Alternative treatment avenues to using antibiotics to meet the AMR challenge*
* This section was co-authored by Archana Madhav and Dr Lara Marks.
Antibiotics could soon become largely useless with antibiotic resistant infections now posing a significant global disease burden. In 2015, there were 671,689 estimated cases of antibiotic resistant infections in Europe alone (Cassini et al), and by 2050, some estimates project an alarming 10 million deaths worldwide (O'Neill). Global antibiotic consumption increased by 65 percent between 2000 and 2015, with low and middle-income countries (LMICs) consuming particularly high quantities of antibiotics due to fewer regulations to prevent over-the-counter sales (Friedrich; Klein et al).
Long-term exposure to sub-lethal concentrations of antibiotic compounds helps to increase resistance. This is because it imposes a selection pressure on the bacterial population to adapt and develop a tolerance in order to survive (Bronzwaer et al). For many years the development of new antibiotics was seen as the means to combat AMR. This, however, does not provide a long-term solution because bacteria always find a way to fight back. Rather than focusing solely on eliminating the causative pathogen, what is needed in the future is to develop strategies to boost the immune system, which would help reduce the unnecessary overuse of antibiotics.
One of the best means of preventing against infection is through vaccination. Vaccines prime the immune system for multiple pathogenic targets, allowing the host to immediately recognise and isolate the pathogen upon subsequent exposure – therefore impeding resistance transmission as well.
Currently undergoing a 'golden-technological-age', vaccination provides an important avenue for slowing down AMR. For example, vaccines against bacterial pathogens can directly reduce antibiotic use by decreasing the incidence of both susceptible and resistant infections. Vaccination also has the advantage that it can target specific pathogens, so unlike antibiotics, it does not necessarily disturb the natural biodiversity of microflora in patients which is an important factor in the spread of AMR.
Figure 8.1 Diagram showing how vaccines work.
High immunisation coverage has the potential to significantly reduce the successful transmission of a resistant pathogen within a population as well (Tagliabue, Rappuoli). Vaccines against viral infections, for example influenza, can also indirectly reduce antibiotic prescriptions. This is because they help to reduce the incidence of febrile illnesses and secondary bacterial infections, such as pneumonia and otitis media, an inflammation of the middle-ear, among children, which often get treated with antibiotics because they display similar clinical symptoms to bacterial infections. Previous studies investigating the behavioural impact of vaccination on antibiotic prescription practices after administering specific vaccines, such as for influenza and pneumococcal disease, highlighted both a drop in antibiotic prescriptions and subsequent invasive drug-resistant infections (Kwong at all; Klugman, Black).
We must aim to improve global immunisation coverage using the current vaccine repertoire alongside developing new vaccines against bacterial pathogens or specifically targeting resistance determinants to help win the fight against AMR. Vaccines are responsible for the eradication of smallpox and elimination of diseases such as polio and measles, paving the way to tackle infectious diseases without generating new drug-resistant pathogens or disrupting the microbiome (Tagliabue, Rappuolili).
In addition to vaccines, scientists have another powerful tool at their fingertips - monoclonal antibodies (mAbs) - that could offer immediate immune boost to combat infectious disease. Derived from the natural antibodies the immune system produces to recognise and fight off foreign invaders, mAbs are one of medicine's strongest allies today.
Millions of different types of antibody can be found in the blood of humans and other animals. Each antibody is highly specific, in that they recognise and bind to a particular tag, known as the antigen, found on the surfaces of all biological substances, including pathogens. Once bound to the antigen, the antibody assists in generating further immune responses to eliminate the intruder.
Antibodies have been used to fight disease ever since the closing decade of the nineteenth century when it was found that serum from animals that survived diphtheria and tetanus conferred immunity in animals with no previous exposure to such diseases, and could cure the diseases. This form of treatment, known as serum therapy, was so successful that it became the mainstay of treatment for infectious diseases until the rise of sulphonamides and antibiotics in the 1930s and 1940s.
One of the reasons serum therapy fell out of favour was because the new antimicrobial drugs were less toxic to patients and easier to administer. They were also much easier to produce. For much of the twentieth century, the only way antibodies could be sourced was from serum extracted from the blood of previously immunised animals. This was a time-consuming and expensive process. The situation only changed after a breakthrough made by César Milstein and Georges Köhler in 1975 who developed a laboratory technique to produce unlimited quantities of mAbs to specific targets (Marks).
