Meeting the challenge of antibiotic resistance
BMJ 2008; 337 doi: https://doi.org/10.1136/bmj.a1438 (Published 18 September 2008) Cite this as: BMJ 2008;337:a1438All rapid responses
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The future of antibiotic resistance as painted by Cars et al. is
certainly a dismal picture: a growing swarm of drug resistant bugs
descending upon a populace unbeknownst to the impending threat.
Inappropriate use of antibiotics allowed these organisms to penetrate our
main modes of pharmaceutical defense, regressing our options for treatment
back to a “pre-antibiotic era”.(1) With the stagnancy of the antibiotic
industry, our medical arsenal is depleted even further. In response to
this crisis, Cars et al. propose a solution that is no more hopeful than
the problem itself. First, they suggest a focus on building bigger, better
and newer antibacterial classes to broaden the availability of treatments
when dealing with resistant organisms. Agreeable, but not exactly the most
ingenious idea, comparable to solving the problem of world hunger with
more food. Second, they emphasize restricting antibiotics from situations
where they would be considered “needless use”, a vague and poorly
constructed idea. For individuals with known bacterial infections, the
authors argue that any treatment with antibiotics promotes the risk of
“becoming long term carriers of antibiotic resistant bacteria”. Therefore,
even if antibiotics are used in ideal, necessary and appropriate
situations, the emergence of resistant strains is still inevitable.
Lastly, the authors support measures to prevent the need for antibiotics
altogether (reduce transmission, invent more specific diagnostic tests for
bacterial infection). These are plausible strategies in delaying the
development of drug resistant bacteria, but the potential for treating
resistance itself is never discussed. The proposal put forth by Cars et
al. is insufficient against the plight of these hardy organisms. Resistant
bugs are evaded, delayed and even circumvented, but never treated. Without
the treatment component, we essentially initiate a cold war with all
things microbial- modern medicine, at a standstill from fear of bacterial
vengeance.
Cold wars make for an interesting segue. Decades before the
introduction of antibiotic therapy in the early 1940’s, the discovery of
bacteriophages by Frederick Twort and Felix d’Hérelle prompted research in
the area of phage therapy against human infectious diseases. Early studies
were disappointing and by the time antibiotic therapy began to dominate
the markets, phage therapy had been long forgotten by most Western
countries. However, paralleling antibiotic trials in the U.S., research in
phage therapy persisted and continued to develop in the old Soviet Union.
Refinement of phage therapy led to great success in clinical treatments of
bacterial infection and has been amassed in an entire library of research
at the Eliava Institute in Tbilisi, Georgia. Unfortunately, with the
advent of the Cold War, none of this knowledge has been accessible to
Western scientists. With the recent recognition of antibiotic resistance,
there is renewed interest in phage therapy as a potential, more effective
alternative to antibiotic therapy.
Phage therapy utilizes bacteriophages that are pathogen specific.(2)
A small dose of phage cocktail can infect targeted pathogens, replicate
and lyse the bacterium as part of the normal phage life cycle. Each cycle
releases progeny that goes on to infect other pathogens, with the net
result being clearance of the pathogen. There are a number of advantages
to using phage therapy over antibiotics, as mentioned by Matsuzaki et
al.(3) First and foremost, phages have been shown to kill multi-drug
resistant bacteria. A single dose of lytic phage therapy was shown to
rescue 100% of mice, 45 minutes after challenge with multi-drug resistant
Pseudomonas aeruginosa.(4) Second, phages are organism-specific, meaning
that treatment with a phage cocktail against pathogens will not deplete
normal host microflora.(5) Third, emerging phage resistance in pathogens
may be overcome by a faster mutation rate inherent to phages.(6) Other
arguments for phage therapy include cheaper development cost of phages
than antibiotics and a lesser chance for side effects due to specificity.
Granted, to simplify phage therapy like this would be naïve, as much
remains to be perfected. For example, rapid pathogen lysis could result in
mass release of bacterial endotoxin.(7) Phages could also proceed toward
lysogenic infection, providing targeted pathogens with immunity against
further lytic infections instead of intended destruction.(8) As foreign
particles, phages could be rendered ineffective by our own immune
system.(9) Lastly, there are some bacteria for which there are no known
phages. These issues all need extensive exploration before full clinical
implementation. Nonetheless, phages show extraordinary promise against the
threat of antibiotic resistance and deserve rightful attention.
To truly meet and surpass the challenge of antibiotic resistance, we
must incorporate strategies to nullify the pathogenic mechanisms for drug
resistance, not just prolong the inevitable. Phage therapy has proven to
be an effective alternative treatment in cases of multi-drug resistant
pathogens and may even become the cornerstone of fighting bacterial
infections. Cars et al. have suggested substantial measures such as
limiting antibiotic use to appropriate situations as well as modulating
our attitudes and behaviors to prevent abuse as well as encouraging the
expansion of our pharmaceutical repertoire. However, these are all
supportive steps towards controlling antibiotic resistant bacteria. Only
by discovering an agent that overrides the resistance acquiring
capabilities of these organisms, will we ultimately be victorious.
