in medicine are prescribed by general practitioners (GP). In fact, primary care accounts for 80�% of all antibiotic prescriptions in Europe and most antibiotics are prescribed for respiratory tract infections [European Centre for Disease Prevention and Control, 2014]. Utilization of antibiotics is also very important in other sectors for instance, approximately 80% of antibiotics in the United States are consumed in agriculture, farming and aquaculture [Hollis and Ahmed, 2013]. Data show a direct correlation between the use of antibiotics and resistance. Countries with a higher consumption of antibiotics show higher rates of resistance [Goossens et al. 2005 Riedel et al. 2007]. Antibiotic prescribing differs profoundly from one European country to the next, although there is no evidence of differences in the prevalence of infectious diseases. On average, the European consumption rate of antibiotics is 18.3 defined as daily doses/1000 inhabitants/day (DID) in 2010, with the highest rate in Greece with 39.4 DID and the lowest in two Baltic countries with 11.1 DID or 11.2 DID of Holland [European Centre for Disease Prevention and Control, 2010]. A recent study has shown that the consumption of antibiotics is even greater in the new southern and eastern European countries, with an antibiotic use of 42.3 DID in Turkey [Versporten et al. 2014].

Apart from spreading resistance, antibiotic overprescribing is also associated with other problems (Box 1). Consumption of antibiotics puts patients at risk of adverse effects. Antibiotics account for approximately 20% of all drug-related emergency department visits in the United States. Although nearly 80% of these visits are attributable to allergic reactions, certain commonly prescribed antibiotics contribute to conditions that range from gastrointestinal to neurologic and psychiatric disorders [Lode, 2010]. Most of these adverse effects are mild, but some life-threatening adverse effects have been reported, such as hepatotoxicity due to amoxicillin and clavulanate [Chang and Schiano, 2007]. Antibiotic overprescribing has been shown to increase patient re-attendance as it medicalizes conditions, which are self-limiting [Little et al. 1997]. And more attendance means more prescription of antibiotics.

Box 1.

Risks that have been shown to be associated with overuse of antibiotics.

Increase of antimicrobial resistance

Increase of more severe diseases

Increase of the length of disease

Increase of the risk of complications

Increase of the mortality rate

Increase of healthcare costs

Increase of the risk of adverse effects, some being life-threatening

Increase of re-attendance due to infectious diseases

Increased medicalization of self-limiting infectious conditions

Why are there such differences in antibiotic consumption in Europe? These differences cannot be explained by a different pattern of infectious diseases across countries. It is clear that the main concern is to avoid under-treatment [Kumar et al. 2003]. None of us wants to be seen to have withheld treatment from a patient who subsequently deteriorates, especially if the patient is hospitalized. Although rare, it might damage doctor–patient relationships and lead to complaints and medical–legal consequences. However, most of the respiratory tract infections attended by GPs are self-limiting. In Europe, upper respiratory tract infections account for 57% of the antibiotics used, with a further 30% for lower respiratory tract infections in contrast, the next most common condition is urinary tract infections at 7% [van der Velden et al. 2013]. Moreover, respiratory tract infections are the most commonly treated acute problem in primary care [Francis et al. 2009], with most caused by a virus, to which antibiotics have shown to have a limited effect on symptoms. In a recent controlled clinical trial with placebo, with data from the GRACE project (http://www.grace-lrti.org) in 12 European countries including more than 3000 adults with acute cough (� days) and without suspicion of pneumonia based on clinical grounds, the percentage of patients with new or worsening symptoms was slightly less frequently observed among those treated with amoxicillin 3 g daily compared with controls (16% versus 19%, number needed to treat = 30) but the prevalence of nausea, diarrhoea, or rash occurred more frequently in the former (number needed to harm = 23) [Little et al. 2013a].

The benefits of antibiotic therapy for most respiratory tract infections are modest in the best-case scenario [Kenealy and Arroll, 2013 Spinks et al. 2013 Venekamp et al. 2013 Smith et al. 2014]. If respiratory tract infections are mostly self-limiting, why do we treat between 52% and 100% of the cases, with a median of 88%, with antibiotics? [Ashworth et al. 2005]. As mentioned recently by Hay and Tilling, how is it possible that 88% of patients with acute bronchitis are special [Hay and Tilling, 2014]?

