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Phage Therapy

 
 The Clinical Problem
 The Unconventional Solution
 What are Lytic Bacteriophages?
 The Phage Advantage
 Historical Background and Context
 Possible Problems and Resistance
 
 
 The Clinical Problem
 
Today's escalating antibiotics crisis is the direct result of the large scale and indiscriminant over-use of antibiotics and disinfectants, which has triggered an increase in the quantity, variety, and proliferation of multidrug-resistant and, consequently, particularly virulent bacterial pathogens. These pathogens have developed resistance to virtually all extant antibiotics, including the antibiotic of last resort, vancomycin.
Pathogens, once considered clinically under control or obliterated, are re-emerging as prolific killers (e.g., Mycobacterium tuberculosis).
Highly virulent and resistant nosocomial infections are rampant in hospitals everywhere.
In US hospitals alone, more than 2,000,000 patients succumb to infectious diseases every year, and over 90,000 die-compared with a yearly mortality of 15,000 in the early 1990s.
Ninety percent (90%) of staphylococci-the pathogens responsible for fifteen percent (15%) of all bacterial infections-are penicillin resistant, and forty percent (40%) are resistant to methycillin.
Physicians are resorting to extreme measures: Sixty-three percent (63%) of US vancomycin prescriptions violate the Centers for Disease Control and Prevention (US CDC) guidelines and, thereby, accelerate the formation of bacterial resistance.
 
The medical community has thus inadvertently entered the "post-antibiotic" era, with no conventional remedy in sight. The indiscriminate over-use of antibiotics has succeeded in eradicating only the antibiotic-susceptible infectious strains while empowering highly resistant "super bugs." Furthermore, without a significant overhaul in antibiotic-use policy, history suggests that most or all chemical antimicrobials in the development pipeline will also trigger rapid evolution of target-bacterium resistance
 
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 The Unconventional Solution
 
A valid, proven, and practical alternative to the chemical-antibiotic treatment of bacterial infections has been successfully practiced in Eastern Europe from as early as the late 1930s.
Phage therapy is a method of antibacterial treatment that harnesses the bacteria-killing properties of otherwise harmless viruses. Phage therapy is practiced routinely in the former Soviet Union as an alternative, combinatory, and complimentary form of treatment in conjunction with, or in lieu of, antibiotics. This time-proven Eastern European practice has received surprisingly little exposure in the West, and, consequently, it has failed to win its due recognition in the West.
Standardized phage medicines in numerous forms are being produced in several locations in Russia and Georgia. These concentrated, polyvalent phage preparations are typically comprised of mixtures of different phages of wide host range that infect and kill many bacterial species and strains, including:

  • Brucellae,
  • Enterococci,
  • Pathogenic strains of Escherichia coli (e.g., O157:H7),
  • Klebsiellae (atypical pneumonia),
  • Mycobacterium tuberculosis,
  • Protei (nosocomial urinary tract infections),
  • Pseudomonas aeruginosa,
  • Salmonellae (typhoid fever and food poisoning),
  • Serratia spp,
  • Shigella spp. (bacillary dysentery),
  • Staphylococci (skin abscesses, food poisoning, toxic shock syndrome),
  • Streptococci (strep throat),
  • Vibrio cholerae (cholera), and
  • Yersinia spp (plague/black death).
In large-scale clinical trials of various phage-therapy preparations and techniques conducted in Poland in the mid-1980s, a decisive recovery rate of ninety-two percent (92%) was achieved. (Slopek et al, 1983, 1985, 1987).
 
Western medical culture has been unaware of phage therapy's considerable achievements in the former Soviet Union owing to a variety of historical, political, and bureaucratic circumstances. Hardly any of the numerous Russian-language publications have been translated into English, let alone reviewed.
 
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 What are Lytic Bacteriophages?
 
Lytic bacteriophages ("phages" for short) are bacteria-specialized viruses, and they are among the simplest and most abundant organisms on earth.
Typically comprised of a head filled with genetic material, a syringe-shaped tail, and several fibers that selectively attach themselves to specific receptors on the host bacterial surface, phages bore into their respective host bacteria and inject them with the phage's own genetic material. Within infected bacteria, phage DNA is replicated and then incorporated into bacteria-infectious particles that are manufactured from chemical components stolen from the bacterial host. These "virions" are then released from their parent bacterial cells via a process known as "lysis," which kills bacterial cell. The production and subsequent release of phage particles allows subsequent phage infection of additional bacteria in a rapid, exponential pattern. (In contrast to lytic phages, temperate phages, which can bolster their bacterial host's virulence, resilience, and general capacity to proliferate are generally unsuitable for therapeutic applications.)
 
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 The Phage Advantage
  • Phages thrive in the presence of bacteria, and die out in their absence.
  • Because of phages' extreme specificity and chemically large nature, they have induced neither side nor adverse effects when used as therapy in clinical practice.
  • Phages do not cause allergies or affect the body's natural immune system.
  • Phages generally display a low chemotherapeutic index, particularly upon primary administration systemically or upon topical administration, and they are vastly more diverse in their potential to overcome bacterial resistance than known antibiotics also displaying comparatively low chemotherapeutic indices.
  • Phages support and enhance vital microflora (in contrast with the indiscriminate action of wide-spectrum antibiotics, which can decimate the body's protective normal microflora).
  • Phages may be used both prophylactically and in the treatment of ongoing infections.
  • Phages constantly evolve and can adapt in situ to resistant bacteria strains.
  • Phages may also be more effectively targeted to growing bacteria in local infections.
  • Phages are administered in a limited number of small doses over a short period of time.
  • Phages eliminate pathogens more rapidly and effectively than standard antibiotics.
  • Phage medicines have a long shelf life (up to 2 years).
  • Production costs of phages are low.
  • Phage therapy is consistent with "green-natural-alternative" ideology, and its production is environment-friendly.
  • Phages present the only viable alternative and, potentially, the last resort for the treatment of antibiotic-resistant pathogens.

