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Archivum Immunologiae et Therapiae Experimentalis, 1999, 47 267–274
Review
Phage Therapy: Past History and Future Prospects
R. M. Carlton: Phage Therapy in the Past and Future
Exponential Biotherapies, Inc., 150 Main Street, Port Washington, NY 11050, USA Abstract. Bacterial viruses (bacteriophages, also called “phages”) can be robust antibacterial agen✝ts in vitro.
However, their use as therapeutic agents, during a number of trials from the1920s to the 1950s, was greatly
handicapped by a number of factors. In part, there were certain limitations inherent in pha✟ge physiology (e. g. nar-row host range, and rapid clearance from the body); in part there were technological limitations in the era(e.g. lysogeny not yet discovered); but the greatest limitation was the highly inadequate scientific methodologies used by practitioners at the time (e.g., their failure to conduct placebo-controlled studies, to remove endotoxins from the preparations, and to re-confirm phage viability after adding sterilizing agents to t✞he preparations). Inrecent years, well-controlled animal models have demonstrated that phages can rescue animals from a variety of fatal infections, while non-controlled clinical reports published in Eastern Europe have s✞hown that phages can be effective in treating drug-resistant infections in humans. This encouraging data, combin☛ed with the fact that drug-resistant bacteria have become a global crisis, have created a window of opportunity for phage therapy to be tested anew, this time using modern technologies and placebo-controlled designs. If successful, it can be used as a stand-alone therapy when bacteria are fully resistant to antibiotics, and as a valuable ✍adjunct to antibiotics when the bacteria are still susceptible.
Key words: bacteriophage; phage; bacterial viruses; bacterial infections; multidrug resistance.
Phages are a kingdom of viruses that infect bacteria, view will describe: 1) some of the key reasons this and are distinct from the animal and plant viruses.
form of therapy failed to take root in the West; 2) its Phages can have either a “lytic” or a “lysogenic” life previous and current use in some enclaves of Eastern cycle. The lytic phages are the most suitable candidates Europe; 3) recent animal models which suggest that for phage therapy, because they quickly reproduce phage therapy might be useful for humans; 4) the fact within and lyse the bacteria in their host range, growing that the emergence of antibiotic-resistant infections has exponentially in number in the process. Depending on opened a second window of opportunity for phage ther- the species and conditions, each “parent” phage can apy; and 5) the advantages that might be gained by produce on average approximately 200 “daughters” per administering phages along with antibiotics, as a com- lytic cycle. If each daughter infects and kills a host bacterium there will be 40 000 progeny at the end of the 2nd cycle; 8 million at the end of the 3rd cycle; 1.6 Past History
billion at the end of the 4th cycle; and so on.
Some practitioners used phages as therapeutic agents in the West, from the 1920s to the early 1950s A number of reviews provide details on phage ther- (referred to hereinafter as the “historic era”). This re- apy’s ascent and decline in the historical era1–3, 13, 14.
R. M. Carlton: Phage Therapy in the Past and Future Table 1 Attributes of phages that tend to favor a therapeutic response
Metabolic destruction of the molecule, as it Exponential growth in numbers, so that the “drug” makes more of itself at the site ofinfection, where it is needed Numerous molecules of the antibiotic are needed “All or nothing” effect: one phage particle is to kill a given bacterium. During initiation of therapy (and between doses), the sub-lethal dosethat bacteria “see” affords them the opportunityto express resistance genes Antibiotics are fixed, immutable chemicals that Phages are “living” organisms that undergo therefore become obsolete. Bacteria that have bacterial mutations. E. g., mutated phage tail resisted them can pass along the resistance trait fibers can allow binding to a mutant bacterial receptor, or mutated phage DNA can escapecleavage by mutant bacterial endonucleases The antibiotics in use tend to be broad spectrum, Although there are some exceptions, phages tendthereby provoking resistance in several species not to cross species boundaries. Thus even and genera of bacteria (in addition to the one though the targeted bacterial species may become resistant to the phage, it is unlikely thatother species will We will summarize some of the more salient features and how the problems can be overcome Phages were discovered in 1915 by British micro- biologist Felix Twort, and, independently in 1917, by French-Canadian microbiologist Felix d’Hérelle.
