Antimikrobiyal direnç [Antimicrobial resistance (AMR)], artan morbidite, mortalite ve tedavi maliyetleriyle ilişkili ekonomik ve sosyal maliyetler nedeniyle önemli bir halk sağlığı sorunudur. AMR artışı, bakteriyel enfeksiyonlara karşı antibiyotik tedavisinden tarihsel olarak önce gelen bakteriyofaj tedavisine olan ilginin yeniden artmasına neden olmuştur. Bakteriyofajlar, Doğu Avrupa'da çeşitli enfeksiyon hastalıklarının tedavisinde 10'larca yıldır başarıyla kullanılmakta olup, bugüne kadar bakteriyofajların yol açtığı herhangi bir ciddi advers etki bildirilmemiştir. Bakteriyofajlar, DNA ya da RNA içeren, insan veya hayvan hücreleri üzerinde herhangi bir olumsuz etkiye neden olmadan bakterileri enfekte ve lize edebilen virüslerdir. Bakteriyel enfeksiyonların tedavisinde, tek başlarına veya antibiyotiklerle kombine hâlde kullanılmaktadır. Ancak kullanılan fajların uluslararası kabul edilmiş resmî kılavuzlarda belirtilen gerekliliklere uygun kalite, etkinlik ve güvenlilik çalışmalarının tamamlanmaması nedeniyle bazı Doğu Avrupa ülkeleri dışında, rutin klinik uygulamaları henüz onaylı değildir. Bakteriyofaj çözeltilerin stabilitesiyle ilgili karşılaşılan sorunları çözmek amacıyla, fajlar dondurarak kurutma (liyofilizasyon) veya püskürterek kurutma yöntemleriyle toz formlarda hazırlanmış, ayrıca lipozomlar, polimerik mikro ve nanopartiküller gibi farklı taşıyıcı sistemler içine enkapsüle edilmiştir. Bu derlemede, faj tedavisi ve güncel durumu özetlenecek, formülasyon ve standardizasyon yönüyle neler gerektiği tartışılacaktır.
Anahtar Kelimeler: Antimikrobiyal direnç; bakteriyofaj tedavisi; bakteriyel enfeksiyon; formülasyon
Antimicrobial resistance (AMR) is a significant public health concern due to the economic and social costs associated with increased morbidity, mortality, and treatment costs. The rise of AMR has resulted in an increased interest in bacteriophage therapy, which historically preceded antibiotic treatment against bacterial infections. To date, there have been no reports of serious adverse effects caused by bacteriophages, and they have been used successfully for decades to treat human diseases in Eastern Europe. Bacteriophages (phages) are viruses that contain DNA or RNA that can infect and lysate bacteria without causing any adverse effects on human or animal cells. They are used alone or in combination with antibiotics in the treatment of bacterial infections. However due to the lack of quality, efficacy and safety studies based international regulatory guidelines, phages are not officially approved for clinical applications other than some East European countries. Hence, in order to meet the regulatory requirements, studies demonstrating quality and safety of the phages are needed to be completed. To enhance their stability, phages are freeze-dried (lyophilized) or spray dried to get dry forms or they are encapsulated into delivery systems such as polymeric micro or nanoparticles, and liposomes. In this review, the current bacteriophage therapy will be reviewed and the needs in regard to standardization and formulation of bacteriophage therapy will be discussed.