Awarded the Nobel prize in 1984, Milstein and Köhler's invention opened up a new chapter in treatments with antibodies. More than 80 mAb drugs have been licensed in the US and Europe since the first one was marketed in 1986. Despite their success, only a handful have so far been approved for infectious diseases. One of the reasons for the slow progress in this area has stemmed from the current high reliance on antibiotics, which are cheaper to produce and easier to administer to patients than mAb drugs.
Figure 8.2 Showing how a monoclonal antibody binds to a antigen which sets off signals to call other immune cells to destroy the intruder.
Another hurdle has been the fact that the burden of infectious diseases tends to fall hardest on LMICs. These countries do not have the financial resources to shoulder the cost of purchasing mAb drugs, which tend to be expensive. The median price for treatment with mAbs in the United States, for example, ranges from approximately $15,000 to $200,000 a year. Even where generic versions of mab drugs, known as biosimilars, are available these are generally only 10 percent to 35 percent less expensive. This is because they are much more complicated, time-consuming and expensive to develop than generic versions of small molecule drugs (Wellcome Trust).
Faced with the devastating loss of human life and massive economic and social disruption caused by the rise of AMR, the incentive to develop mAbs for infectious diseases is poised to change. Both governments and companies are beginning to wake up to the urgent need to invest in the development of mabs to help deal with infectious diseases and make them more affordable. New methods are also appearing which could mean that mAb drugs will no longer have to be given intravenously which will help reduce the cost of drug delivery (Wellcome Trust; Pelfrene at al ).
Where mAbs might be particularly helpful is as an adjunct therapy to standard-care antibiotics. Used in this way, mAbs could potentially extend the efficacy of antimicrobial drugs by destroying pathogens if they develop resistance. In addition, they could be useful as a prophylactic to prevent infection. A number of mAb drugs are already in the pipeline for treating drug resistant infections caused by both bacteria and viruses. One has already been approved in the US and Europe for Clostridium difficile, which is listed as one of the world's ten most dangerous antibiotic-resistant bacteria. A number of mAbs are now in pre-clinical development for S. aureus infections, P. aeruginosa infections and against Acinetobacter species, E. coli and other bacteria (Theuretzbacher at al;Baker et al; Sause et al; Zurawski McLendon).
Listen to Professor Stephen Baker discussing the future for vaccines and mAb based treatments to meet the AMR challenge. Click here to see a transcript of the interview with Professor Stephen Baker.
Balancing the biodiversity of microbes in the body
One of the major problems with antibiotics is that they interfere with the equilibrium of the diverse community of microbes within the body. The human microbial community, known as the human microbiota, is made up of bacteria, archaea, eukaryotic microbes such as fungi (especially yeasts), and an abundance of viruses that exclusively infect bacteria (bacteriophages).
Bacteria comprise the bulk of the microorganisms that inhabit our bodies. More than 1,000 bacterial species are estimated to live in the body. They can be found in and on nearly every part of the body, including the gut, brain, ear, skin, nose, the oral, gastrointestinal, respiratory, urinary and vaginal tracts and the bloodstream.
The vast majority of the bacteria associated with the human body dwell in the gut. These bacteria play a critical role in the breakdown and absorption of nutrients, help break down starches, sugars and proteins that humans cannot otherwise digest and synthesise essential amino acids and vitamins. They also play a part in fat storage and the production of anti-inflammatory factors (Singh, Verma, Taneja).
Overall, the human gut microbiome hosts a dense population of approximately 1014 bacteria. These are arranged into diverse communities consisting of various bacterial species that can either be mutually beneficial (symbiotic) with the host, commensal bacteria that use the body's resources but cause no harm, or opportunistic pathogens awaiting an imbalance in microbial composition (e.g., through antibiotic use) to invade and colonise the host (Backhed).
Due to the ease of resistance transmission between bacterial species through horizontal gene transfer (HGT), the human gut microbiota can act as a reservoir harbouring multiple resistance determinants (known as the gut resistome) (Stecher et al). These resistance determinants can be transferred to opportunistic or otherwise drug susceptible pathogenic bacterial strains, increasing their resilience to antibiotic treatments. In a healthy gut microbiome, commensal bacteria can outcompete the growth and prevent colonization by MDR strains due to the fitness costs associated with harbouring an MDR phenotype (van Schaik).