The issue. Phages tend to have a relatively narrow Twort did not pursue his discovery, whereas d’Hérelle host range, posing certain disadvantages. A disadvant- systematically investigated the nature of bacteriophages age is that one should administer only those phage and explored their ability to function as therapeutic strains shown to be strongly lytic for the bacterial strain infecting the given patient. If the patient’s condition is D’Hérelle received a fair measure of fame for his too critical to take the time required for this matching, discovery. He was appointed Professor of Protobiology then one should use a grouping (a panel) of phages, at Yale University Medical Center, and was also on the where each of the phages therein has a broad-enough staff of the Pasteur Institute. In 1931 he gave a series host range that most strains of the bacterial target are of monthly lectures on phage therapy to the New York likely to be targeted. In his lectures to the New York Academy of Medicine. He established phage therapy Academy of Medicine in 1931, d’Hérelle cited the re- centers in several countries, including the U. S., France, ports of other colleagues whose initial trials used and Soviet Georgia. A fictionalized account of his work phages “off the shelf” (without being shown to be viru- was depicted in Arrowsmith, the Pulitzer-prize winning lent for the bacteria infecting the patient) and had ne- gative outcomes, but who did match the phage to the There are many attributes of phages (see Table 1) bacteria in subsequent trials and obtained positive out- that would tend to favor a positive outcome in therapy.
Despite these attributes of phages, there were so The solution. 1) Screen the bacteria infecting many problems with the way phage therapy was prac- a given patient against a panel of phages, to ensure that ticed in the historical era that, by the time antibiotics one of the phage strains will be lytic (analogous to the were introduced in mid-century, it was already in sharp “culture and sensitivity test” that physicians should per- decline in the West. The investigators who developed form; and 2) develop “multivalent” phages that lyse all antibiotics did not make the kinds of mistakes exhibited or most of the bacterial strains within a given species R. M. Carlton: Phage Therapy in the Past and Future Problem 2. Bacterial debris present in the phage prep- exposed to bacteria or bacteriophages (and so would not have antibodies). Moreover, the phages in Merril’s The issue. Injection of even minute amounts of en- experiment remained viable in the spleens of these ani- dotoxin and other bacterial debris can be fatal to pa- mals over a period of several days, indicating that they tients. Unfortunately, many of the phage preparations were neither neutralized by antibody nor engulfed by used by practitioners in the historical era were crude macrophages. Rather, they appeared to have been pas- lysates. When these preparations were injected i.v., i.p., sively entrapped in (sequestered by) these filtering or- and in some cases even intrathecally, any beneficial gans. Such trapped phages would be unavailable to effect of the phages would likely have been counter- acted by illness and deaths resulting from the endo- The solution. The author of this review collaborated with investigators at the U.S. National Institutes of The solution. Modern technology allows density ERRIL et al.11) in the development of a method centrifugation, banding, and other methods of purifica- to isolate and amplify phage strains that are cleared at a slower rate. We reasoned that in all species of phage, minor variations in coat proteins might be present that Problem 3. Attempts to remove host bacteria from ther- would enable some variants to be less easily recognized by the RES organs and to thereby remain in the circu- The issue: In order to ensure that phage prepara- lation for longer periods of time than the “average” tions would not contain live bacteria, some early inves- wild-type phage. In this “serial passage” method, the tigators added mercurials and/or oxidizing agents, wild-type preparation is injected into an animal, and while others heated them. It is now known that such then blood samples are taken at progressively longer agents and procedures will denature or otherwise inac- time points. Any phages found in the blood sample are tivate the phage coat proteins. These investigators grown to high titer and reinjected. Through iterative did not check for continued viability of the phages.
rounds of passage, one can amplify the long-circulating The false-negative results of such studies were the strains being isolated. U.S. and PCT patents have been unintended (but inevitable) consequence of such prac- For coliphage lambda as well as for salmonella The solution: Sterile filtration. If chemical agents phage P22, phage variants were isolated in this manner must be used, retitrate the preparation over time to en- that were much longer-circulating than the wild-type.
