How the microbiome affects the development of allergies

Increasing evidence suggests that a disruption of the healthy human microbiome (i.e. communities of microbes, their genetic content and their interaction with the human host) is linked to an increased risk of developing allergic diseases.

Studies have shown that newborns who later develop either asthma or allergies commonly have a different composition of microbes in their guts (the gut microbiota) within the first few months of life compared to those who are unaffected by these disorders. There are many factors that can alter the composition of the microbiome in early life including:

Caesarean birth
Numerous studies have also shown that the mode of delivery (vaginal or caesarean) impacts the diversity of the microbiome. During a vaginal birth a baby encounters some of the first microbes that will colonise the gut from the mother. On the other hand, during a caesarean the baby is not exposed to these microbes and in addition encounters other microbes from the hospital environment. This alteration in the microbiota is believed to contribute to the development of allergy and asthma. One study in 2013 found that babies born by caesarean were 5 times more likely to develop allergies prior to turning two years old compared to babies born by vaginal delivery.
In an attempt to restore microbial diversity to caesarean-born babies, studies have swabbed newborn babies with the mother's vaginal fluid. As unusual as this may seem, it has shown some success with the swabbed babies presenting with a gut microbiota more similar to those in babies born vaginally than babies who were not swabbed. This research is still in its early stages and more needs to be done to determine any risks of passing on pathological bacteria, but current results look promising.

Breast-feeding
In addition to the mode of delivery, an infant's microbiota population is also impacted whether they are breastfed. One recent study showed that up to 28% of the infants microbiome comes directly from the mother's breast milk, with an additional 10% from the skin on the mother's breast. There is some evidence to suggest that breastfeeding protects against the development of allergies such as asthma, however research into this is still ongoing.

Pets
An emerging body of evidence suggests that exposure to pets at an early age may offer a level of protection from the later development of allergies and asthma. Originally it was believed that the protection conferred by early exposure to animals was due to desensitisation to potential allergens. However, new research suggests that the connection is linked to beneficial changes in the gut microbiome through exposure to a more diverse range of microbes. In particular, it appears that this is most effective prior to birth and during the first year of life.
Many epidemiological studies show that children who grow up in with regular contact with animals (i.e. on a farm or pets-owners) have a lower risk for developing allergies and asthma. As well as the presence animals themselves, other factors such as traces of soil that are brought in with them also contribute to an environment with a greater diversity of microbes.

Antibiotics
Antibiotic use causes long term alterations to our gut microbiota and increasing evidence suggests that this is significantly associated with a rise in allergies. Dr Gary Huffnagle, University of Michigan, provided the first experimental evidence for the role of antibiotics and microbes in the development of allergic airway disease. The study showed that an alteration of the gut microbiota following a course of antibiotics caused an increased hypersensitivity and reactivity in the lungs of mice in response to harmless yeast spores. In particular, antibiotic use during the early years of life is shown to significantly impact the risk of childhood atopy (a genetic tendency to develop allergic diseases), in particular sensitivity to food allergens.

What to do in an allergic reaction emergency

Allergic reactions can be potentially fatal and it is essential that you know what to do if you or someone else experiences one. People can react to all sorts of different allergens, from food to insect stings to medication, and recognising the symptoms of an allergic reaction and understanding what action needs to be taken could save their life.

Mild to moderate allergic reactions

Signs may include:
  • Hives or a rash 
  • Tingling mouth 
  • Swelling of lips, face or eyes 
  • Stomach pain or vomiting → for most allergic reactions stomach pain/vomiting is a sign of mild/moderate allergic reactions, however for insect sting allergies they can be an indication on anaphylaxis 
Action 
  • If the reaction is caused by an insect sting and it can be seen, flick it out (if ticks are the culprit do not remove them) 
  • Stay with the affected person 
  • Give medications such as antihistamines for mild-moderate allergic reactions to treat symptoms 
  • If reaction is progressing to more severe symptoms or anaphylaxis call for help and locate their epinephrine (adrenaline) autoinjector 
  • If the affected person has a history of severe allergic reactions do not wait for symptoms of anaphylaxis to show, administer their adrenaline autoinjector immediately. 
Severe allergic reactions and anaphylaxis

Even allergic reactions that begin with only mild symptoms can quickly progress to anaphylaxis which can be potentially life threatening. It is essential to stay with the person having the allergic reaction and continue to watch their symptoms. Anaphylaxis is a medical emergency and requires immediate treatment. Knowing the signs of anaphylaxis and what to do in an emergency could save someone's life.

