Tagged: antibiotics overuse

  • Influenza, or flu, outbreaks are recurrent and every year pose  a significant risk to global health
  • Influenza affects millions: each year 3m to 5m cases of severe disease and 500,000 deaths
  • Pandemics occur about three times a century
  • The 1918 flu pandemic killed 21m . . . Total deaths in World War I was 17m
  • Effective treatment of patients with respiratory illness depend on accurate and timely diagnosis
  • Early diagnosis of influenza can reduce the inappropriate use of antibiotics and provide the option of using antiviral therapy
  • Rapid Influenza Diagnostic Tests (RIDTs) are useful in determining whether outbreaks of respiratory disease might be due to influenza
  • RIDTs vary in their sensitivity, specificity, complexity, and time to produce results
  • There is a pressing need for faster, cheaper, and easier-to-use flu tests with higher levels of sensitivity and specificity than those currently available
  • The large, fast-growing, global and under-served RIDT market drives a host of initiatives
  • Various development challenges pose significant threats
The critical importance of new rapid influenza diagnostic tests
What challenges face developers of cheap, easy-to-use, rapid and accurate diagnostic tests for influenza, or flu, which improve on tests currently available?


Influenza is a highly contagious respiratory illness caused by a virus, and occurs in distinct outbreaks of varying extent every year. Its epidemiologic pattern reflects the changing nature of the antigenic properties of influenza viruses. The viruses subsequent spread depends upon multiple factors, including transmissibility and the susceptibility of the population. Influenza A viruses, in particular, have a remarkable ability to undergo periodic changes in the antigenic characteristics of their envelope glycoproteins; the hemagglutinin and the neuraminidase. Anyone can get influenza. It is usually spread by the coughs and sneezes of an infected person. You can also catch flu by touching an infected person (e.g. shaking hands). Adults are contagious one to two days before getting symptoms and up to seven days after becoming ill, which means that you can spread the influenza virus before you even know you are infected. Influenza presents as a sudden onset of high fever, myalgia, headache and severe malaise, cough (usually dry), sore throat, and runny nose. There are several treatment options, which aim to ease symptoms until the infection goes, and aims to prevent complications. Most healthy people recover within one to two weeks without requiring any medical treatment. However, influenza can cause severe illness or death especially in people at high risk such as the very young, the elderly, and people suffering from medical conditions such as lung diseases, diabetes, cancer, kidney or heart problems.
Costly killer

Influenza is a cruel, costly killer with a history of pandemics. It causes millions of upper respiratory tract infections every year as it spreads around the world in seasonal epidemics, and poses on-going risks to health. The most vulnerable are the young, the old and those with chronic medical conditions such as heart disease, respiratory problems and diabetes. Each year, on average 5% to 20% of populations in wealthy countries get influenza. In the US it causes more than 200,000 hospitalizations and 36,000 deaths annually, and each year costs the American economy between US$71 to US$167bn.
History of pandemics

The 1918-19 “Spanish Flu” pandemic caused 21m deaths, and was one of three 20th century influenza pandemics. At least four pandemics occurred in the 19th century, and the first pandemic of the 21st century was the 2009 “Swine Flu”. Its virulence and global human impact was less deadly than originally feared, but it still resulted in 18,449 laboratory confirmed deaths. If you account for people who died as a result of complications precipitated by the Swine Flu, the actual death toll is significantly higher. Mindful of the potential accelerated spread of a pandemic subtype of the influenza virus, the World Health Organization (WHO), and national governments continuously monitor influenza viruses. Assessment of pathogenicity and virulence is the key to taking appropriate healthcare actions in the event of an outbreak.

However, without widespread access to improved diagnostic tests, each year millions will not receive timely anti-viral medication, tens of thousands of influenza sufferers will develop complications, and thousands will die unnecessarily, as the growing interconnections and complexity of the world present an increasing challenge to influenza prevention and control.

The influenza viruses

Influenza is a single-stranded, helically shaped, RNA virus of the orthomyxovirus family. Influenza viruses are divided into two groups: A and B. Influenza A has two subtypes which are important for humans: A(H3N2) and A(H1N1). The former is currently associated with most deaths. Influenza viruses are defined by two different protein components, known as antigens, on the surface of the virus. They are haemagglutinin (H) and neuraminidase (N) components. Influenza viruses circulate in all parts of the world, and mutate at a low level, referred to as "genetic drift", which allows influenza to continuously evolve and escape from the pressures of population immunity. This means that each individual is always susceptible to infections with new strains of the virus. "Genetic shift" occurs when a strain of influenza A virus completely replaces one or more of its gene segments with the homologous segments from another influenza A strain, a process known as reassortment. If the new segments are from an animal influenza virus to which humans have had no exposure and no immunity, pandemics may ensue.
Gold standard diagnosis rarely used

The gold standard method for the detection of influenza viruses is rarely performed, as patients with suspected influenza are most likely to be seen by a primary care doctor with limited resources, and the gold standard test requires sophisticated laboratory infrastructure, and takes at least 48 hours. Even the faster Reverse Transcription-Polymerase Chain Reaction (RT-PCR) test, which is a relatively new type of molecular assay that uses isothermal amplification of viral cells, has a turnaround time of four to six hours. It is also expensive, and therefore not commonly used.