Keywords: Antimicrobial resistance; bacteriophage therapy; bacterial infection; formulation
- WHO. "No time to wait: securing the future from drug-resistant infections". (Erişim tarihi: 10.9.2019)[Link]
- O'Neill J. Tackling drug-resistant infections globally: Final report and recommendations. (Erişim tarihi: 10.9.2019)[Link]
- Republic of Turkey ministry of health public health institution. [National antimicrobial resistance surveillance system 2016 annual report]. (Erişim tarihi: 10.9.2019)[Link]
- WHO/Europe. "Central asian and eastern european surveillance of antimicrobial resistance annual report 2018". (Erişim tarihi: 9.9.2019)[Link]
- Principi N, Silvestri E, Esposito S. Advantages and limitations of bacteriophages for the treatment of bacterial infections. Front Pharmacol. 2019;8;10:513.[Crossref] [PubMed] [PMC]
- Mulani MS, Kamble EE, Kumkar SN, Tawre MS, Pardesi KR. Emerging strategies to combat ESKAPE pathogens in the era of antimicrobial resistance: a review. Front Microbiol. 2019;1;10:539.[Crossref] [PubMed] [PMC]
- Moelling K, Broecker F, Willy C. A wake-up call: we need phage therapy now. Viruses. 2018;5;10(12):688.[Crossref] [PubMed] [PMC]
- Malik DJ, Sokolov IJ, Vinner GK, Mancuso F, Cinquerrui S, Vladisavljevic GT, et al. Formulation, stabilisation and encapsulation of bacteriophage for phage therapy. Adv Colloid Interface Sci. 2017;249:100-33.[Crossref] [PubMed]
- Vandenheuvel D, Lavigne R, Brüssow H. Bacteriophage Therapy: advances in formulation strategies and human clinical trials. Annu Rev Virol. 2015;2(1):599-618.[Crossref] [PubMed]
- Puapermpoonsiri U, Spencer J, van der Walle CF. A freeze-dried formulation of bacteriophage encapsulated in biodegradable microspheres. Eur J Pharm Biopharm. 2009;72(1):26-33.[Crossref] [PubMed]
- Merabishvili M, Vervaet C, Pirnay JP, De Vos D, Verbeken G, Mast J, et al. Stability of Staphylococcus aureus phage ISP after freeze-drying (lyophilization). PLoS One. 2013;2;8(7):e68797.[Crossref] [PubMed] [PMC]
- Leung SS, Parumasivam T, Gao FG, Carrigy NB, Vehring R, Finlay WH, et al. Production of inhalation phage powders using spray freeze drying and spray drying techniques for treatment of respiratory infections. Pharm Res. 2016;33(6):1486-96.[Crossref] [PubMed] [PMC]
- Ma Y, Pacan JC, Wang Q, Xu Y, Huang X, Korenevsky A, et al. Microencapsulation of bacteriophage felix O1 into chitosan-alginate microspheres for oral delivery. Appl Environ Microbiol. 2008;74(15):4799-805.[Crossref] [PubMed] [PMC]
- Esteban PP, Alves DR, Enright MC, Bean JE, Gaudion A, Jenkins AT, et al. Enhancement of the antimicrobial properties of bacteriophage-K via stabilization using oil-in-water nano-emulsions. Biotechnol Prog. 2014;30(4):932-44.[Crossref] [PubMed]
- Vinner GK, Rezaie-Yazdi Z, Leppänen M, Stapley aGF, Leaper MC, Malik Dj, et al. Microencapsulation of salmonella-specific bacteriophage felix O1 using spray-drying in a ph-responsive formulation and direct compression tableting of powders into a solid oral dosage form. Pharmaceuticals. 2019;12(43).[Crossref] [PubMed] [PMC]
- Furfaro LL, Payne MS, Chang BJ. Bacteriophage therapy: clinical trials and regulatory hurdles. Front Cell Infect Microbiol. 2018;23;8:376.[Crossref] [PubMed] [PMC]
- Hyman P, Abedon ST. Bacteriophage: Overview. In: Schmidt TM, ed. Encyclopedia of Microbiology. 4th ed. Oxford: Academic Press; 2019. p.441-57.
- Domingo-Calap P, Delgado-Martínez J. Bacteriophages: protagonists of a post-antibiotic era. Antibiotics (Basel). 2018;27;7(3):66.[Crossref] [PubMed] [PMC]
- Harada LK, Silva EC, Campos WF, Del Fiol FS, Vila M, Dąbrowska K, et al. Biotechnological applications of bacteriophages: State of the art. Microbiol Res. 2018;212-213:38-58.[Crossref] [PubMed]
- Gündoğdu A, Ulu-Kılıç A. [Bacteriophage therapy: an unforgetten source of cure]. Klimik Derg. 2018;31(2):78-87.[Link]
- Kakasis A, Panitsa G. Bacteriophage therapy as an alternative treatment for human infections. A comprehensive review. Int J Antimicrob Agents. 2019;53(1):16-21.[Crossref] [PubMed]
- Hawkins C, Harper D, Burch D, Anggård E, Soothill J. Topical treatment of Pseudomonas aeruginosa otitis of dogs with a bacteriophage mixture: a before/after clinical trial. Vet Microbiol. 2010;15;146(3-4):309-13.[Crossref] [PubMed]