Signs may include
  • Difficult, loud or laboured breathing
  • Swelling of the lips, tongue or throat 
  • Difficulty talking or hoarseness of voice 
  • Persistent cough or wheezing 
  • Racing heart rate/pulse 
  • Dizziness or collapse 
  • Stomach pain and vomiting following an insect allergy reaction 
  • Young children may become pale and floppy 
Action 
  • Administer their adrenaline autoinjector if they are unable to do so themselves (see below) 
  • Call an ambulance 
  • Contact their emergency contact 
  • Do not allow them to stand or walk → Ideally lay them flat on their back with feet raised off the floor, if breathing is difficult get them to sit down or if they are vomiting or bleeding get them to lay on their side 
  • Keep them calm and stay with them 
  • If there is no response after 5 minutes of administering the adrenaline autoinjector then further doses may be given if available 
  • Begin cardiopulmonary resuscitation (CPR) if the person becomes unresponsive or stops breathing 

Using an adrenaline autoinjector 

If the person is experiencing anaphylaxis they may be unable to inject their adrenaline themselves. Adrenaline autoinjectors are easy to use and come with simple instructions to allow rapid administration. For a video demonstration please click here.

The key points to remember are: 
  • Pull off the safety release to ready the device 
  • Inject the adrenaline into the muscle of the OUTER MID THIGH 
  • Push down HARD until a click is heard/felt and HOLD for 10 seconds to administer the medicine 

The adrenaline administered by the autoinjector is life-saving and its use must not be hesitated over. A single dose of adrenaline is not dangerous to a person not having an allergic reaction (although unnecessary administration can have unpleasant side effects), whereas delaying or withholding the administration of adrenaline can lead to rapid deterioration and death in someone experiencing anaphylaxis. Even if there are any doubts it is essential to give the adrenaline autoinjector FIRST, and then give further treatment such as an asthma reliever or CPR if required.

Patients will usually be given oxygen in the ambulance, and then kept in the hospital for medical observation for a minimum of 4 hours (often longer). Someone should stay with the patient for 24 hours after their allergic reaction to ensure they do not suffer any further complications.

Are allergies lifelong?

Who gets allergies?
Although certain allergies may have a genetic tendency (atopy), exposure to environmental factors are also instrumental in the development of allergies. Generally, most people develop allergies during their childhood, however they can emerge in adulthood too. For example, seasonal allergies including hayfever may develop as you get older due to an increased exposure to environmental allergens such as pollen.

The severity of an allergic reaction varies significantly between people, with some people presenting with only mild symptoms whilst others quickly progress into anaphylaxis. Allergies can also change over time within the individual, differing in frequency and severity or even disappearing completely. For example, the severity of seasonal allergies can fluctuate season to season and pet allergies may affect you differently depending on the cat or dog you encounter. Some allergies can be outgrown, whereas others last a lifetime.

Why do some allergies last a lifetime?
Certain allergies are more likely to be lifelong, particularly food allergies which first develop in adulthood or certain types of food allergen which cause reactions from early childhood. A study published in the Journal of Allergy and Clinical Immunology found that long-lasting memory B cells are responsible for lifelong sensitivity to food allergens. When the immune system mistakes a food allergen as something harmful, it triggers the production of the IgE antibody in an attempt to neutralise the 'threat'. IgE levels are not sustained long term, however upon re-encountering a specific food allergen, memory B cells are activated and replenish the cells which produce IgE. In turn, IgE then signals the immune system to react, causing an allergic reaction.

Why do some people outgrow their allergies?
Not all allergies are lifelong, and in fact many children outgrow their allergies (particularly food allergies) as they get older. It isn't currently known exactly why some people outgrow their allergies. It may be that a tolerance to some allergens develop through repeated exposure to low levels of the allergen over time. This is the method used in allergy shots to decrease the person's allergic response to a particular allergen, but it can occur naturally too. In affect, this means the person's body may simply become accustomed to the allergen, thus reducing the level and sensitivity of the immune response.

Will my child outgrow their food allergy?
Food allergies are estimated to affect approximately 1 in 20 children (5%). However, approximately only 2 in 100 (2%) adults are affected, showing that some children will outgrow their food allergy as they get older.
It was previously believed that the majority of children may outgrow allergies to cow's milk, wheat, soy and eggs before the age of three. However, research from John Hopkins Medicine have showed that milk and egg allergies now often persist until adolescence. A study of approximately 1700 patients that had either a milk or egg allergy over a period of 13 years found that fewer children are outgrowing these allergies, and those that do are outgrowing them later than before.

On the other hand, allergic reactions to peanuts, tree nuts, fish and shellfish are more likely to persist throughout life. It is thought that up to 20% of children with a peanut allergy will outgrow it as they get older, whereas only approximately 9% of children with tree nut allergies would be expected to outgrow them. However, if they have multiple food allergies the likelihood of them outgrowing their nut allergies are significantly reduced, and are far more likely to be lifelong.

