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Bacteriophage Therapy Archivum Immunologiae et Therapiae Experimentalis, 2000 PL ISSN 0004-069X Bacteriophage Therapy of Bacterial Infections: an Update of Our Institute's Experience. Beata Weber-Dubrowska*, Marian Mulczyk and Andrzej GórskiLaboratory of Bacteriophages, Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Weigla 12, 53-114 Wrocław, PolandAuthor's fees were financed by the Association for the Joint Administration of Copyright KOPIPOL (Kielce, Poland) from funds collected on the basis of the Law on Author's Rights. * Correspondence to: Dr Beata Weber-Dąbrowska, Laboratory of Bacteriophages, Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Weigla 12, 53-114 Wrocław, Poland, tel.: +48 71 373 22 74, fax: +48 71 373 25 87, e-mail: secret@immuno.iitd.pan.wroc.plAbstract. 1307 patients with suppurative bacterial infections caused by multidrug-resistant bacteria of different species were treated with specific bacteriophages (BP). BP therapy was highly effective; full recovery was noted in 1123 cases (85.9%). In 134 cases (10.9%) transient improvement was observed and only in 50 cases (3.8%) was BP treatment found to be ineffective. The results confirm the high effectiveness of BP therapy in combating bacterial infections which do not respond to treatment with the available antibiotics. Key words: phage therapy; drug resistance; bacterial infections.Bacteriophages (BP) are viruses that attack bacteria, multiply within and cause disruption of bacterial cells (lysis).Their lytic action is highly specific. After the discovery of BP 85 years ago, it was hoped that they would be useful in the treatment of bacterial infections. BP therapy was initiated in 1921 by Bruynoghe and Maisin4 in the treatment of staphylococcal infections. Although the results were promising, little was accomplished in this field during the following years. The idea of potential applications of BP therapy was abandoned after the introduction of sulphonamides and then antibiotics into medical practice. However, the lytic action of BP in vitro enabled some investigators to use specific BP for the differentiation of various species of bacteria. Many phage-typing schemes were elaborated. These methods of differentation are still used worldwide and are very useful in epidemiological investigation1. Renewed interest in BP therapy emerged again with the appearance of drug-resistant bacteria. In the recent years bacteria highly resistant to most or all drugs, including the antibiotic of last resort, vancomycin, have been spreading all over the world6, 7, 10, 12–15, 27. This resistance is mainly disseminated by plasmids, transposons and insertion elements. Resistance markers may be transmitted between cells of different species of bacteria. Thus, antibiotic treatment of infections caused by multi-drug-resistant bacteria is ineffective and the growing resistance of pathogenic bacteria is of great importance in medical practice. During last two decades data have been accumulated to show that BP therapy has become an important alternative to antibiotics in the treatment of bacterial infections. In many cases, successful results were obtained in combating infections in humans and in animals1–3, 5, 8, 9, 11, 17, 18, 28–31.BP therapy has been extensively used at the Bacteriophage Institute, Tbilisi, Georgia (for rev. see Kutter10).It was found that specific BP are effective in both the prophylaxis and treatment of bacterial infections caused by drug-resistant bacteria of different origin. Extensive studies on BP therapy have also been carried out at the Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wrocław, Poland. Between 1981 and 1986 BP therapy was applied in 550 cases of suppurative bacterial infections caused by staphylococci and Gram-negative bacteria Klebsiella, Escherichia, Proteus andPseudomonas). In 518 cases, BP therapy followed ineffective treatment with all available antibiotics. Positive therapeutic effects were obtained in 508 cases, i.e. 92.4% (range 75–100%). It was found that BP therapy effectively controls the infections process irrespective of its localization, patient age and sex, and type of infection (monoinfections, polyinfections). The highest effectiveness of BP was noted in furunculosis (100% cured). High effectiveness (over 90% cured) was also observed in osteomyelitis, infections of connective tissue and lymphatic vessels, as well as chronic suppurative fistulas19–26.In this paper we present our results of the BP treatment of bacterial infections in the years 1987–1999. During that period BP were applied in 1307 patients with different suppurative infections caused by multi- -drug-resistant bacteria. The majority of cases were long, persisting infections in which antibiotic therapy had failed. The age of patients ranged from 4 weeks to 86 years. Our studies included isolation and identification of bacterial strains from patient specimens, determination of the sensitivity of the isolated strains to specific BP, and preparation of crude sterile BP lysates for therapy, as described in detail earlier20. In each case, BP were administered