In general, prescribing has been shown to be influenced by several factors, including cultural aspects related to the country background, sociocultural and socio-economic factors, and the cultural beliefs of the patient and the prescriber, patient demand, and clinical autonomy [Butler et al. 1998 Moore and McNulty, 2012]. In different countries, people hold different ideas about health, causes of disease, labelling of illness, coping strategies, and treatment modalities [Hulscher et al. 2010]. Diagnostic uncertainty plays an important role in antibiotic overprescribing [Harbart and Samore, 2005]. In a Dutch study, the use of antibiotics was strongly associated with uncertainty avoidance (unwillingness to accept uncertainty and risks). The authors also observed that hierarchical societies such as those in Southern Europe consume more antibiotics than mainly egalitarian societies such as Scandinavian countries, the UK or the Netherlands [Deschepper and Vander Stichele, 2001]. Socioeconomic factors have also been associated with variability of antibiotic prescription. Aspects such as the way in which healthcare is funded or reimbursed, the percentage of generic drugs in the market, the economic incentives or the pressure of pharmaceutical industries can affect antibiotic prescription by clinicians [Hulscher et al. 2010]. Inequalities might also explain the variability of antimicrobial use. Moreover, Kirby and Herbert observed a moderate correlation between AMR and income inequality with the utilization of data from 15 large European countries [Kirby and Herbert, 2013].

Other factors related to the professional care-delivery system of antibiotics are probably important, such as care coordination, professional’s collaboration, communication teamwork, clinician’s knowledge about management of infectious diseases and doctor–patient relationship. Misconceptions and uncertainties regarding the role of antibiotics also exist among patients [Altiner et al. 2007]. For example, a European study reported that around half of the patients believed antibiotics were effective in treating viruses, cold and flu, with considerable differences across countries [European Commission, 2010].There also appears to be a dissonance between physician and patient expectations during a consultation of a respiratory tract infection [Coenen et al. 2013]. Clinicians’ attitudes on antibiotics also play an important role in antibiotic overprescribing. A recent survey including more than 1000 GPs carried out in the UK found that 55% felt under pressure, mainly from patients, to prescribe antibiotics, even if they were not sure that they were necessary, and 44% admitted that they had prescribed antibiotics to get a patient to leave the surgery [Cole, 2014].


Vaccines for bacterial infections are urgently needed. Vaccines could be used to mitigate symptoms and disease progression, or to prevent infection or reduce colonization. For example, NIAID is supporting research on vaccine targets for N. gonorrhoeae, how the bacteria cause disease and how our immune systems respond to it. NIAID also is funding the Sexually Transmitted Infections Cooperative Research Centers which aim to develop vaccines against gonorrhea, chlamydia and syphilis.

In 2019, NIAID established the Infectious Diseases Clinical Research Consortium, a clinical trials network that encompasses the Institute’s long-standing Vaccine and Treatment Evaluation Units (VTEUs). The consortium leadership group will prioritize candidate vaccines and other interventions to test in clinical trials.

NIAID scientists also are developing a potential immunotherapy approach for the treatment of multidrug-resistant Klebsiella pneumoniae infections. While antibiotics target bacterial pathogens, immunotherapy approaches enhance the immune system’s ability to fight specific bacteria. NIAID’s Antibacterial Resistance Leadership Group (ARLG) also has evaluated investigational antibody-based therapies aimed at preventing potentially antibiotic-resistant infections.


Drug Resistance: Meaning, Origin and Transmission

Antimicrobial drug resistance refers to the acquired ability of a microbial pathogen to resist the effects of a therapeutic agent (antimicrobial drug) to which it is normally susceptible. Drug resistance does not involve the host, but is a function of the microbial pathogen present inside the host.

As we know that antibiotics are produced by microorganisms and the latter, in order to survive, developed resistance mechanisms to neutralize or destroy their own antibiotics. In addition, genes encoding these resistance mechanisms can be transferred to other, usually related microorganisms.

As a result, most antimicrobial drug resistance involves ‘resistance genes’ which get transferred between and among microorganisms by genetic exchange. However, the spread of drug resistance in microbial pathogens has become one of the most serious threats to the successful treatment of microbial disease.

Drug resistance has become an extremely serious public health problem especially because of the massive quantities of antibiotics being prepared and used.

Following are some examples of drug resistance that were reported in the past:

1. Neisseria gonorrhoeae, the causative agent of gonorrhoea is a good example. Gonorrhoea was first treated successfully with sulfonamides in 1936, but, by 1942, most strains were resistant and physicians turned to penicillin.