Although it currently remains unknown why some people outgrow their allergies where others don't, doctors can perform allergy blood tests to determine IgE levels and predict a child's likelihood of outgrowing various food allergies.


The eight major food allergens

Although over 160 food products can cause allergic reactions, over 90% of reactions are caused by eight main food allergens. Some of these allergies may be outgrown during the early years of life, however others remain lifelong.

Sensitivity and reaction to food allergens can range from mild (hives, rash, itching, swelling) to severe (trouble breathing, wheezing, anaphylaxis) and can be potentially fatal in some people. It is advised that people with food allergies have quick access to an epinephrine autoinjector (e.g. EpiPen®) at all times in case of anaphylaxis.

The following food allergens are generally associated with mild to moderate allergic reactions, although severe reactions can occur:

Milk
Cow's milk is a common food allergy in infants and young children that usually develops during the first year of life, although most children do eventually outgrow it, usually by the time they turn 5 years of age. Those in whom the allergy persists usually have a high level of cow's milk antibodies in their bloodstream, which can be measured in blood tests and used to predict the likeliness of the child outgrowing their allergy.
Sensitivity and reaction to cow's milk can range from mild (hives, rash, itching, swelling) to severe (trouble breathing, wheezing, anaphylaxis) and can be potentially fatal in some people.
An allergy to cow's milk is not the same as lactose intolerance. A food allergy involves the overreaction of the immune system to a specific food protein whereas food intolerances do not involve the immune system. People who are lactose intolerant do not have the enzyme lactase which digests a sugar found in milk and dairy products (lactose) and thus experience discomforting symptoms including cramps, gas, bloating and diarrhoea.


Eggs
Eggs are another common food allergen for children. Symptoms of an egg-allergic reaction range from mild (hives, rash, itching, swelling) to severe (trouble breathing, wheezing, anaphylaxis) or potentially fatal. Like with cow's milk allergies, most children do eventually outgrow their egg allergy.
It is the egg whites that contain the allergenic proteins that cause the sensitivities and reactions, however people with an egg allergy must avoid eggs completely, including the egg yolk. This is due to cross-contact between the egg white and egg yolk, as it is near impossible to completely separate the two from each other. Therefore, strict avoidance of egg and egg products is vital in preventing a reaction.
Although some vaccines may contain residual egg proteins, such as the influenza vaccine, evidence shows that they can be safely administered to egg-allergic patients, including those with a history of severe reactions to egg. However, it is recommended to discuss your or your child's egg allergy with your doctor prior to receiving the vaccine.


Wheat
Wheat is the predominant grain product and thus restricting it from your diet can present a challenge for those who are wheat-allergic. Wheat allergy is most common in children but is often outgrown after the age of three years. Sensitivity and reaction to wheat can range from mild (hives, rash, itching, swelling) to severe (trouble breathing, wheezing, anaphylaxis) and can be potentially fatal in some people.
A wheat allergy is not the same as celiac disease - an intolerance to gluten. A wheat allergy is caused by the overreaction of the immune system to a specific protein found in wheat. Although this protein could be gluten, it could also be a number of other allergens. Therefore, gluten-free foods are not necessarily safe for wheat-allergic people as they may contain other wheat products that can provoke a reaction. Gluten also occurs grains such as in barley and rye, and thus need to be avoided by celiac disease patients. People with a wheat allergy may be able to tolerate other grains however it is advised to check first with your doctor as some people who are wheat-allergic are also allergic to other grains.

Soybeans
Soybeans, a type of legume, can also present allergic reactions, especially amongst babies and children. Generally soy-reactions are mild, however in rare cases a severe allergic reaction can occur. The majority of children with a soy allergy are expected to outgrow it.
Being allergic to soy does not increase your chances of being allergic to other types of legume such as peanuts. Soybeans themselves are not a major component of most diets, however they are often used in processed food products which can make dietary planning difficult. Consulting with a dietician can help you plan a balanced, nutritious, soy-free diet.

The following food allergens are often associated with severe allergic reactions:

Fish
Finned fish such as salmon, tuna and halibut are the most common types of fish to cause an allergic reaction. The majority of people who experience an allergic reaction to fish do so for the first time as an adult, with fish allergies being less common in children. Fish allergies can be quite severe and extra precaution should be taken.
Over half of people who are allergic to one type of fish are also allergic to other fish, thus it is generally advised to avoid all fish and fish products to prevent a reaction. However, allergy testing for specific fish can be performed by your doctor if you wish to know exactly what fish you are allergic to in order to still include some fish in your diet.
Finned fish and crustacean shellfish do not belong in the same, or related, food families thus being allergic to one does not necessarily mean you are allergic to the other.