For example, for every 100 000 particles of the wild--type lambda used at baseline, only one particle re- mained in circulation at 18 h; whereas for the long-cir- The issue. In fairness to phage investigators in the culating phage mutant isolated at the 8th round of serial historical era, at the time it was not an accepted prac- passage, for every 100 000 injected, at 18 h 62 500 par- tice, in any discipline, to conduct pharmacokinetic ticles remained in circulation. For each moment of studies. However, had the early phage investigators time, far more of these long-circulating phages are pro- conducted such studies, they would have discovered pagating exponentially, as compared to the situation for that bacteriophages (being foreign proteins) tend to be rapidly cleared from the circulation. This clearance As predicted, these long-circulating phages were far problem was first documented by Merril and his col- superior to the wild-types from which they were leagues in 1973 who injected high titers of phage lamb- derived, in terms of rescuing animals from an other- da into non-immune germ-free mice. They discovered wise-fatal fulminant bacteremia: 1) with no treatment, that the phages were rapidly cleared by the spleen, liver all animals were dead within 48 h; 2) treatment with and other filtering organs of the reticulo-endothelial the wild-type phages prevented death, but the animals system (RES)7. This was a seminal observation, given became critically ill (a human with such degrees of Gunther Stent’s widely-accepted statement that one of illness would be in the intensive care unit); and 3) in the principal reasons phages had failed as a therapeutic contrast, with administration of the long-circulating was their supposed inactivation by pre-existing anti- phage strain, the only sign of illness seen was mild bodies to them. However, any clearance of the phages lethargy. These results were published in the Proceed- from the bloodstream of the germ-free animals used by ings of the National Academy of Sciences (ref. 11✦), and Merril and his group (ref.7) would not be due to anti- were accompanied by a Commentary by Nobel laureate bodies, since those animals had never previously been R. M. Carlton: Phage Therapy in the Past and Future We have elucidated the molecular basis of the mu- Problem 7. Failure to establish scientific proof of effi- tation in lambda that reduced its rate of clearance: a single point mutation, an A to G transition, had oc- In scholarly reviews of comparative styles of re- curred in the gene encoding the major head protein E.
search, Dutch historian TON VAN HELVOORT has dis- This mutation substituted a basic amino acid (lysine) cussed d’Hérelle’s systematic failure to conduct for an acidic one (glutamic acid), causing a double double-blind studies. As van Helvoort pointed out, charge shift readily seen on 2D gel electrophoresis.
while it is true that ethical problems are faced by Computer modeling predicted that the mutation oc- anyone who has to administer placebo to some patients curred in a loop of the E protein that sticks out into (in order to prove efficacy), nevertheless the investi- space and that therefore may interact with the external gators who later tested antibiotics did conduct double- environment. A double charge shift in this region of -blind, placebo-controlled trials. Van Helvoort points a protein that is highly represented on the surface of the out that, even when using phages to treat an epidemic virion could conceivably alter the phage’s interaction of diarrhea in poultry on a French farm, d’Hérelle with the microcirculation of the spleen, in such a way failed to use a placebo on half the flock (a situation that the mutant phage is less easily entrapped than the where ethical considerations would not have been an issue). As a consequence, all reports of phage therapy’ssuccesses in the historical era were anecdotal. No sys- tematic proof was available to demonstrate that the re- The issue. It was not until the late 1950s that Lwoff demonstrated the ability of some phage genomes to integrate into the bacterial chromosome as “pro- Problem 8. The scientific style of phage investigators phages”. After a period of time (up to days or weeks, or longer), such prophages can enter the lytic cycle, and D’Hérelle’s failure to conduct placebo-controlled will thus appear as plaques on a bacterial lawn. It is studies, even on chickens, is an important example of likely that some phage therapy trials in the historic era his style. This story is a notable example of the nega- had a negative outcome due to the inadvertent use of tive impact an investigator’s personality can have on phage strains that, being lysogens, could not provide the outcome of a discovery, and d’Hérelle’s style con- the rapid lysis and exponential growth in numbers that trasts sharply to the strongly positive influence that other scientists (such as Pasteur) have had on the out- The solution. Use only phages that are lytic; se- comes of their discoveries. Whereas Pasteur excelled at quence phages that are strong candidates for clinical conceiving of definitive experiments, and was persua- trials, looking for (among other things) homologies to sive in style, d’Hérelle failed to conduct definitive ex- periments, and was antagonistic rather than persuasive.