1. Cars O, Hogberg LD, Murray M, Nordberg O, Sivaraman S, Lundborg
CS, et al. Meeting the challenge of antibiotic resistance. BMJ.
2008;337:a1438.
2. Parisien A, Allain B, Zhang J, Mandeville R, Lan CQ. Novel
alternatives to antibiotics: bacteriophages, bacterial cell wall
hydrolases, and antimicrobial peptides. J Appl Microbiol. 2008
Jan;104(1):1-13.
3. Matsuzaki S, Rashel M, Uchiyama J, Sakurai S, Ujihara T, Kuroda M,
et al. Bacteriophage therapy: a revitalized therapy against bacterial
infectious diseases. J Infect Chemother. 2005 Oct;11(5):211-9.
4. Vinodkumar CS, Kalsurmath S, Neelagund YF. Utility of lytic
bacteriophage in the treatment of multidrug-resistant Pseudomonas
aeruginosa septicemia in mice. Indian J Pathol Microbiol. 2008 Jul-
Sep;51(3):360-6.
5. Duckworth DH, Gulig PA. Bacteriophages: potential treatment for
bacterial infections. BioDrugs. 2002;16(1):57-62.
6. Kysela DT, Turner PE. Optimal bacteriophage mutation rates for
phage therapy. J Theor Biol. 2007 Dec 7;249(3):411-21.
7. Hagens S, Habel A, von Ahsen U, von Gabain A, Blasi U. Therapy of
experimental pseudomonas infections with a nonreplicating genetically
modified phage. Antimicrob Agents Chemother. 2004 Oct;48(10):3817-22.
8. Cheng CM, Wang HJ, Bau HJ, Kuo TT. The primary immunity
determinant in modulating the lysogenic immunity of the filamentous
bacteriophage cf. J Mol Biol. 1999 Apr 16;287(5):867-76.
9. Merril CR, Biswas B, Carlton R, Jensen NC, Creed GJ, Zullo S, et
al. Long-circulating bacteriophage as antibacterial agents. Proc Natl Acad
Sci U S A. 1996 Apr 16;93(8):3188-92.
We declare no conflict of interest.
Competing interests:
None declared
Competing interests: No competing interests
General practitioners/family physicians should be regularly
updated about the use of antibiotics.
Patient education is a must.
Antibiotics should not be sold over the counter with out the
prescription of doctors.
To bring about this awareness national ,International efforts
must be made regularly.
BMJ has brought out a very important issue for discussion.
N.P.Viswanathan
Competing interests:
None declared
Competing interests: No competing interests
Antibiotic-resistance of bacteria : An intractable problem
In connection to the revealing article by Cars et al 1, it appears
relevant to point out that while imprudent use of antibiotics is
considered a major reason behind emergence and spread of antibiotic-resistance, substantial tolerance to antibiotics is noticed even among
bacteria isolated from pristine environments. For example, bacterial
strains belonging to several genera, isolated from different types of
Antarctic samples (soil, fast ice, cyanobacterial mat), at CCMB (India)
were found to be resistant to a number of therapeutically useful
antibiotics. Co-occurrence of the genes that confer resistance to
antibiotics and heavy metals on the same plasmid makes the problem further
complicated since antibiotic-resistant bacteria are selected to flourish
in a natural environment, polluted by heavy metals even in absence of
antibiotics.
A recent survey conducted by us at IGB-Neuglobsow (Germany)
reveals co-occurrence of resistance to antibiotics (viz, ampicillin,
streptomycin, erythromycin, chloramphenicol, oxytetracycline, kanamycin,
rifampicin , norfloxacin, ciprofloxacin, trimethoprim, vancomycin) and
heavy metal salts (viz, zinc chloride, cadmium chloride, potassium
chromate) in various combinations among 66 bacterial isolates having
different phylogenetic affiliations, obtained from water bodies located in
some least populated areas of north Germany. About 15% of the total
isolates were resistant to 5 antibiotics and 3 heavy metals. Surprisingly
about 19% of the isolates were resistant to chloramphenicol, which is no
longer used in clinical practice in western countries. Plasmids,
which carry both antibiotic and heavy metal resistance genes, are
remarkably stable even in absence of any selection pressure. Hence, we
could only defer the emergence of antibiotic-resistance but cannot bypass
it simply by minimizing the use of antibiotics.
M.K.Chattopadhyay
Centre for Cellular and Molecular Biology (CSIR), Hyderabad 500 007,
India, mkc@ccmb.res.in
H-P Grossart
Leibniz Institute of Freewater Ecology and Inland Fisheries, 16775
Stechlin, Germany
hgrossart@igb-berlin.de
1. Cars O, Hogberg L.D, Murray M , Nordberg O, Sivaraman S, Lundborg
C.S, D So A, Tomson G. Meeting the challenge of antibiotic resistance.
BMJ 2008; 337: a1438
Competing interests: No competing interests