Shellfish
Shellfish allergies are usually lifelong and for the majority of people first occur during adulthood. There are two types of shellfish: crustacea (e.g. shrimp, crab and lobster) and mollusks (e.g. clams, mussels and oysters). It is possible to be allergic to one group of shellfish yet still be able to eat some types of shellfish from the other group. However, the majority of people who are allergic to one variety of shellfish are allergic to others thus it is usually advised to avoid all shellfish and shellfish products.
Allergic reactions to shellfish can be particularly severe. In addition to avoiding consumption of shellfish and their products, shellfish-allergic people should avoid touching shellfish entirely, being in an area where shellfish are cooked – as the protein in the steam may present a risk of reaction, and going to fish markets.

Tree nuts
Tree nuts such as walnuts, almonds, cashews, hazelnuts, pistachio and Brazil nuts are common food allergens for both children and adults. Tree nut allergies tend to be lifelong, although some children may outgrow their allergy. Often, tree nuts provoke severe allergic reactions in patients and strict avoidance of nuts and nut products are advised.
People who are allergic to one type of tree nut are likely to be allergic to other varieties thus it is advised for people with an allergy to a specific tree nut to avoid all nuts entirely. It is also sometimes recommended that patients also avoid peanuts. Unlike tree nuts, peanuts are actually a type of legume and are not in the same food family. However, there is a high chance of cross-contact between tree nuts and peanuts, particularly during manufacturing and processing, which may increase the risk of reaction.


Peanuts
Similar to tree nuts, peanut-allergic people can suffer a severe, or possible fatal, allergic reaction to peanuts and peanut products. Peanut allergy is particularly common in children and incidence appears to be on the rise. Overall peanut allergies tend to be lifelong, however some children will outgrow their allergy.
Unlike tree nuts which grow on trees, peanuts are part of the legume family and grow underground. Other examples of legumes include peas, beans, lentils and soybeans, however being allergic to peanuts does not increase your chances of being allergic to another type of legume. However, people with peanut allergies are often also allergic to tree nuts, and even if they aren't, there is a risk of cross-contact between peanuts and tree nuts. Therefore it is usually recommended that people with a peanut allergy also avoid tree nuts and their products.
Although trace amounts of peanut can cause an allergic reaction, casual contact such as touching peanuts is less likely to provoke a severe allergic reaction. However, if the contact area then comes into contact with the mouth, eyes or nose it can trigger a severe reaction that could even be fatal.

Another major food allergen to add to the list?

Sesame
Currently sesame is not included in the list of the major food allergens that must be identified on food product packaging. However, sesame allergy prevalence has significantly increased over the last two decades. This is thought to be due to the increase use and consumption of sesame due to the increase in popularity of Asian and Middle Eastern dishes where sesame is a common ingredient, as well as the use of sesame oil as a healthy cooking alternative. In addition, sesame is often used in pharmaceutical products and cosmetics.

Recent considerations suggest that sesame should be added to the list of major food allergens. Although not as common as a peanut allergy, reactions to sesame can be severe.

Are allergies a 'First World Problem'?

Over the last few decades there has been a dramatic rise in the rate and severity of allergies, particularly in children. This increased prevalence of allergy is heavily associated with an increasingly wealthy, modern Western society. Allergies are not overly prevalent in under-developed countries, suggesting that the rise of allergy in industrialised countries is due to factors specific to Western society, bringing the question – are allergies a 'First World Problem'?

What is causing this rise in allergy?
There is some support for the rise of allergies being partially due to increased awareness and diagnosis, however the majority of experts agree that overall the increase is largely due to a higher percentage of people developing allergies. However, the precise cause of this increase is still under debate, with a number or theories suggested.

Hygiene Hypothesis
In 1989 the term 'Hygiene Hypothesis' was coined to address the theory that an increasingly sterile environment in modern society has caused our immune system to initiate and react to various substances (allergens) as if they were harmful. Factors such as decreased family sizes and increased cleanliness and hygiene standards (such as the increased use of liquid soap, most of which boast 'anti-bacterial' properties) have dramatically reduced the exposure to dangerous disease-causing pathogens. However as an unattended consequence it may have also contributed to the significant increase in allergic sensitivities.

Old Friends Mechanism
However, although there is some evidence to support the 'Hygiene Hypothesis', critics suggest that the rise in allergy isn't due to a more sanitised environment, but rather a decreased exposure to a diverse range of microbes. In 2003 this refinement was termed the 'Old Friend's Mechanism' and suggests that it is the microbes that co-evolved alongside our immune systems that are essential for building a diverse gut microbiome and sustaining a well-regulated immune system.