For example, d’Hérelle maintained to the end that phages are the sole mechanism of defense against bac- The issue. There are reports in the literature20 that terial infection. While he may have been correct in his neutralizing antibodies appear a few weeks after ad- view that epidemics can sometimes be checked by the ministering phages to humans or animals. Given the spontaneous appearance of a lytic strain of phage, time lag, antibodies would not seem likely to interfere nevertheless he was incorrect in categorically dismis- with an acute treatment lasting a week or so. However, sing the discoveries of Nobel laureates Metchnikoff and in chronic treatment, or in treatment of a recurrence of Ehrlich, who had shown that cellular elements (white the same bacterial infection, the neutralizing antibodies blood cells) and humoral elements (antibodies and might prevent some proportion of the administered complement) constitute the innate host defenses against dose of phages from being able to adhere to the bac- infection. D’Hérelle was afforded many opportunities to integrate his discovery with those of Metchnikoff and The solution. In treating chronic or recurrent Ehrlich, but refused to the end (see below).
infections it may be possible to administer a higher In addition to the damage he was doing to himself and dose of phage, to compensate for those that are ren- his cause with this adamance, d’Hérelle was attacked by dered non-viable by interaction with neutralizing anti- Nobel laureate Jules Bordet (for whom ✯Bordetella pertussis bodies. In any case, the types and titers of antibodies was named), who had an intense dislike not just for d’Hé- that develop should be systematically studied in hu- relle’s science but also for the man himself. Bordet used his considerable influence to discredit D’H R. M. Carlton: Phage Therapy in the Past and Future D’Hérelle retreated from attacks by Bordet and the phages grew exponentially in number, overwhelm- others, and moved to Soviet Georgia in the 1930s (see ref. 13✦). An ardent communist, he dedicated the last of his published treatises to Josef Stalin. He was in Paris Current Status of Human Phage Therapy Efforts
at the outbreak of World War II, refused to offer hisskills with phage therapy to the Germans*, and spent Poland. Phage therapy is practiced in Poland, albeit the occupation years in prison. By the time of the libera- on a small scale. In the mid-1980s a series of papers tion his health had been broken. He was invited to a post- was published by a group led by the late Prof. S. S War international scientific symposium, where colleagues and his colleagues, including Dr. M. Mulczyk and Dr.
made a last effort to see if they could help him bridge the B. Weber-Da˛browska, working at the L. Hirszfeld In- gulf. He persisted in his belief that phages were the body’s stitute of Immunology and Experimental Therapy (a sole mechanism of defense against bacteria (“Ce n’est ✱que branch of the Polish Academy of Sciences). These la phage…”), and he died in isolation in 1949.
reported on 550 cases of suppurative bac- Surely the prospects of phage therapy in the histori- terial infections (empyemas, peritonitis, osteomyelitis, cal era would have been better served if d’Hérelle had etc.) in humans. Most of the cases were chronic; most possessed some of the personality traits and scientific were resistant to all available antibiotics; and most had not been referred for this form of therapy until all elsehad failed, meaning that it was often quite late in the Animal Models of Phage Therapy
The bacterial pathogens targeted included ✳Staphylococ- From the 1950s to the 1980s there was little pub- cus aureus, Pseudomonas aeruginosa, Klebsiella pneu- lished on the subject of phage therapy. Then papers moniae and E. coli. The phages used by these investigators began to appear demonstrating the utility of phage ther- are reported to have cured approximately 90% of the cases.
apy in animal models. For example, phages were shown The criteria of cure were cessation of suppuration and, to be effective in rescuing rats from fatal systemic in- where applicable, complete closure of wounds/fistulae fections (induced with E. coli✦)14 in rescuing calves and (many of which had been draining for months).
