|
|
|
European Biopharmaceutical Review
|
In order to develop effective antibiotics, researchers must investigate
changes in the composition of bacteria in the body over time. However,
current microbiology methods have only revealed a fraction of the
species that are present, making advances in this area difficult
There has been a dramatic decline in the development of new antibiotics.
Between 1950 and 1960, eight classes of antibiotics were introduced for
human use whereas, in the last 40 years, there have only been five.
When coupled with the rising threat of antibiotic resistance, this leads
many to believe that we are fast approaching a ‘post-antibiotic era’,
where common infections can no longer be treated and may even prove
fatal.
Growing Concern
The current crisis started to become apparent in the late 1990s, when
resistance among grampositive bacteria was rising rapidly.
Penicillin-resistant pneumococci were widespread internationally and
vancomycin-resistant enterococci were also circulating in hospital
specialist units most extensively in the US (1,2).
At the start of 1990, methicillin-resistant Staphylococcus aureus (MRSA)
were still relatively uncommon, at least in serious infections in the
UK. However, between 2000 and 2003, resistance had proliferated to the
point where they accounted for 40 per cent of all Staphylococcus aureus
bacteraemias, and 10 per cent of all bacteraemias in the UK excluding
Scotland. Similar increases were seen in most of Europe (except The
Netherlands and Scandinavia) and in the US.
Although MRSA has been brought under control by improved infection
control measures, resistance has increased in a wide array of
gramnegative pathogens, including those with extended-spectrum
betalactamases, quinolone resistance and carbapenemases – which
inactivate what were previously the most universally active antibiotic
class, carbapenems.
A growing concern is that without effective antibiotics, we will be
unable to conduct many types of modern medicine, such as therapies for
autoimmune disorders and cancer treatments that lead to
immunosuppression. Additionally, the risk of untreatable infection will
make many routine surgical procedures too dangerous to perform. Studies
being conducted at Norwich Research Park are directed at addressing this
situation through antibiotic discovery, as well as by lowering the
barriers that prevent the translation of drug discovery into marketable
treatments and by improving the precise diagnosis of infectious disease.
Obstacles to Development
Even when new antibiotics are identified via drug discovery, there are
still several phases of clinical trials to go through before a drug can
be brought to market. These include stages to establish pharmcokinetic
behaviour (blood levels and tissue distribution), safety and efficacy,
and performance in comparison with current standard of- care drugs.
Although there is worldwide recognition of the need for new antibiotics,
developing them is not currently an attractive business opportunity for
Big Pharma. Companies such as Roche, Pfizer, Bristol Myers Squibb and
Eli Lilly have all moved away from the field. The reasons for the
dramatic decline in antibiotic development are three-fold.
First, there is the difficulty of finding new agents which need to not
only bind to the target but reach it across the complex cell wall of
gram-negative bacteria. The agent must also function accordingly in
different body parts. (In contrast, a new heart drug only has one target
in the body.)
Second is the low return on investment. Antibiotics are mostly taken for
acute illnesses over a short space of time, and are far less profi
table than drugs required over longer periods for chronic illness, such
as cancer or neurodegenerative diseases. In addition, new antibiotics
are likely to have their usage restricted in an attempt to slow down the
development and proliferation of resistant strains of bacteria.
The third reason is the high, and frequently changing, regulatory
barrier. The purpose of clinical trials is to establish safety and
efficacy, but the proofs of efficacy demanded by the Food and Drug
Administration (FDA) and the European Medicines Agency vary. The FDA’s
requirements, in particular, have changed repeatedly; it is now
extremely difficult and sometimes expensive to recruit patients for some
indications. For this reason, drugs tend to be trialled in settings
where they are likely to get a licence, rather than where there is a
serious clinical need.
Narrow Spectrum Antibiotics
One consequence of Big Pharma’s dwindling interest in antibiotic
development is that the field is now a major opportunity for smaller
microbiology players. Indeed, exciting technology emerging from labs is
opening up the possibility for narrow spectrum, targeted antibiotics,
which have many advantages.
All antibiotics exert a Darwinian selection on bacteria, favouring those
that are resistant, changing the healthy bacterial flora and
encouraging the emergence of ‘superbugs’. Broad spectrum antibiotics –
compared to narrow spectrum ones – have a devastating effect on the gut
flora, which contains more bacterial cells than the body contains human
cells, some of them with the potential to act as future opportunistic
pathogens. In some cases, resistance arises by mutation, in others it
occurs through the exchange of DNA (usually in the form of plasmids)
among different strains of bacteria. Horizontal gene transfer is
facilitated in the human or animal gut, with its complex and diverse
ecosystem of different bacterial species.
It is now important to develop narrowspectrum antibiotics which destroy
just the pathogen – for example, Clostridium difficile – thereby curing
the infection while leaving the host’s intestinal microflora intact. The
search for new targets is directed at mechanisms that either act on
fundamental processes within the organism so that it cannot replicate,
or that weaken it sufficiently to ensure that competitive pressure
within the gut reduces its virulence.