This hypothesis suggests that lifestyle changes have decreased our exposure to these generally harmless microbes and have caused our immune systems to raise an immune response to harmless allergens. For example, children in today's society are more likely to be found inside in front of a screen rather than playing outside in the dirt where they would be exposed to numerous microbes. Studies have demonstrated that children who are raised on a farm have a low prevalence of allergic sensitisation. Likewise, children who attend day care, have older siblings or have a pet are also less likely to develop allergies. What all these factors have in common is an increased exposure to a diverse range of microbes, suggesting that a decreased exposure to such microbes may indeed contribute to the significant rise in allergic sensitivities.

Antibiotics
Another arm of the 'Old Friends Mechanism' believed to contribute to the rise of allergy incidence is the increased use of antibiotics. Today, antibiotics are prescribed frequently and quickly, often at the first sign of illness. It is well-documented that antibiotic use causes long term alterations to our gut microbiota (the microbes that live in our gut), and considerable evidence indicates that this may contribute to the development of certain allergies. Dr Gary Huffnagle, University of Michigan, provided the first experimental evidence for the role of antibiotics and microbes in the development of allergic airway disease. The study showed that an alteration of the gut microbiota due to a course of antibiotics caused an increased hypersensitivity and reactivity in the lungs of mice in response to harmless yeast spores.

In particular, antibiotic use during the early years of life is shown to significantly impact the risk of childhood atopy (a genetic tendency to develop allergic diseases), in particular sensitivity to food allergens. The immune system continues to evolve throughout the early years of life and having a diverse gut microbiome is highly beneficial to health. Disruptions to the gut microbiota (due to antibiotic use and other factors) are increasingly shown to be associated with a variety of diseases, including allergy.

Vitamin D deficiency
In addition to the role of microbes in allergy, vitamin D deficiency has been linked to the rise in allergies, with a noticeable increase in allergies in climates where vitamin D levels tend to be lower, such as those further away from the equator. Vitamin D deficiency has increased over recent years and has been contributed to inadequate exposure to sunlight due to people spending more time indoors, which could be contributed to a modern Western lifestyle. Australian researchers have demonstrated that children with vitamin D deficiency are three times more likely to develop food allergies. Currently there is conflicting evidence regarding the role of vitamin D in allergic diseases with further research required to determine how much of a role vitamin D deficiency has on the development of allergy.


A modern, Western society is often associated with more wealth, increased hygiene and cleanliness, increased access to and use of medications including antibiotics, and more time spent indoors for both work and leisure. Various studies have shown that these lifestyle factors may contribute to the development of allergic sensitivity due to a decreased exposure to a diverse range of microbes, however, further research is required to determine how much of a role this has in why the immune system reacts to harmless environmental factors. For now, it certainly appears that the so called 'First World' lifestyle has contributed to the rise in allergy.





The development of non-traditional approaches to prevent and treat bacterial infections


Non-traditional approaches to prevent and treat bacterial infections
Although research is underway to develop new antibiotics, it is essential that other, non-traditional avenues for preventing and treating bacterial infections are also explored to combat the rise in antibiotic resistance. Examples of non-traditional therapies include:

Antibodies

  • Antibodies are proteins naturally produced by the immune system to identify, target and help remove potential pathogens.
  • Antibodies can specifically target and bind to bacteria and inactive them in a variety of ways.
  • These capabilities may be able to be adjusted for novel therapies.

Virulence inhibitors

  • Virulence is the severity and degree of damage that a pathogen causes.
  • Using molecules to prevent and neutralise the harmful effects of a pathogen's virulence factors (e.g. bacterial toxins) effectively disarms the pathogen.
  • Virulence inhibitors could also be used to weaken bacteria defence mechanisms in order to enhance the response of the patient's immune system.

Peptide immunomodulators

  • Modulate the immune system in order to enhance its response to a bacterial infection.

Lysins

  • A component derived from bacteriophages (viruses that infect bacteria).
  • Lysins target and degrade the structure of bacterial cell walls.

Probiotics

  • A course of antibiotics can indiscriminately kill any gut bacteria regardless of whether they are harmful pathogens or the beneficial bacteria that colonise our intestines.
  • Killing the beneficial bacteria can increase the colonisation of harmful pathogens and their side effects.
  • Probiotics are live cultures of microorganisms that restore the beneficial bacteria populations in our gut.
  • Using probiotics alongside antibiotics may help maintain a healthy balance of beneficial gut bacteria.