Within 16 years a penicillin-resistant strain had emerged in the Far East. A penicillinase- producing gonococcus reached the United States in 1976 and is still spreading in this country.

2. In 1946 almost all strains of Staphylococcus were penicillin sensitive. Today, most hospital strains are resistant to penicillin G, and some are now also resistant to methicillin and/or gentamicin and only can be treated with vancomycin. Some strains of Entefococcus have become resistant to most antibiotics, including vancomycin.

Recently a few cases of vancomycin-resistant S. aureus have been reported in the United States and Japan. At present these strains are only intermediately resistant to vancomycin. If full vancomycin resistance develops and spreads, S. aureus may become untreatable.

3. An epidemic of dysentery caused by Shigella was reported in Guatemala in late 1968 and it affected at least 112,000 persons and resulted in 12,500 deaths. The strains responsible for this devastation carried an R plasmid giving them resistance to chloramphenicol, tetracycline, streptomycin, and sulfonamide.

In 1972 a typhoid epidemic swept through Mexico producing 100,000 infections and 14,000 deaths. It was due to a Salmonella typhi strain with the same multiple-drug-resistance pattern seen in the previous Shigella outbreak.

4. Haemophilus influenzae type b is responsible for many cases of childhood pneumonia and middle ear infections, as well as respiratory infections and meningitis. It is now becoming increasingly resistant to tetracyclines, ampicillin, and chloramphenicol.

The same situation is occurring with Streptococcus pneumoniae. It has been estimated that by sometime in 2004, as much as 40% of S. pneumoniae may be resistant to both penicillin and erythromycin.

2. Mechanisms of Drug Resistance:

No therapeutic drug (antibiotic) inhibits all microbial pathogens and some microbial pathogens possess natural ability to resist to certain antibiotics. Bacteria become drug resistant using several different resistance mechanisms. A particular type of resistance mechanism is not confined to a single class of drugs. Two bacteria may employ different resistance mechanisms to counter the same antibiotic.

However, bacteria acquire drug resistance using resistance mechanisms such as:

(i) Reduced permeability to antibiotic,

(ii) Efflux (pumping) antibiotic out of the cell,

(iii) Drug inactivation through chemical modification,

(iv) Target modification, and

(v) Development of a resistant biochemical pathway.

A summarized account of different mechanisms of drug resistance is given in Table 46.1.

(i) Reduced Permeability to Antibiotic:

Bacteria often develop impermeability and become resistant simply by preventing entrance of the drug. Many gram-negative bacteria are unaffected by penicillin G because the drug fails to penetrate the envelope’s outer membrane. Modifications in penicillin binding proteins also render a cell resistant.

A decrease in permeability in bacterial pathogens can lead to resistance against sulfonamide. Mycobacteria resist many drugs because of the high content of mycolic acids in a complex lipid layer outside their peptidoglycan. This layer is impermeable to most drugs.

Decrease in permeability also can occur as a result of loss of porin proteins. Escherichia coli produces two types of porins, OmpC and OmpF. Mutations result in deficiency in outer membrane porin OmpF confers low- level resistance to tetracycline as well as to β-lactam antibiotics, chloramphenicol, and quinolones. Narrow spectrum imipenem resistance, which can arise in Pseudomonas aeruginosa, is also an example of reduced permeability.

(ii) Efflux (Pumping Antibiotic Out of the Cell):

Microbial pathogenes possess resistance strategy by which they 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 nonspecific and can pump many different drugs, these transport proteins often are called multidrug-resistance pumps.

Efflux systems are present in E. coli, Pseudomonas aeruginosa, Mycobacterium smegmatis, Mycobacterium tuberculosis. Staphylococcus aureus, Streptococcus pneumoniae, and Neisseria gonorrhoeae.

Gram-positive and gram-negative bacteria that become resistant to tetracyclines commonly overproduce related membrane proteins that act as efflux pump. Tetracycline resistant bacterial cell takes up the drug as rapidly as do sensitive ones but differ in being able to pump it out again.

Drug efflux is mediated by the Tet membrane proteins which use an antiport mechanism of transport involving the exchange of a proton for a tetracycline-cation complex. Plasmid-encoded multidrug efflux pump confer resistance to olaquindox in E. coli. Salt-inducible multidrug efflux pump is reported Chromohalobacter sp.