One advantage of narrow-spectrum drugs is that the molecular target for
each drug only needs to exist in a limited number of bacterial species,
and this significantly increases the possibilities of finding new
classes of antibiotic for each bacterial pathogen.
A new platform technology called SATIN (Selective Antibiotic Target
IdentificatioN) detects more targets for antibiotics in any species of
bacteria and ascertains potential mechanisms of resistance. This
platform has been used to identify multiple, chemicallytractable small
molecules with activity against Escherichia coli, Pseudomonas
aeruginosa, Klebsiella pneumoniae and Acinetobacter baumannii,
representing a wide range of gram-negative pathogens.
Improved Diagnostics
Narrow-spectrum antibiotics, however, present special challenges when it
comes to the clinical trials process and finding a market in clinical
medicine. Recruiting participants with resistant strains of bacteria is
problematic as these patients tend to be scattered geographically across
non-trial sites. More critically, as the clinical researcher will not
know what bacteria are causing the infection until the lab results
arrive two days after clinical diagnosis, it is necessary – at least in
severe, lifethreatening infection – to begin with broad spectrum
antibiotics. Once these have been given, however, the patient then
becomes ineligible for enrolment into a trial for any other antibiotic
for that infection.
To overcome this challenge, researchers are working to improve
techniques for early diagnosis in order to identify the specific strains
of bacteria that are implicated. This will facilitate recruitment of
patients to trials for narrow-spectrum antibiotics, identifying those
with pathogens that are likely to be susceptible.
One collaborative project is investigating the use of next-generation
sequencing technology – which resembles a molecular version of the agar
plate for bacteria and electron microscopy for viruses – to accelerate
the identification of pathogens in blood samples from patients with
bacterial infections. Using nucleic acid removes the need for
microbiological culture and speeds up the microbiological diagnosis.
Aside from facilitating clinical trails, rapid and accurate diagnosis
would allow appropriate narrow-spectrum antibiotics to be prescribed
within a matter of hours, benefiting patients and improving antibiotic
stewardship. Next-generation sequencing may even be able to detect
whether the patient’s pathogen belongs to an outbreak strain or not, and
if the organism is resistant to antibiotics.
Encouraging Antibiotic Development
We would like to see the UK Government create an educational,
entrepreneurial and regulatory climate that encourages investment and
innovation in antibiotic development, with the following measures:
● Increasing the funding for research and development, as is being done under the EU’s Innovative Medicines Initiative
● Modifying the clinical trial requirements, as in the Limited
Population Antibacterial Drug (LPAD) initiative, currently under
discussion in the US
● Extending effective patient lives, as recently introduced in the US as
part of the Generating Antibiotic Incentives Now (GAIN) Act
These three approaches would make it easier to translate earlystage
research into marketable drugs and increase the attractiveness of
antibiotic development. Also, this would enable highly specific,
narrowspectrum antibiotics to be designed, benefiting both patients and
societal management of infections.
References
1. Munoz R, Musser JM, Crain M et al, Geographic distribution of
penicillin-resistant clones of Streptococcus pneumoniae:
characterisation by penicillinbinding protein profile, surface protein A
typing, and multilocus enzyme analysis, Clin Infect Dis 15: pp112-118,
1992
2. Woodford N, Morrison D, Johnson AP and George RC, Antimicrobial
resistance amongst enterococci isolated in the United Kingdom: a
reference laboratory perspective. J Antimicrob Chemother 32: pp344-346,
1993
|
Read full article from PDF >>
|
|
 |
|
| Rate this article |
You must be a member of the site to make a vote. |
|
Average rating: |
0 |
| | | | | |
|
|
 |
News and Press Releases |
 |
Rentschler Biopharma joins forces with Ikarovec to accelerate novel gene therapies for treatment of ophthalmic disease
Norwich, Stevenage, UK and Laupheim, Germany, June 1, 2023 – Rentschler Biopharma SE, a leading global contract development and manufacturing organization (CDMO) for biopharmaceuticals, including advanced therapy medicinal products (ATMPs), and Ikarovec, which is developing novel multicistronic gene therapies to treat major ophthalmic indications, today announced that the two companies have entered into a collaboration. Under the agreement, Rentschler Biopharma’s ATMP site in Stevenage, UK, will support the bioprocess development of AAV material for planned pre-clinical testing of Ikarovec’s novel gene therapy for the treatment of geographic atrophy. This condition is an advanced form of age-related macular degeneration that can result in the progressive and irreversible destruction of retinal tissue, which can lead to loss of vision over time.
More info >> |
|
 |
White Papers |
 |
|
Clinical Trial Labelling – More Than Just Labels
Faubel & Co. Nachfolger GmbH
Deciding which label is best for a particular trial project is not always easy. Labels have become multifunctional tools which are able to convey variable data in different languages, indicate first opening, product originality, support ease of use or blind study drugs. They are no longer used as mere carriers of specified contents.
More info >> |
|
|