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 Historical Background and Context
 
The biologic phenomena known as "bacteriophages" were discovered during the mid-1910s. Phage-therapy experiments during the 1920s and 1930s yielded inconclusive results (mostly owing to a lack of knowledge about phages' high specificity). Phage therapy, as a clinical method, was rejected altogether in the West upon the discovery, immediate popularization, and wide-scale dissemination of penicillin in the early 1940s.
However, in the USSR, interest and research in phages persisted. The G. Eliava Institute of Bacteriophage, Microbiology, and Virology, founded in Tbilisi in 1934-and generously funded and staffed on Stalin's directive-engaged in the laborious process of sampling, cultivating, matching, and producing phage preparations against most known pathogens. In the late 1980s, when the institute was at the height of its scientific achievement, 1,200 scientists were employed in R&D, maintaining the extensive phage collections and producing two tons of phage preparations per day. Unfortunately, the Georgian civil war of the early 1990s instigated the demise of the institute, the loss of most of its phage collections, the collapse of its infrastructure, and, subsequently, the relocation of phage research and production to Russia.
Prior to the dismantlement of the Soviet Union, phage preparations had been produced in most of the main metropolitan centers. Phage therapy had been spurred by the chronic shortage of adequate and sufficient antibiotics. The phage industry has been adversely affected by the general collapse of the post-Soviet economy, and only a handful of producers remain. Presently, demand for phage therapeutics greatly exceeds supply.
Unreliable Soviet research and clinical practices, the absence of an adequate Soviet scientific publication culture, the Cold War, communication and language barriers, and lack of interest due to the entrenched, Western antibiotics doctrine have all contributed to keeping the accumulated phage-therapy experience out of Western sight and mind.
Meanwhile, breakthroughs in genetic and molecular biology research in the 1970s stimulated the emergence of an increasingly analytic approach to phage research in the West. Thanks to their relatively simple structure, phages have been extensively researched as biologic models, with an eye to areas of research ranging from genome mapping to cancer to AIDS research. Phage typing and display methods have become standard tools in bacteriology.
The accumulated Western analytic knowledge of phage structure, functions, and mechanisms of host interaction has yet to be merged with the Eastern body of knowledge, which draws additionally on a hands-on, empirical, and clinical experience of phage ecology and phage interaction with bacterial and mammalian systems.
The emerging antibiotics crisis of the 1990s, however, has triggered a renewed-though fledgling-interest in phage therapy within the American and European research communities. Attempts are currently being made to review the vast body of Eastern European work in the area.
Veterinary phage applications have been introduced in Western Europe over the last decade. A couple of American biotech start-ups are preparing to file for FDA approval for a maiden staphylococci phage product that they hope to introduce in the near future. Another group is striving to develop a phage preparation for vancomycin-resistant enterococci (VRE). Myriad phage technologies are already employed in a variety of diagnostic applications.
The world market for antibacterial products exceeds $25 billion. The American market for new-generation antibiotics was valued at more than $10 billion in 1999.
Phage technologies and products are certain to gain a foothold in clinical applications, if only to compensate for the ever-increasing decline in the efficacy of antibiotics. In addition, there is still an untapped, immeasurable market for phage applications in veterinary, agricultural, industrial, and environmental remediation.

 
"The Stalinist Antibiotics Alternative" (New York Times, Mar. 2000),
"The Curing Virus" (B.B.C., 1997),
"Revealed: our best hope to beat the killer superbugs "(Independent, Sept. 1999),
"Viruses may help fight bacteria that resist antibiotics"(The Guardian, Sept. 1999)
"Superbug victim saved by killer virus treatment" (Daily Telegraph, Sept., 1999) - are just some of recent articles featured in the mass media.
Unable to refute its validity, doctors will soon face an adamant demand from patients to provide them with the phage alternative.
 
The inevitable acceptance of phage technologies will soon trigger the onslaught of biotech companies vying for a prominent market position.
 
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 Possible Problems and Resistance
 
The introduction of Phage Therapy is expected to encounter the following obstacles:
  • Pervasive fixation on chemical antibiotics within the clinical establishment;
  • Resistance of the pharmaceutical sector, which is heavily invested in chemical antibiotics;
  • Physicians' reluctance to forego wide-spectrum antibiotics in favor of the highly specific phages;
  • Structural and functional reorganization required for a coordinated and responsive diagnosis-production-administration chain;
  • Pervasive aversion within the biotech research establishment to revert to "archaic" microbiology;
  • Need to constantly adapt and refresh phage preparations in response to pathogen evolution;
  • Delay between clinical presentation and antibacterial administration;
  • General disregard for Russian research and clinical practices;
  • Concerns with bacterial evolution of resistance to phages; and
  • Lack of a regulatory reference basis.
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