The slowness and expense of traditional influenza tests led to the development of an array of commercially available Rapid Influenza Diagnostic Tests (RIDTs), which screen for influenza viruses, and provide results within as little as 15 minutes after sample collection and processing. Such tests are largely immunoassays that can identify the presence of influenza A and B viral nucleoprotein antigens in respiratory specimens and display the results in a qualitative way (positive or negative). About 10 such tests have FDA approval and are available in the US. About 20 have been determined suitable for the European market. All are growing in their usage. However, the RIDTs vary in their sensitivity, specificity, complexity, and in the time needed to produce results.
Tests rule in Influenza but do not rule it out
According to the Centers for Disease Control and Prevention (CDC) the commercially available RIDTs in America have a sensitivity ranging from 50% to 70%. This means that in up to 50% of influenza cases, test results will still be negative. A study showed that tests for the N1H1 virus, a subtype of influenza A that was the most common cause of the Swine Flu in 2009, and is associated with the 1918 Spanish Flu pandemic, have a sensitivity ranging from 32% to 50% depending on the brand of test. A 2012 meta-analysis of the accuracy of RIDTs reported an average sensitivity for detecting influenza in adults of only 54%. Sensitivity in children is somewhat higher since they tend to shed a greater quantity of virus. Thus some 30% to 50% of flu samples that would register positive by the gold standard viral culture test may give a false negative when using a RIDT, and some may indicate a false positive when a person is not infected with influenza. Thus, RIDTs that are currently available allow Influenza to be ruled in but not ruled out. More sensitive tests are needed.
New flu tests

There are a number of innovative nano-scale molecular diagnostic influenza tests in development, which are expected to deliver more accurate validations than existing antigen-based molecular tests. The new tests use a platform, comprised of an extremely thin layer of material, which detects the presence of influenza proteins in saliva or blood. This is attached to an electronic chip, which transforms the platform into a sensor. This is an essential part of the measuring device as it converts the input signal to the quantity suitable for measurement and interpretation. The presence of influenza proteins in saliva or blood triggers an electrical signal in the chip, which is then communicated to a mobile phone.
Here Roger Kornberg, Professor of Medicine at Stanford University and 2006 Nobel Laureate for Chemistry describes how advances in molecular science are enabling the replacement of traditional in vitro diagnostics with rapid, virtually instantaneous point-of-care diagnostics without resort to complex processes or elaborate infrastructure.  Antiviral drugs for influenza are available in some countries and may reduce severe complications and deaths. Ideally they need to be administered early (within 48 hours of onset of symptoms) in the disease.  An almost instantaneous point-of-care test will enable better access to appropriate treatment particularly in primary care:


Notwithstanding all the recent scientific advances, new and innovative influenza detection tests will need to overcome significant challenges to outperform current RIDTs. In addition to the usual challenges associated with sensitivity and specificity, new developers have to be aware of recent changes in immunochromatographic antigen detection testing for influenza viruses, and the rapid development of commercially available nucleic acid amplification tests. Also, there are the usual development challenges associated with miniaturization, fabrication, scaling, marketing, and regulation. Effective from 13 February 2017, the FDA reclassified antigen based rapid influenza detection tests from class I into class II devices. Class II devices are higher risk than Class I, and require greater regulatory controls to provide reasonable assurance of the device’s safety and effectiveness. This was provoked by the potential for the devices to fail to detect newer versions of the influenza virus. For instance, a novel variant of influenza A,H7N9, has emerged in Asia, and H5N1 is also re-emergent.
Another challenge, especially for start-ups with limited resources, is the fluctuating nature of the influenza virus itself. A bad year for patients, when influenza causes millions of people to become ill, is a good year for manufacturers of RIDTs. Conversely, a good year for patients, when influenza affects a lower percentage of the population, is a bad year for manufacturers who suffer from unsold inventory, and reduced revenues. Thus, the vagaries of the flu virus not only have the potential to kill millions of people, they also pose a significant threat to start-ups dedicated to developing RIDTs.

