and pyrazinamide reduce the duration of treatment from 18 months to
six months.
Patient compliance with the combination is crucial. Low compliance, in
other words poor adherence to the regimen, is associated with the
emergence of resistance. In tuberculosis, where the treatment regimen
lasts for six months, shortening the course of drugs is a priority for drug
development in order to increase patient adherence to the regimen.
5. Widen the spectrum of bacteria which are targeted
Broadening of the species of bacteria which are killed is also important.
For instance, in acutely sick patients with sepsis, the responsible bacterial
species may not be known initially. Accordingly, doctors often treat such
patients with a combination of a beta-lactam and an aminoglycoside.
When the blood culture results are known, more specific antibiotic
therapy can be introduced, but if multiple different species are thought
to be the cause of the infection, the combination may be continued.
Ideal characteristics
In my view, the partner drug should target the bacterial cell membrane
rather than a single enzyme. This would reduce the likelihood of induction
of resistance. It should avoid exposure to the gut bacterial flora, where it
is likely to induce resistance. The combination regimen should be short
in order to increase patient compliance and reduce the risk of emergence
of resistance.
The ideal second partner would be synergistic and active against dormant
bacteria, thus potentially reducing the duration of therapy and be able to
kill a wide range of resistant mutants which arise during therapy to the
old antibiotic which is its partner.
The partner drug should also be able to enhance the efficacy of the old
antibiotic against sensitive and resistant bacteria, and should be active
against dormant bacterial subpopulations which may help to reduce the
emergence of resistance. In addition, it should broaden the number of
species which the old antibiotic kills.
1+1= 4…
PROFESSOR ANTHONY COATES
ON HOW THE COMBINATION OF TWO
ANTIBIOTICS RESULTS IN SYNERGISM AND ADDITIONAL BENEFITS,
SUCH AS REDUCING THE EMERGENCE OF RESISTANCE
IN
my previous Pan European Networks articles, I have
suggested that the research and development of new
antibiotics should be boosted in the following ways: the
European Commission should set up an antibiotic recovery programme,
which would deliver loans and grants to SMEs, large pharmaceutical
companies and universities. This programme should aim to provide the
world with 20 new classes of antibiotics. In addition, the guidelines which
are implemented by the regulators should be adapted to cope with the
increased need for novel antibiotics, for example by widening the number
of clinical indications for which microbiological endpoints are allowed for
marketing purposes. Moreover, I have suggested that the UK and other
countries should set up collaborative networks, at the national and
international level, of universities and pharmaceutical companies which
would aim to rebuild the infrastructure of antibiotic discovery.
In this article, I address the role of combinations of antibiotics in the
treatment of antibiotic resistant bacterial infections. In this context, at
least one drug in the combination would be a new compound.
Successful combinations
1. Prevent resistance
The first, and most successful, antibiotic combination was the addition of a
second drug to streptomycin in the 1950s to prevent the emergence of
resistance in tuberculosis patients during treatment. Modern therapy of
tuberculosis is based upon these principles which were developed by Denny
Mitchison and his colleagues. Using a combination of drugs to prevent
resistance was extended to the treatment of leprosy, AIDS and cancer,
and it is important to realise that the success of tuberculosis combination
therapy is dependent on the fact that the causative agent,
Mycobacterium
tuberculosis,
becomes resistant to antibiotics by chromosomal mutations.
2. Synergy
Combinations are used in order to enhance the action of one antibiotic
by another. For example, the combination of penicillin and gentamicin
for the treatment of endocarditis with organisms which are sensitive to
both antibiotics. Such combinations are synergistic.
3. Target resistance
Combinations have been developed which will enhance the activity of an
antibiotic against resistant bacteria. An example of this approach is the
combination of amoxicillin with the bacterial beta-lactamase inhibitor
clavulanic acid. This combination has been shown to be superior to
amoxicillin alone in the treatment of impetigo.
4. Shorten regimens
Combinations can target dormant subpopulations. This can shorten
regimens, for instance in tuberculosis where the addition of rifampicin
Pan European Networks: Science & Technology
06
168
Professor Anthony Coates
Director
Helperby Therapeutics Ltd
phone
+44 (0)208 725 5731
email
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