orally 3 times daily in the amount of 10 ml (children 5 ml) 30 min before eating, after neutralization of the gastric juice. Local administration depended upon a localization of the suppurative process. BP were applied directly to the wounds, as ear and nose drops, as infusions to the fistulas, washing of the nasal cavity suppurative lesions of pleura and peritoneum, decubitus and fistulas, intraperitoneally during the washing of the peritoneal cavity and topically in the cases of multiple skin abscesses.The BP therapy was carried out at university clinics and hospital wards. The clinical results of the BP therapy were evaluated by the physicians responsible for the patients' care. BP treatment lasted 1–12 weeks, with an average of 32 days. The results of BP therapy applied to bacterial infections are depicted in Table 1. As may be seen, BP therapy was highly effective in the treatment Escherichia, Klebsiella, Proteus, Enterobacter, Pseudomonas and Staphylococcus aureus (furunculosis). It must be stressed that 2738 strains (69.2%) were isolated from infections caused by one species of bacteria (monoinfections), the great majority by S. aureus (1674 strains). The remaining 1218 strains (30.8%) were isolated from infections caused by several species of bacteria (polyinfections). Staphylococcus and Pseudomonas occured more frequently in monoinfections; Klebsiella, Escherichia, Enterobacterand Proteusoccured more frequently in polyinfections. In 1123 patients (85.9%) treated with BP, a complete recovery or healing of the local lesions was obtained (range 64–100%), according to the etiologic factor and type of infection. Noteworthy is that BP therapy was most effective in purulent meningitis and furunculosis (100% cured). High effectiveness was also noted in septicemia of different origin, purulent otitis media, suppurative peritonitis, pyogenic arthritis and myositis, osteomyelitis of the long bones, suppurative osteitis after bone fractures, pyogenic infections of burns, purulent mastitis and chronic suppurative fistulas. In 134 cases (10.4%) transient improvement was observed and in 50 cases (3.8%) BP therapy was found to be ineffective. Of particular importance is that two dangerous pathogens, S. aureus and P. aeruginosa (which frequently cause serious infections), were highly sensitive to our sets of specific phages (95 and 89%, respectively). Other pathogens, E. coli and Klebsiella, were inhibited by specific phages in 81 and 60% of cases, respectively (Table 2). Figures1 and 2 depict representative results of BP therapy.Our results extend and confirm our earlier data showing the effectiveness of BP therapy in the combating of antibiotic-resistant bacterial infections. In fact, our results suggest that BP therapy is more effective than antibiotic treatment. In many cases, specific BP therapy constituted the only means of eliminating life- -threatening infections. It must be stressed, however, that the success of BP therapy is associated only with the sensitivity of the causative bacteria to its specific phage.It should be highlighted that in many cases following BP therapy an increased protection against subsequent bacterial and viral infections has been observed. Thus, it may be that the BP therapeutic effect (disappearance of clinical symptoms and negative bacteriologic tests) is not only a result of the destruction of bacterial cells in the infections sites, but also a consequence of BP up-regulation of the immune response. While monitoring the immune status of patients receiving BP we noted that effective BP therapy is associated with a normalization of cytokine production by blood cell cultures32. Moreover, our preliminary data indicate that purified BP may induce intracytoplasmatic cytokine synthesis in human lymphocytes and monocytes (Górski et al., unpublished observations). One may assume that BP also have immunoregulatory properties by interacting with immunocompetent cells. Further studies on the immunoregulatory effect of BP are underway. In addition, a double-blind placebo-controlled clinical trial on the effectiveness of BP therapy should be completed within the next 6 months.We hope that our data open new perspectives for BP therapy and its worldwide application in the treatment and eradication of bacterial infections. Acknowledgment This work was supported by grant 4PO5BO1219 from the State Committee for Scientific Research (KBN).References 1. Ackerman H. W. and Dubow M. (1987): Viruses of prokaryotes. I. General properties of bacteriophages. CRC Press, Boca Roton, Florida. 2. Barrow R. A. and Soothill J. S. (1997): Bacteriophage therapy and prophylaxis: rediscovery and renewed assessment of potential. Trends Microbiol., 5, 258–271. 3. Berchieri A. Jr., Lovell M. A. and Barrow P. A. (1991): The activity in the chicken alimentary tract of bacteriophages lytic for Salmonella typhimurium. Res. Microbiol., 142, 541–549. 4. Bruynoghe R. and Maisin J. (1921): Essais de therapeutique au moyem du bactériophage. C. R. Soc. Biol., 85, 1120–1121. 5. Carlton R. M. (1999): Phage therapy: past history and future prospects. Arch. Immunol. Ther. Exp., 47, 267–274. 