Despite all the challenges, there is a significant commercial opportunity in the current under-served global RIDT market for improved tests. Each year, in the US, more than 1bn people visit primary care doctors, and in the UK, the NHS, deals with over 1m patients every 36 hours. The global in vitro diagnostics market was valued at US$60bn in 2016. Between 2016 and 2021, the market is expected to grow at a CAGR of 5.5% to reach US$79bn by 2021. Over the same period, the global point-of-care diagnostics sub-market is expected to grow at a CAGR of 10% to reach US$37bn by 2021. Large corporates, small start-ups, and university research laboratories have spotted the opportunity, and started developing new and innovative RIDTs. Given that each-year influenza causes widespread morbidity as well as mortality, it should be a matter of priority to support all efforts to develop swift and reliable RIDTs. A significant step forward would be a RIDT with greater sensitivity and usability such that the test could be administered and a result given within a 10-minute primary care consultation.
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  • Currently 700,000 people die each year from Antimicrobial Resistance (AMR) and this could rise to 10 milion by 2050
  • AMR could make routine surgeries and childbirth as dangerous and lethal as in the pre-antibiotic era killing millions and costing trillions worldwide
  • Doctors inappropriately prescribing antibiotics for minor aliments shorten the useful life of antibiotics threatening modern medicine as there is an antibiotic pipeline deficiency
  • 90% of GPs feel pressured by patients to prescribe antibiotics
  • 70% of GPs are unsure whether sore throat and respiratory infections are viral or bacterial resulting in 50% of sore throats receiving antibiotics
  • Clinical diagnosis leads to 50% of patients with a sore throat being prescribed antibiotics without having Group A Streptococcal infection
  • 30% of patients with pharyngitis will not be treated but will be infected with Group A Streptococci
  • 24% of doctors say they lack easy-to-use diagnostic tools
  • 10m prescriptions for antibiotics are handed out in England each year to patients who do not need them
  • A Nobel Laureate has developed a new technology to provide rapid, accurate, cost-effective diagnosis of bacterial sore throat resulting in informed prescribing and reducing unnecessary antibiotic usage
Slowing the steep rise of antimicrobial resistance
Should we listen when a professor of medicine and a Nobel Laureate 
says that the technology already exists to develop a cheap hand held device, which can rapidly and accurately diagnose a bacterial sore throat?  
Without such a device to determine whether minor ailments require antibiotics, doctors will continue to prescribe them, and thereby contribute to the steep rise in Antimicrobial Resistance (AMR). In 2016 the National Institute for Health and Care Excellence (NICE), the UK government’s NHS watchdog, reported that as many as 10m prescriptions for antibiotics are handed out in England every year to patients who do not need them. According to a 2016 report on AMR, by 2050 a staggering, “10m people will die from AMR each year . . . . The world needs rapid diagnostics to improve our use of antibiotics,” says the report.

Sore throat
Acute throat infections are among the most common infectious diseases presented to primary healthcare and A&E departments and are frequently misdiagnosed. They are responsible for 2 to 4% of all primary care visits. Viruses cause 85% to 95% of throat infections in adults and children younger than 5. For those aged 5 to 15, viruses cause about 70% of throat infections, with the other 30% due to bacterial infections, mostly group A β-hemolytic streptococcus (GAS), which can cause 0.5m deaths a year. There are challenges in diagnosing GAS because its signs and symptoms are often indistinguishable from viral and other causes of sore throat.
If a doctor intends to treat suspected GAS pharyngitis, it is generally recommended that laboratory confirmation of the presence of GAS be sought to limit unnecessary antibiotic prescription. The gold standard laboratory investigation is of a bacterial culture of a throat swab. However, this is expensive, and there is a relatively long lag time between the collection of the specimen and final microbiological diagnosis: so doctors tend not to it. 
Rapid antigen diagnostic tests (RADTs) are an alternative to the gold standard laboratory test for GAS. However, widespread use of RADTs has been hindered by low sensitivity for most commonly used RADTs (immunoassays). Reviews of RADTs performance have identified significant variability in the diagnostic accuracy, especially sensitivity, between different test methodologies.

Urgent need for rapid and accurate diagnostic test
A principal recommendation of a 2016 report on AMR is to ban doctors from prescribing antibiotics until they have carried out rapid tests to prove the infection is bacterial. The report also stresses that doctors need urgent help to temporise their use of antibiotics if AMR is to be reduced.

