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ANALYSIS: Otto Cars, Liselotte Diaz Högberg, Mary Murray, Olle Nordberg, Satya Sivaraman, Cecilia Stålsby Lundborg, Anthony D So, and Göran Tomson Meeting the challenge of antibiotic resistance BMJ 2008; 337: a1438 [Full text]

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Antibiotic resistance

N.P. viswanathan   (12 October 2008)

Surpassing the Challenge of Antibiotic Resistance

Rex G. Cheng, Douglas F. Nixon   (20 October 2008)

Antibiotic resistance 12 October 2008
N.P. viswanathan, Family physician Svclinic gm palya Bangalore-560075,India Send response to journal: Re: Antibiotic resistance	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
Surpassing the Challenge of Antibiotic Resistance 20 October 2008
Rex G. Cheng, Medical Student Division of Experimental Medicine, University of California, San Francisco, 94110, Douglas F. Nixon Send response to journal: Re: Surpassing the Challenge of Antibiotic Resistance	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