(iii) Drug Inactivation Through Chemical Modification:

Many bacterial pathogens show resistance to drug by inactivating drugs through chemical modification. The best-known example is the hydrolysis of the β- lactam ring of many penicillins by the enzyme penicillinase.

Drugs also are inactivated by the addition of groups. For example, chloramphenicol contains two hydroxyl groups that can be acetylated in a reaction catalyzed by the enzyme chloramphenicol acyltransferase with acetyl CoA as the donor.

Aminoglycosides can be modified and inactivated in several ways. Acetyltransferases catalyze the acetylation of amino groups. Some aminoglycoside-modifying enzymes catalyze the addition to hydroxyl groups of either phosphates (phosphotransferases) or adenyl groups (adenyltransferases).

(iv) Target Modification:

Since 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.

Enterococci become resistant to vancomycin by changing the terminal D-alaninc-D- alanine in their peptidoglycan lo a D-alanine-D-lactate. This drastically reduces antibiotic binding. Antimetabolite action may be resisted through alteration of susceptible enzymes.

In sulfonamide-resistant bacteria the enzyme that uses p-aminobenzoic acid during folic acid synthesis (the tetrahydropteroic acid synthetase) often has a much lower affinity for sulfonamides. Mycobacterium tuberculosis becomes resistant to the drug rifampin due to mutations that alter the β subunit of its RNA polymerase. Rifampin cannot bind to the mutant RNA polymerase and block the initiation of transcription.

(v) Development of a Resistant Biochemical Pathway:

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 instance, certain bacteria are resistant to sulfonamides simply because they use preformed folic acid from their surroundings rather than synthesize it themselves. Other strains increase their rate of folic acid production and thus counteract sulfonamide inhibition.

3. Origin of Drug Resistance:

Origin of drug resistance has genetic basis. Drug resistance can be genetically encoded by the microbial pathogen and the genes responsible for it are present on both the chromosome and plasmids (Table 46.1).

(i) Chromosome-Mediated Drug Resistance:

Spontaneous mutations in the chromosome, although they do not occur very often, will make bacteria drug resistant. Usually such mutations result in a change in the drug receptor and therefore the antibiotic cannot bind and inhibit the pathogen (e.g., the streptomycin receptor protein on bacterial ribosomes).

Many mutants are probably destroyed by natural host resistance mechanisms. However, when a patient is being treated extensively with antibiotics, some resistant mutant may survive and flourish because of their competitive advantage over non-resistant strains.

Transposons are a type of transposable elements in bacterial chromosome that, in addition to genes involved in transposition, carries other genes often genes conferring antibiotic resistance. Many composite transposons contain genes for antibiotic resistance, and some bear more than one resistance gene.

They are found in both gram-negative and gram-positive bacteria. Some examples and their resistance markers are Tn5 (kanamycin, bleomycin, streptomycin), Tn9 (chloramphenicol), Tn10 (tetracycline), Tn21 (streptomycin, spectinomycin, sulfonamide), Tn551 (erythromycin), and Tn4001 (gentamicin, tobranycin, kanamycin).

(ii) Plasmid-Mediated Drug Resistance:

Plasmid is an extra-chromosomal genetic element that replicates independently of the host chromosome, is not essential for growth, and has no extracellular form. We know that large number of different plasmids occur naturally in bacterial cells.

Among the most widespread and well-studied groups of plasmids are the R plasmids (resistance plasmids), which confer resistance to antibiotics. R plasmids were first discovered in Japan in enteric bacteria that had acquired resistance to a number of antibiotics (multiple resistance) and have since been found throughout the world.

R plasmid resistance is usually due to the presence of genes in it encoding new enzymes that inactivate the antibiotic or genes that encode enzymes that either prevent antibiotic update or actively pump it out of the bacterial cell.

For example, the aminoglycoside antibiotics streptomycin, neomycin, kanamycin, and spectinomycin possess identical chemical structures. Strains carrying R plasmids for these antibiotics can synthesis enzymes that chemically modify the antibiotics either by phosphorylation, acctylation, or adenylalion (Fig. 46.1). The modified antibiotics then lack antibiotic-property.