Notwithstanding, the AMR challenge is bigger than doctors overprescribing antibiotics. Farmers feed antibiotics to livestock and poultry, and spray them on crops to make our food supply ‘safer’. We dump antibiotics in rivers, and even paint them on the hulls of boats to prevent the build up of barnacles. However, it seems reasonable to suggest that successfully reducing doctors’ over prescribing antibiotics would represent a significant contribution to denting the burden of AMR. To do this, “We need a step change in the technology available . . . Governments of the richest countries should mandate now that, by 2020, all antibiotic prescriptions will need to be informed by up to date surveillance and a rapid diagnostic test,” urges the AMR report.
The technological ‘step change’, which the report says is essential, has already been achieved, says Roger Kornberg, Professor of Medicine at Stanford University and Nobel Laureate for Chemistry.Advanced biosensor technology enables virtually instantaneous, extraordinarily sensitive, electronic detection of almost any biomarker (protein, nucleic acid, small molecule, etc.). With relatively modest resources it would only be a matter of months to develop a simple, affordable handheld device, which not only would tell you immediately and accurately whether a sore throat requires antibiotics or not, but would also tell you which antibiotics you require, and for how long you should take them,” says Kornberg. See videos below in which Kornberg describes how tried and tested biosensor technology could facilitate rapid and accurate diagnosis of a sore throat.

Bionsensors in diagnosing a sore throat


Instant diagnosis of a strep throat

Serious and growing threat
Each year, millions of people throughout the developed world present themselves to their doctors with minor ailments, such as a sore throat. 97% of these patients demand antibiotics although 90% of their ailments are viral and therefore do not require antibiotics. 90% of doctors, who do not have the means to rapidly and accurately determine whether a minor ailment requires antibiotics, feel pressured by patients to prescribe them.
A 2014 study of four million NHS patients from 537 GP practices in England found that more than 50% of those presenting with a minor ailment were prescribed antibiotics, despite warnings that the medication will not help, but increases their risk of developing resistance. The study, by scientists at Public Health England and University College London, published in the Journal of Antimicrobial Chemotherapy, found that antibiotic prescriptions for minor ailments increased by some 40% between 1999 and 2011. 70% of GPs surveyed said they prescribed antibiotics because they were unsure whether patients had viral or bacterial infections, and 24% of GPs said it was because of a lack of an easy-to-use, rapid and accurate diagnostic device.
Superbugs will kill millions and cost trillions
Concerned about the rising levels of drug resistance whereby microbes evolve to become immune to known drugs, in 2014 the UK Government, in collaboration with the Wellcome Trust, commissioned a review of the large and growing global burden of AMR. Jim O’Neill, a former Goldman Sachs chief economist who coined the phrase “BRICS”, was appointed to lead the endeavour and propose actions to tackle AMR. In 2015 O’Neill was elevated to the House of Lords, and appointed Secretary to the UK government’s Treasury.

During the 18 months it took O’Neill to complete his final report, one million people worldwide died from AMR. At least 25,000 people die each year in Europe from AMR. According to the Centers for Disease Control and Prevention (CDC), more than 2m people in the US become infected with resistant bacteria every year, and at least 23,000 of them die. According to O’Neill, “If we don't do something about antibiotic resistance, we will be heading towards a world with no-antibiotic treatments for those who need them.”
A threat to modern medicine
O’Neill’s findings are congruent with warnings from the World Health Organization (WHO), which suggests AMR is a crisis worse than the Aids epidemic – which has caused some 25m deaths worldwide – and threatens to turn the clock back on modern medicine. The misuse of antibiotics has created, “A problem so serious that it threatens the achievements of modern medicine. A post-antibiotic era, in which common infections and minor injuries can kill, far from being an apocalyptic fantasy, is instead a very real possibility for the 21st century,” says a 2014 WHO report. “Superbugs risk making routine surgery potentially lethal, killing millions and costing the world economy US$100 trillion a year by the middle of the century,” says O’Neill.
These dire warnings are supported by a case study of AMR published in Antimicrobial Agents and Chemotherapy in 2016, which suggests that we might be closer to a "post-antibiotic era" than we think. A particular group of bacteria (Gram-negative) have become increasingly resistant to currently available antimicrobial drugs. Colistin is one of the only antibiotics that still show some effectiveness against such infections, but the study suggests that even Colistin may no longer be effective.
AMR is widely recognized as a serious and growing worldwide threat to human health. New forms of AMR continue to arise and spread, leaving doctors with few weapons to bring potentially life-threatening infections under control. The injudicious use of antimicrobials, and the proliferation of AMR pathogens are compounded by the inability to rapidly and accurately diagnose minor ailments such as sore throats. Professor Kornberg has an answer.
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