Vaccines

  • Vaccines generally contain inactivated disease-causing pathogens, or components that resemble them.
  • They stimulate the immune system to recognise and destroy pathogens in order to protect against infection.


Current development of non-traditional approaches to prevent and treat bacterial infections
According to The Pew Charitable Trusts (PEW), there are currently 32 non-traditional products in the pipeline of clinical development in the US to combat systemic bacterial infections. The majority of these are active against a limited range of pathogens and are unlikely to fully substitute or replace antibiotic use. However, they may provide new options for preventing infections from taking hold and for use in combination with antibiotics.

Key findings

  • Current analysis shows that of the 32 products in development, 7 are in Phase 1 clinical trials, 21 are in Phase 2 clinical trials and 3 are in Phase 3 clinical trials. So far only one new product has been approved by the FDA.
  • Over 1/3 of the products being developed are vaccines, with almost another third being antibodies. The others include probiotics, lysins and immunomodulators.



This remains an ongoing area of research and development. PEW continues to assess and update the list of non-traditional products including the identity of each product and the manufacturer, the type of approach, potential targets and the stage in the clinical development process.

The development of new antibiotics

The development of new drugs requires a large investment in time, effort, scientific research and money. Developing new antibiotics to combat the rise in antibiotic-resistant bacteria in particular is a challenge as currently only a small number of patients contract these infections and meet the requirements for traditional clinical trial participation. However, with antibiotic resistance reaching dangerously high levels across the global it is critical that we work towards new ways to prevent and treat bacterial infections.

The progression of new drugs to market
There has been a lot of study into the clinical development success rates for new drugs in development. With a number of stages and approval processes to pass, a vast number of potential drug candidates never come close to making it to market.

Phase 1

  • Safety testing, not dependent on efficacy of results to advance
  • Approximately 63.2% of drug candidates progress past Phase 1 clinical trials

Phase 2

  • The first stage where proof-of-concept is deliberately tested in human subjects
  • A decision must be made by the industry whether to pursue the drug candidate through Phase 3 clinical trials which are large and expensive
  • Approximately 30.7% of drug candidates progress past Phase 2 clinical trials

Phase 3

  • Generally the longest and most expensive trials to conduct
  • Approximately 58.1% of drug candidates progress past Phase 3 clinical trials

FDA Approval

  • Drug candidates that pass through all three clinical trial phases are then submitted to the FDA (in the US) for approval either for a New Drug Application (NDA) or a Biologic License Application (BLA).
  • The likelihood of drug candidates being approved by the FDA at this stage is 85.3%.

Overall, the probability of a new drug candidate progressing from Phase 1 clinical trials to approval by the FDA and progression to market is only 9.6%.

Current development of new antibiotics
According to The Pew Charitable Trusts (PEW), there are currently 41 new antibiotics in clinical development for the US market. In response to the growing global concern regarding increasing antibiotic resistance, PEW has been tracking the pipeline of clinical development for new antibiotics. PEW regularly updates the data which identifies the drug, manufacturer, potential targets and the stage in development process.

Key findings

  • The current analysis shows that of the 41 new antibiotics in development, 15 are in phase 1 clinical trials, 13 are in phase 2 clinical trials and 11 are in phase 3 clinical trials. Two drugs have completed phase 3 clinical trials and their New Drug Applications are currently being reviewed by the FDA.
  • At least 16 of the new drugs in development have the potential to address pathogenic infections considered an urgent threat to public health by the CDC.
  • Fewer than 1 in 3 drugs currently being developed represent a novel drug class or mechanism of action.
  • Over 80% of the products being developed are done by small companies rather than the large pharmaceutical firms.

As demonstrated, the overall probability of a new drug in development progressing to market is estimated to be less than 10%. Therefore, it is inevitable that many of these new antibiotics will not be approved. Considering the urgent need for new antibiotics, there are not enough drugs in development and more needs to be done to address the threat of antibiotic resistance.

PEW is also analysing the development of non-traditional products to prevent or treat bacterial infections.

Stopping the spread of superbugs

Antimicrobial resistance (AMR) is accelerated by the misuse and overuse of antimicrobial medicines, as well as poor hygiene and poor infection prevention and control, and is an increasingly serious global health concern. There are various steps that can be taken at every level of society to reduce the impact and limit the spread of antimicrobial resistance.

As an individual:

  • Only use antimicrobials when prescribed by your doctor.
  • Never demand antimicrobials when your doctor says you don't need them.
  • Always follow the instructions and advice of your doctor on how to use your antimicrobials.
  • Complete the entire course of your prescribed antimicrobial medicine, as advised by your doctor.
  • Never share or use leftover antimicrobial medicines.
  • Prevent the spread of infection by regularly washing hands, preparing food hygienically, practising safer sex and keeping vaccines up to date etc.