Hospitalised patients undergoing immunosuppressive treatments, such as those admitted to transplant units and oncology/haematology wards, are at the highest risk of acquiring resistant infections. In conjunction, these patients often endure several rounds of antibiotic treatments to prevent hospital-acquired (nosocomial) infections, leaving the gut microbiome in an imbalanced state – known as dysbiosis. This provides a window for opportunistic pathogens to exploit this vulnerable state and colonise the host (Bilinski et al). Often, these pathogens will either have developed a resistance phenotype through antibiotic selection pressure or acquired resistance determinants from the gut resistome through HGT. These co-infections are likely to be extremely difficult to treat and are consistently associated with poor patient outcomes.
Faecal microbiota transplantation
Also known as a stool transplant or faecal bacteriotherapy, faecal microbiota transplantation (FMT), is a therapeutic procedure used to revive the microbial composition in a patient that has failed to respond to traditional therapies like antibiotics. The procedure is carried out by transferring faecal bacteria from a healthy donor.
Figure 8.3 showing how stool is taken from a healthy donor, processed and given to a patient.
FMT has successfully been used against notoriously difficult-to-treat C. difficile infections resistant to antibiotics (Kelly et al). Such infections are responsible for most hospital-acquired diarrhoea, especially among the elderly and people with weakened immune systems. One review of thirty-seven studies of FMT, including randomised clinical trials, showed the therapy to be effective in 88 to 92 per cent of C. difficile cases (Quraishi et al).
Elsewhere FMT has recently proven helpful in decolonising multiple drug resistant (MDR) bacteria from the gut (Gargiullo et al). Just how effective it can be was demonstrated by Polish researchers who administered the treatment to 20 patients with blood disorders between 2015 and 2016. The patients were infected with one to four strains of MDR organisms, including Pseudomonas aeruginosa, carbapenem-resistant Enterobacteriaceae, methicillin-resistant S.aureus and vancomycin-resistant E.faecalis. The treatment proved highly efficient at eradicating antibiotic resistant bacteria. Repeated administration of FMT managed to completely decolonise such bacteria in 75 per cent of the patients treated (Bilinski et al).
FMT is still a long way off becoming a routine treatment but it holds major potential for helping patients struck down with untreatable bacterial infections. There are currently several unknowns with regard to the optimal mode of delivery, donor selection, sample preparation and selectively targeting specific MDR organisms in addition to establishing a robust regulatory framework to improve the safety, efficacy and tolerance of FMT among recipients. For more on the past, present and future of FMT click here..
Phage therapy also provides an important alternative treatment to the use of antibiotics. This treatment makes use of bacteriophages or phages, viruses that attack bacteria. Phages selectively target and destroy certain bacteria without harming the host organism or other beneficial bacteria, such as gut flora, thereby minimising the possibility of developing complications.
Figure 8.4 Diagram illustrating phage therapy.
Phage therapy was first used in Europe in the late nineteenth century to treat bacterial infections and kept alive in the Soviet Union, Central Europe and France until antibiotics emerged. This therapeutic avenue is now undergoing a major revival in Western medicine as a means to treat various bacterial infections not amenable to antibiotics.
Phage therapy has already been shown to be effective in animals for treating various multidrug resistant pathogens, such as Acinetobacter baumannii, Pseudomonas aeruginosa, E. coli and Klebsiella spp. All three pathogens are serious threats to patients in the hospital setting and to those with weakened immune systems (Schooley et al; McCallin et al).
One of the major advantages with phage therapy is the fact that for every strain of bacteria, there are several phage types that can kill it. While very promising, phage therapy faces several challenges. The biggest challenge is to find the right phage strain for treatment. It also poses major regulatory issues because phage therapy does not mimic conventional industrial pharmaceutical products. The very fact that phages can self-replicate in the body makes the therapy very different from other drugs like antibiotics whose concentration in the body diminishes over time.
Phage therapy has yet to receive regulatory approval to treat humans in the European Union and the United States. However, it can be used in these regions for compassionate treatment where all other conventional intervention options have been exhausted. Since 2000, there have been 29 reports of compassionate use of phage therapy, half of which were published between 2017 and 2019. The therapy has been most frequently used to treat patients with S. aureus infections, followed by P. aeruginosa and E. coli (Schooley et al; McCallin et al).
For more on the past, present and future of phage therapy click here.
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