These investigators administer phages orally, be- rescuing chicks from fatal diarrhea (induced with S. ty- cause they are aware of the hazards of administering phimurium) , and in preventing destruction of skin them parenterally (not all of the bacterial debris has grafts in burned rabbits by Pseudomonas aeruginosa18.
been removed). They pre-treat the patients with anta- As mentioned above M✭ERRIL et al.11 demonstrated in cids and gelatin in order to protect the phages from 1996 that mice with fulminant E. coli bacteremia could destruction by gastric acidity. These same investigators be rescued by phages, and that long-circulating phage have published evidence that phages administered variants were superior to the wild-types (see below).
orally to humans in this manner do in fact reach the In one of those studies cited, Smith and Huggins (ref. 6✦) demonstrated that, in rats inoculated with a le- The Polish investigators have been rigorous in thal intramuscular dose of E. coli, a single injection of matching the phages to the bacterial strain infecting the a phage preparation was more effective than multiple given patients. Their practice, as stated in the published injections of antibiotics (chloramphenicol, tetracycline, reports, is to culture the bacteria during the course of etc.). This work was replicated in 1997 by LEVIN and treatment, so that the occurrence of a mutant resisting ULL , who used mathematical modeling in a popula- the phage can be countered by switching to a different tion dynamics approach to study the titers of phages phage strain. The group also has panels of multivalent and bacteria in the animals. The investigators con- phages available, for use in fulminant infections (such cluded that the reason a single injection of phage was as septicemia with acute respiratory distress syndrome) superior to multiple injections of antibiotics was that where time is insufficient to classify the offending bac- teria or to match phages to bacteria.
The group now has statistics on the treatment of * The push of the German army into the region of Georgia was approximately 1 300 cases. The overall cure rate across intended not only to capture the region’s oil wells, but also to obtain the spectrum of pathogens and sites of infection is ap- the collection of phages manufactured at the Eliava-d’Hérelle In- proximately 86% (personal communication from Dr.
stitute in Tblisi. That institute was providing phages to the Russian ❀ army, to control dysentery, Staphylococcus aureus infections of ❂ wounds, and other bacterial problems associated with war.
R. M. Carlton: Phage Therapy in the Past and Future the absence of placebo controls means the power of ance. Unfortunately, it has been demonstrated that some suggestion cannot be definitively ruled-out. It is clear hospital strains of methicillin-resistant ✳S. aureus (MRSA) that the difficulties of that nation’s economy over recent that are widespread have become vancomycin resistant decades has denied the investigators the financial re- upon exposure of the patients to vancomycin1, 2. Ex- sources needed to enroll matched cohorts in a placebo perts predict that S. aureus will progress to become arm of a clinical trial. While the criticism is valid, and completely resistant to vancomycin (the antibiotic of absolute proof of principle can be obtained only last resort for most strains of this pathogen), and that through placebo-controlled trials, nevertheless the use- when this occurs, millions of people will die each year fulness of the data is improved by the detailed statistical from infections that had until recently been fairly easy accounting of the percentages of complete, partial and to control. Based on such developments and impending nil response. One of the factors that enables this author developments with pathogens such as MRSA and VRE, to find the data from Poland more believable (even in opinion leaders have been warning that we are entering the absence of double-blind proof) is that in conditions such as emphysema where phage efficacy might be While pharmaceutical companies are developing somewhat impeded, the group’s statistics show that the new antibiotics to counter the trend, it has been shown success rate is considerably lower than for other condi- that half a century of global antibiotic abuse has tions where such impediments do not obtain*.
equipped the surviving bacteria with “supergenes” that The Republic of Georgia. The work started in Tblisi enable them to quickly resist new classes of antibiotics, in the 1930s by d’Hérelle and his Georgian colleague, even those to which they have never been exposed1.