6. Cisło M., Dąbrowski M., Weber-Dąbrowska B. and Wojtoń A. (1987): Bacteriophage treatment of suppurative skin infection. Arch. Immunol. Ther. Exp., 35, 175–183. 7. Cohen M. L. (1992): Epidemiology of drug resistance: implications for a post-antimicrobial era. Science, 257, 1050. 8. Gilmore M. S. and Hoch J. A. (1999): A vancomycine surprise. Nature, 399, 524–527. 9. Holzman D. (1988): Phage as antibacterial tool. Genet. Eng. News, 15 Oct., pp. 1,12, 41, 48. 10. Kutter E. (1997): Phage therapy. Bacteriophages as antibiotics. Evergreen State College. Olympia WA 98505 Nov. 15. 11. Lorch A. (1999): Bacteriophages an alternative to antibiotics. Biotech. Develgo Monitor, 39, 14–17. 12. Lederberg J. (1996): Commentary. Proc. Acad. Sci. USA, 93, 3167–3168. 13. Neu H. C. (1992): The crisis in antibiotic resistance. Science, 257, 1064–1071. 14. Novak R., Henriques B., Charpentier E., Normark S. and Tuomanen E. (1999): Emergence of vancomycin tolerance in Streptococcus pneumoniae.Nature, 399, 590–593. 15. Sieradzki K., Roberts R. B., Haber S. W. and Tomasz A. (1999): The development of vancomycin resistance in a patient with methicillin-resistant Staphylococcus aureus. N. Engl. J. Med., 340, 517–523. 16. Smith T. L., Pearson M. L., Wilcox K. R., Cruz C., Lancaster M. V., Robinson-Dunn B., Tenover F. C., Zervos M. J., Band J. D., White E. and Jarvis W. R. (1999): Emergence of vancomycin resistance in Staphylococcus aureus. N. Engl. J. Med., 340, 493–501. 17. Smith H. W. and Huggins R. B. (1983): Effectivenes of phages in treating experimental E. coli diarrhoea in calves, piglets and lambs. J. Gen. Microbiol., 129, 2659–2675. 18. Smith H. W. and Huggins R. B. (1987): The control of experimental E. coli in calves by means of bacteriophage. J. Gen. Microbiol., 133, 1111–1126. 19. Strój L., Weber-Dąbrowska B., Partyka K., Mulczyk M. and Wójcik M. (1999): Successful bacteriophage treatment in purulent cerebrospinal meningitis in a newborn (in Polish). Neur. Neuroch. Pol., 33, 693–698. 20. Ślopek S., Durlakowa I., Weber-Dąbrowska B., Kucharewicz-Krukowska A., Dąbrowski M. and Bisikiewicz R. (1983): Results of bacteriophage treatment of suppurative bacterial infections. I. General evolution 31, 267–291. 21. Ślopek S., Durlakowa I., Weber-Dąbrowska B., Kucharewicz-Krukowska A., Dąbrowski M. and Bisikiewicz R. (1983): Results of bacteriophage treatment of suppurative bacterial infections. II. Detailed evaluation of the results. Arch. Immunol. Ther. Exp., 31, 293–327. 22. Ślopek S., Durlakowa I., Weber-Dąbrowska B. and Kucharewicz-Krukowska A. (1984): Results of bacteriophage treatment of suppurative bacterial infections. III. Detailed evaluation of the results obtained in further 150 cases. Arch. Immunol. Ther. Exp., 32, 317–335. 23. Ślopek S., Kucharewicz-Krukowska A., Weber-Dąbrowska B. and Dąbrowski M. (1985):Results of bacteriophage treatment of suppurative bacterial infections. IV. Evaluation of the results obtained in 370 cases. Arch. Immunol. Ther. Exp., 33, 219–240. 24. Ślopek S., Kucharewicz-Krukowska A., Weber-Dąbrowska B. and Dąbrowski M. (1985): Results of bacteriophage treatment of suppurative bacterial infections. V. Evaluation of the results obtained in children. Arch. Immunol. Ther. Exp., 33, 241–260. 5. Ślopek S., Kucharewicz-Krukowska A., Weber-Dąbrowska B. and Dąbrowski M. (1985): Results of bacteriophage treatment of suppurative bacterial infections. VI. Analysis of treatment of suppurative Staphylococcus infections. Arch. Immunol. Ther. Exp., 33, 261–273. 26. Ślopek S., Weber-Dąbrowska B., Dąbrowski M. and Kucharewicz-Krukowska A. (1987): Results of bacteriophage treatment of suppurative bacterial infections in the years 1981–1986. Arch. Immunol. Ther. Exp., 35, 569–583. 27. Valdvogel F. (1999): New resistance in Staphylococcus aureus. N. Engl. J. Med., 340, 556–557. 28. Vieu J. F. (1975): Les Bacteriophages. In Fabre J. (ed.): Fraite de Therapeutique, Vol. Serums et Vaccins. Flammarion, Paris, 337–400. 29. Vieu J. F. et al. (1979): Donnees actueles sur les applications therapeutiques des bacteriophages. Bull. Natl. Med., 103–161. 30. Weber-Dąbrowska B., Koźmińska J., Mulczyk M. and Kaczkowski H. (1996): The use of bacteriophages in the treatment of chronic suppurative sinusitis (in Polish). Post. Med. Klin. Dośw., 5, 291–293. 31. Weber-Dąbrowska B., Mulczyk M. and Górski A. (2000): Therapy of infections in cancer patients with bacteriophages. Clin. Appl. Immunol. Rev. (in press). 32. Weber-Dąbrowska B., Zimecki M. and Mulczyk M. (2000): Effective phage therapy is associated with normalization of cytokine production by blood cell cultures. Arch. Immunol. Ther. Exp., 48, 31–37.Received in August 2000 Accepted in August 2000Results of Bacteriophage Treatment Table 1. Results of bacteriophage treatment of suppurative bacterial infections obtained in 1307 cases
top *Full recovery and complete elimination of bacteria. ** Improvement, bacteria still detectable. Table 2. Sensitivity of bacterial strains within different species to specific bacteriophages
Fig. 1. Abscess of nasal are A. Prior to therapy B. After therapy
A. Infected foot ulcer B. After therapy
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