R plasmid genes encode penicillinase enzyme (β-lactamase) that splits the β-lactam ring in penicillins, and inactivate the antibiotic. Chloramphenicol resistance is due to an R plasmid gene-encoded enzyme that acetylates the antibiotic (Fig. 46.2). Several R plasmids confer multiple antibiotic resistance because a single R plasmid may possess different genes, each encoding a different antibiotic-inactivating enzyme.

4. Transmission of Drug Resistance:

Drug resistance and its spread has become an extremely serious public health problem.

Following are the main factors responsible for development and spread of drug resistance:

(i) Drug Misuse:

Misuse of drugs have resulted in much of the difficulty. It has been estimated that over 50% of the antibiotic prescriptions in hospitals are given without clear evidence of infection or adequate medical indication. Many physicians have administered antibacterial drugs to patients with colds, influenza, viral pneumonia, and other viral diseases.

A recent study showed that over 50% of the patients diagnosed with colds and upper respiratory infections and 66% of those with chest colds (bronchitis) are given antibiotics, even though over 90% of these cases are caused by viruses.

Frequently antibiotics are prescribed without culturing and identifying the pathogen or without determining bacterial sensitivity to the drug. Toxic, broad-spectrum antibiotics are sometimes given in place of narrow-spectrum drugs as a substitute for culture and sensitivity testing, with the consequent risk of dangerous side effects, super-infections, and the selection of drug-resistant mutants.

The situation is made worse by patients not completing their course of medication. When antibiotic treatment is ended too early, drug-resistant mutants may survive. People in many countries usually practice self-administration of antibiotics and thus help increase the prevalence of drug-resistant strains.

(ii) Extensive Drug Treatment:

Extensive drug treatment helps the development and spread of antibiotic- resistant strains. It is because the excess antibiotic destroys normal, susceptible bacteria that would usually compete with drug-resistant strains.

The result may be the emergence of drug resistant pathogens leading to a superinfection. Super-infections are a significant problem because of the existence of multiple-drug-resistant bacteria that often produce drug-resistant respiratory and urinary tract infections. A classic example of a superinfection resulting from antibiotic administration is the disease pseudomembranous enterocolitis caused by Clostridium difficile.

When a patient is given clindamycin, ampicillin, or cephalosporin, many intestinal bacteria are killed, but C. difficile is not. This intestinal inhabitant, which is normally a minor constituent of the population, flourishes in the absence of competition and produces a toxin that stimulates the secretion of a pseudo-membrane by intestinal cells.

If the superinfection is not treated early with vancomycin, the pseudo-membrane must be surgically removed otherwise the patient will die. Fungi, such as the yeast Candida albicans, also produce super-infections when bacterial competition is eliminated by antibiotics.

(iii) Movement of Resistance-Genes:

Resistance genes present on composite transposons can move rapidly between plasmids and through a bacterial population. Often several resistance genes are carried together as gene cassettes in association with a genetic element known as an integron. An integron has an attachment site for site-specific recombination into which genes can be inserted as an integrase gene.

Thus integrons can capture genes and gene cassettes. Gene cassettes are genetic elements that may exist as circular non-replicating DNA when moving from one site to another, but which normally are a linear part of a transposon, plasmid, or bacterial chromosome. Cassettes usually carry one or two genes and a recombination site.

Several cassettes can be integrated sequentially in an integron. Thus integrons also are important in spreading resistance genes. Finally, conjugative transposons, like composite transposons, can carry resistance genes. Since they are capable of moving between bacteria by conjugation, they are also effective in spreading resistance.

(iv) Use of Drugs in Animal Feed:

The use of antibiotics in animal feeds is undoubtedly another contributing factor to increasing drug resistance. The addition of low levels of antibiotics to livestock feeds does raise the efficiency and rate of weight gain in cattle, pigs, and chickens (partially because of infection control in overcrowded animal populations).

However, this also increases the number of drug-resistant bacteria in animal intestinal tracts. There is evidence for the spread of bacteria such as Salmonella from animals to human populations.

In 1983, 18 people in four mid-western States of America were infected with a multiple- drug-resistant strain of Salmonella new-port. Eleven were hospitalized for salmonellosis and one died. All 18 patients had recently been infected by eating hamburger from beef cattle fed sub-therapeutic doses of chlortetracycline for growth promotion.

Resistance to some antibiotics has been traced to the use of specific farmyard antibiotics. Avoparcin resembles vancomycin in structure, and virginiamycin resembles synercid synercid is a mixture of the antibiotics, streptogramin, quinupristin and dalfopristin that inhibits protein synthesis.