Eliava, continues to this day. In the 1970s, under the Examples of the “supergenes” are mutations that 1) en- direction of Dr. Teimuraz Chanishvili, the Eliava-d’Hé- able bacteria to pump out several classes of antibiotics relle Institute had a large staff manufacturing consider- (through an efficient efflux pump), or that 2) alter the able quantities of phage preparations per year, primarily antibiotic binding sites on ribosomal subunits, so that for the control of dysentery in the troops of the Soviet several different classes of antibiotics can no longer Army. This group has anecdotal evidence of the effi- inhibit those subunits. As a consequence, in recent cacy of phage therapy. They report, for example, that years, by the time newer antibiotics have gone through in certain adult and pediatric hospitals it is routine for clinical trials and have reached the market, 20% or their phage preparations to be administered topically on more of clinical isolates in the hospitals are already surgical incisions. Given the lack of statistical analysis, resistant to them at the time of regulatory approval, and there is little to be said other than the anecdotal reports within a few more years the majority of strains are re- are encouraging that phage therapy can be useful.
Multidrug-Resistant (MDR) Bacteria Have
Future Prospects for Phage Therapy
Created a Need for Phage Therapy
Infectious disease experts have warned that there is Several species of bacteria have become resistant to now a compelling need to develop totally new classes of most antibiotics, with some strains being resistant to all antibacterial agents, ones that cannot be resisted by the antibiotics. One example is vancomycin-resistant En- same genes that render bacteria resistant to antibiotics.
terococcus faecium (VRE), a low-virulence pathogen Phage therapy represents such a “new” class. We that now frequently causes fatal bacteremias due to believe that the impediments cited above (bacterial de- complete resistance2. Another example is vancomycin bris in the preparations, rapid clearance in the body, intermediate-resistant ✳Staphylococcus aureus (VISA), etc.) can be overcome, freeing up the phages so that strains of which have recently emerged in three nations their attributes (such as exponential growth, and the (Japan, U.S. and Scotland), and are known to have ability to mutate against resistant bacteria) can be used killed 4 patients to date. Such strains spread throughout Japanese hospitals within a year of their first appear- There are 3 additional attributes of phages that Host specificity. While the host specificity is some- * Conditions where phage efficacy is predicted to be reduced what of a drawback (requiring a matchup of phage to would include 1) hypoxic sites, where bacterial replication is slower bacterial target, and/or the development of highly and therefore phage replication is reduced; and 2) chronic obstruc- ✾ tive pulmonary disease, where high acidity and proteases would be multivalent phages), it also offers the great advantage ❇ expected to inactivate some percentage of the phages. that the phages will not kill other species of bacteria.
R. M. Carlton: Phage Therapy in the Past and Future Thus, e.g., phage therapy is not likely to kill off the that are still susceptible to antibiotics, by helping to healthy flora of the intestines, lungs or urogenital tract, prevent the emergence of bacterial mutants against and it is therefore unlikely to provoke the illnesses and deaths seen when antibiotics cause overgrowth of pa- thogens (such as Clostridia difficile and Candida albi- References
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ODPcat2014-@1@_Layout 1 11/02/14 14:38 Pagina 21 Terra Santa e Giordania 13-22 maggio 5° giorno - Petra 9° giorno - Gerusalemme/Masada/Ein Gedi/Wadi 23 luglio - 1 agosto Intera giornata dedicata alla visita della città na- el Kelt/Gerusalemme batea, dichiarata patrimonio del ’Umanità dal-Al mattino, partenza per Masada. Salita in funivia 4-13 novembre l’Unesco. Di

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