Working in the healthcare industry:

  • Only prescribe antimicrobials when they are needed, according to current guidelines.
  • Ensure patients understand how to take antimicrobial medications correctly and understand the dangers of misuse and antimicrobial resistance.
  • Ensure your patients are aware of the best practices for preventing infections (vaccinations, safer sex, hand washing etc).
  • Prevent the spread of infections by ensuring your hands, instruments and environment are kept clean and effective barrier equipment (goggles, gloves, gown etc) is used.
  • Maintain safe handling and disposal of sharps and clinical waste.
  • Report antimicrobial-resistant infections to surveillance teams.
  • Invest in research and development of new antimicrobials, vaccines and diagnostic tools.
When caring for those infected with an antimicrobial-resistant microbe: 
  • Use a single occupancy room with an en-suite or a dedicated toilet.
  • Have dedicated care equipment for that patient.
  • Restrict movement of the patient and their healthcare workers.


Working in the agriculture sector:

  • Only give antimicrobials to animals under veterinary supervision.
  • Vaccinate animals and use alternatives to antimicrobials when available.
  • Only use antibiotics to treat infections, not for growth promotion or to prevent disease.
  • Promote and apply good practices throughout stages of production and processing of food from animal and plant sources.
  • Improve hygiene, animal welfare and biosecurity on farms to prevent infections.

As policy makers:

  • Ensure a robust national action plan is in place to tackle antibiotic resistance.
  • Educate on the impact of antibiotic resistance.
  • Strengthen policies for infection prevention and control measures.
  • Improve surveillance of antibiotic-resistant infections.
  • Regulate the appropriate use and disposal of quality medicines.

Are we at risk of a post-antibiotic era?


Globally, antimicrobial resistance (AMR) is becoming an increasingly serious public health concern. In particular, the development of antibiotic resistance – due to the frequent and commonplace use of antibiotics in modern society – has become a highlighted medical issue in recent times. Antibiotic resistance is now considered to be one of the biggest threats to global health, food security and development, and is rising to dangerously high levels all over the world.

What are antibiotics?
Antibiotics are medicines used to prevent and treat bacterial infections and have completely revolutionised medicine. In 1928, Scottish scientist Sir Alexander Fleming invented the first antibiotic when an apparently accidental contamination led to the discovery of what is now known as penicillin.

Worldwide, antibiotics have been used to prevent and treat common bacterial infections that used to be incurable and were often deadly. For example, STI's and tuberculosis amongst other diseases are far more easy to treat nowadays than they were 100 years ago. In addition, before antibiotics were invented any wound – no matter how minor – could become infected and lead to death. Likewise, common surgical procedures and childbirth were extremely high risk.

Having effective antibiotics against bacterial infections are essential in modern medicine, and not having drugs to prevent and treat common bacterial infections will seriously impact global public health efforts.

Antibiotic resistance
Concerns over antibiotic resistance have been reported as far back as 1945, including by Sir Alexander Fleming himself who warned about the dangers of antibiotic resistance in an article for the New York Times, cautioning that:

"... the microbes are educated to resist penicillin and a host of penicillin-fast organisms is bred out....In such cases the thoughtless person playing with penicillin is morally responsible for the death of the man who finally succumbs to infection with the penicillin-resistant organism. I hope this evil can be averted.”

It's been less than 100 years since Sir Alexander Fleming invented the first antibiotic, and just over 70 years since he warned of the dangers of antibiotic resistance, yet today antibiotic resistance is a serious global public health concern.


What's causing antibiotic resistance?
Although antibiotic resistance occurs naturally overtime, it is being accelerated due to overuse and misuse of antibiotics, combined with a lack of new drug developments. Antibiotics have no affect on viral infections such as the common cold or the flu, yet are all too often demanded and/or prescribed as a first line of attack. Even when prescribed correctly, many patients misuse their antibiotics – in particular stopping their treatment course early because they feel better. A lot of research has been performed to determine the shortest treatment course required to completely kill all bacteria, and by stopping treatment early you run the risk that the antibiotics won't have killed all of the bacteria in the infection. These bacteria can then mutate, become resistant to that antibiotic, and spread throughout the population.

In addition, antibiotics are heavily used in the agriculture industry as growth promoters and to prevent and treat infections in animals, as well as being mixed into stock food and sprayed on crops. It is very easy for antibiotics to enter the food-chain and be passed on to humans. Most recently, a US preliminary study has shown the presence of antibiotic-resistant bacteria in many ready-to-eat food products such as dairy and fresh produce.