There is good circumstantial evidence that extensive use of these two antibiotics in animal feed has led to an increase in vancomycin and synercid resistance among enterococci. The use of the quinolone antibiotic enrofloxacin in swine herds appears to have promoted ciprofloxacin resistance in pathogenic strains of Salmonella. Elimination of antibiotic food supplements might well slow the spread of drug resistance.

(v) Use of Triclosan:

Triclosan is an antibacterial substance found in products such as soaps, deodorants, mouth-washes, cutting boards, and baby toys. There is increasing evidence that the widespread use of triclosan actually favours an increase in antibiotic resistance.

5. Drug-Resistance Encounter:

Various strategies can be used to encounter the emergence of drug resistance.

Important ones are the following:

(i) Strategic Use of Drugs:

Following are some specific modes proposed to use drugs to discourage the emergence of drug resistance:

(i) The drug can be used in a high enough concentration. This is considered to destroy susceptible bacterial pathogens and most spontaneous mutants of pathogens that might arise during drug- treatment.

(ii) Two different drugs can be given to the patient simultaneously. This may help in the way that each drug will prevent the development of resistance to the other.

(iii) Chemotherapeutic drugs, particularly broad-spectrum antibiotics, should be used only when definitely necessary. If possible, the pathogen should be identified, drug sensitively tests should be performed, and finally, a proper narrow-spectrum antibiotic should be given to the patient.

(ii) Search for New Antibiotics:

Search for new antibiotics that microbial pathogens have never faced is a major approach. Drug manufacturing companies collect and analyse samples from around the world in a search for completely new antimicrobial drugs. Structure-based or rational drug design is emerging as an important tool in this area.

If the three dimensional structure of a susceptible target molecule such as an enzyme essential to microbial function is known, computer programs can be used to design that precisely fit the target molecule. These drugs might be able to bind to the target and disrupt its function sufficiently to destroy the pathogen.

Pharmaceutical companies are using this approach to attempt to develop drugs for the treatment of AIDS, cancer, and the common cold. At least one company is developing “enhancers”, which are cationic peptides that disrupt bacterial membranes by displacing their magnesium ions.

Antibiotics then penetrate and rapidly exert their effects. Other pharmaceutical companies are developing efflux-pump inhibitors to administer with antibiotics and prevent their expulsion by the resistant pathogen.

There has been some recent progress in developing new antibiotics that are effective against drug-resistant pathogens. Two new drugs are fairly effective against vancomycin-resistant enterococci, and they are synercid and linezolid (zyvox). Synercid, as stated earlier, is a mixture of the streptogramin antibiotics (quinupristin and dalfopristin) that inhibits protein synthesis.

A second drug, linezolid (Zyvox), is the first drug in a new family of antibiotics, the oxazolidinones. It inhibits protein synthesis and is active against both vancomycin-resistant enterococci and methicillin-resistant Staphylococcus aureus.

(iii) Identifying New Targets for drugs:

Recent knowledge coming from the sequencing and analysis of pathogen genomes almost certainly will be useful in identifying new targets for antimicrobial drugs. For convenience, data obtained from genomics studies can be used for research on inhibitors of both aminoacyl- tRNA synthetases and the enzyme that removes the formyl group from the N-terminal methionine during bacterial protein synthesis.

Bacteria must synthesize the fatty acids they require for growth rather than acquiring the acids from their environment. The drug susceptibility of enzymes in the fatty acid synthesis system is being analyzed by screening pathogens for potential targets.

(iv) Phage Therapy:

Phage therapy is emerging as a most interesting approach to overcome the problem of drug resistance. This therapy is based on the idea proposed by d’Herelle in mid of second decade of 20th century. d’Herelle proposed that bacteriophages could be used to treat bacterial disease.

Although many microbiologists did not favour d’Herelle idea due to technical difficulties and the advent of antibiotics, Russian scientists pursued his proposal actively and developed the medical use of bacteriophages.

Currently, Russian physicians use bacteriophages to treat many bacterial infections. Bandages are saturated with phage solutions, phage mixtures are administered orally, and phage preparations are given intravenously to treat Staphylococcus infections. Three American companies are actively conducting research on phage therapy and preparing to carry out clinical trials.


Watch the video: Antibiotic Classes in 7 minutes!! (September 2022).


Comments:

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