Present day
Already, a growing list of infections – such as pneumonia, tuberculosis, gonorrhoea and blood poisoning – are becoming harder and harder to treat as antibiotics are becoming less effective. Worryingly, some bacteria have become resistant to multiple antibiotics, and the list of treatment options is getting smaller.

Last year, a US woman in her 70's died following an infection with Klebsiella pneumoniae – a carbapenem-resistant Enterobacteriaceae (CRE) that is resistant to the carbapenem (or 'the last resort') class of antibiotics. It is thought that she contracted the infection after being hospitalised in India following a broken leg injury. Upon her return to the US she was again hospitalised and treated with 26 different antibiotics – everything the hospital had available – yet sadly went into septic shock and died. The K. pneumoniae infection was resistant to every one of those 26 antibiotics, and as a result the doctors were unable to save her life.


Worryingly, reports like this one are likely to become more and more common as we continue to battle against the rise in antibiotic resistance. It is essential that everyone works towards preventing, or at the very least delaying, a post-antibiotic era, as without urgent action common infections and minor injuries will once again be deadly.

The rise of 'Superbugs' and the threat of antimicrobial resistance


What is antimicrobial resistance?
Antimicrobial resistance (AMR) occurs when microorganisms (e.g. bacteria, viruses, fungi and parasites) evolve in response to exposure to antimicrobial medicines (including antibiotics, antivirals, antifungals, antimalarials and anthelmintics etc). Antimicrobial-resistant microbes are often termed 'superbugs' and are not affected by medicines usually used to treat the infection. This means that infections persist which may cause further complications to the patient as well as increase the risk of spread to others.

Why is this a concern?
AMR threatens the effective prevention and treatment of a ever widening range of infections and is becoming an increasingly serious threat. Antimicrobial drug resistance can: compromise common surgical procedures including caesarean, organ transplantation and hip replacements; affect the success of cancer chemotherapy; and complicate the fight against diseases such as HIV and malaria. This means that currently preventable or treatable situations become very high-risk and result in an increased likelihood of worse clinical outcomes, disability and death.
In addition, the cost of healthcare for patients with drug-resistant microbial infections is also higher due to prolonged illness and lengthier hospital stays, additional medical tests and more intensive care and the use of more expensive drugs.

What causes AMR?
AMR does occur naturally over time, however this process is being accelerated due to the overuse and misuse of antimicrobial medicines and poor hygiene standards. Antimicrobials should only be used following professional advice and not as a 'quick fix'. For example, antibiotics will have no impact on viral infections such as the common cold or the flu, and are also overused in animals and fish as a method of promoting growth. Antimicrobial resistant-microbes can be found in people, animals, food and the environment and can easily spread from one to another. Poor hygiene standards, unsanitary conditions and unsafe food-handling can all increase the spread of the drug resistant microbes.

Examples of AMR
All sorts of microorganisms can become resistant to antimicrobial medicines and cause infections with an increased cause for concern, with some of the most common including:

MRSA
  • One of the most well-known 'superbugs' is methicillin-resistant Staphylococcus aureus (MRSA), a bacterial strain resistant to the first-line antibiotics that are used to treat the infection. MRSA is particularly prevalent in healthcare settings and is a common cause of severe infections. Patients are estimated to be 64% more likely to die from an infection caused by MRSA than a non-resistant strain of Staphylococcus aureus.

Tuberculosis
  • The World Health Organisation (WHO) estimated that there were approximately 480,000 new cases of multi-drug resistant tuberculosis (MDR-TB) in 2015 alone. This strain of bacteria that causes TB is resistant to the two most powerful anti-TB drugs and treatment causes for MDR-TB infection are much longer and less effective than those cause by non-resistant strains. Extensively drug-resistant TB (XDR-TB) is a form of MDR-TB that is resistant to at least four of the core anti-TB drugs and has so far been reported in 117 countries.

Malaria
  • There are currently 5 countries in which resistance to the first-line treatment for Plasmodium falciparum (the parasite that causes malaria) has been reported. In addition, along the Cambodian-Thailand border P. falciparum has become resistant to almost all available antimalarials. The risk of multi-drug resistant P. falciparum emerging in other regions is increasing and would pose challenging public health concerns.

Is AMR a worldwide problem?
Yes, AMR is an increasingly serious threat to global public health. Drug-resistant microbes are present in every country and new resistance mechanisms are emerging and spreading globally. AMR is a complex, interconnected problem and response to this threat requires a coordinated, multifaceted approach from government sectors and societies across the globe. This includes: increased investment and innovation in the research and development of new antimicrobial medicines, vaccines and diagnostic tools; national and global action plans and collaboration for the prevention and management of AMR.

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