- Merabishvili M, Pirnay JP, Vogele K, Malik DJ. Production of phage therapeutics and formulations: innovative approaches. In: Górski A, Międzybrodzki R, Borysowski J, eds. Phage Therapy: A Practical Approach. Cham: Springer International Publishing; 2019. p.3-41.[Crossref]
- Bruttin A, Brüssow H. Human volunteers receiving Escherichia coli phage T4 orally: a safety test of phage therapy. Antimicrob Agents Chemother. 2005;49(7):2874-8.[Crossref] [PubMed] [PMC]
- Abedon ST, Kuhl SJ, Blasdel BG, Kutter EM. Phage treatment of human infections. Bacteriophage. 2011;1(2):66-85.[Crossref] [PubMed] [PMC]
- García P, Martínez B, Obeso JM, Rodríguez A. Bacteriophages and their application in food safety. Lett Appl Microbiol. 2008;47(6):479-85.[Crossref] [PubMed]
- Svircev A, Roach D, Castle A. Framing the Future with bacteriophages in agriculture. Viruses. 2018;25;10(5):218.[Crossref] [PubMed] [PMC]
- Sulakvelidze A, Alavidze Z, Morris JG Jr. Bacteriophage therapy. Antimicrob Agents Chemother. 2001;45(3):649-59.[Crossref] [PubMed] [PMC]
- Gündoğdu A, Kılıç H, Ulu Kılıç A, Kutateladze M. [Susceptibilities of multidrug-resistant pathogens responsible for complicated skin and soft tissue infections to standard bacteriophage cocktails]. Mikrobiyol Bul. 2016;50(2):215-23.[Crossref] [PubMed]
- Debarbieux L, Pirnay JP, Verbeken G, De Vos D, Merabishvili M, Huys I, et al. A bacteriophage journey at the European Medicines Agency. FEMS Microbiol Lett. 2016;363(2):fnv225.[Crossref] [PubMed] [PMC]
- Loc-Carrillo C, Abedon ST. Pros and cons of phage therapy. Bacteriophage. 2011;1(2):111-4.[Crossref] [PubMed] [PMC]
- Wittebole X, De Roock S, Opal SM. A historical overview of bacteriophage therapy as an alternative to antibiotics for the treatment of bacterial pathogens. Virulence. 2014;1;5(1):226-35.[Crossref] [PubMed] [PMC]
- Jault P, Leclerc T, Jennes S, Pirnay JP, Que YA, Resch G, et al. Efficacy and tolerability of a cocktail of bacteriophages to treat burn wounds infected by Pseudomonas aeruginosa (PhagoBurn): a randomised, controlled, double-blind phase 1/2 trial. Lancet Infect Dis. 2019;19(1):35-45.[Crossref] [PubMed]
- Rhoads DD, Wolcott RD, Kuskowski MA, Wolcott BM, Ward LS, Sulakvelidze A, et al. Bacteriophage therapy of venous leg ulcers in humans: results of a phase I safety trial. J Wound Care. 2009;18(6):237-8.[Crossref] [PubMed]
- Speck P, Smithyman A. Safety and efficacy of phage therapy via the intravenous route. FEMS Microbiol Lett. 2016;363(3):fnv242.[Crossref] [PubMed]
- Schooley RT, Biswas B, Gill JJ, Hernandez-Morales A, Lancaster J, Lessor L, et al. Development and use of personalized bacteriophage-based therapeutic cocktails to treat a patient with a disseminated resistant acinetobacter baumannii infection. Antimicrob Agents Chemother. 2017;22;61(10):e00954-17.[Crossref] [PubMed] [PMC]
- Colom J, Cano-Sarabia M, Otero J, Cortés P, Maspoch D, Llagostera M, et al. Liposome-encapsulated bacteriophages for enhanced oral phage therapy against salmonella spp. Appl Environ Microbiol. 2015;81(14):4841-9.[Crossref] [PubMed] [PMC]
- Sarker SA, Sultana S, Reuteler G, Moine D, Descombes P, Charton F, et al. Oral phage therapy of acute bacterial diarrhea with two coliphage preparations: a randomized trial in children from bangladesh. EBioMedicine. 2016;5;4:124-37.[Crossref] [PubMed] [PMC]
- Markoishvili K, Tsitlanadze G, Katsarava R, Morris JG Jr, Sulakvelidze A. A novel sustained-release matrix based on biodegradable poly(ester amide)s and impregnated with bacteriophages and an antibiotic shows promise in management of infected venous stasis ulcers and other poorly healing wounds. Int J Dermatol. 2002;41(7):453-8.[Crossref] [PubMed]
- Jikia D, Chkhaidze N, Imedashvili E, Mgaloblishvili I, Tsitlanadze G, Katsarava R, et al. The use of a novel biodegradable preparation capable of the sustained release of bacteriophages and ciprofloxacin, in the complex treatment of multidrug-resistant Staphylococcus aureus-infected local radiation injuries caused by exposure to Sr90. Clin Exp Dermatol. 2005;30(1):23-6.[Crossref] [PubMed]
- Pirnay J-P, Merabishvili M, Van Raemdonck H, De Vos D, Verbeken G. Bacteriophage production in compliance with regulatory requirements. In: Azeredo J, Sillankorva S, eds. Bacteriophage Therapy: From Lab to Clinical Practice. New York, NY: Springer New York; 2018. p.233-52.[Crossref] [PubMed]
- Pirnay JP, Verbeken G, Ceyssens PJ, Huys I, De Vos D, Ameloot C, et al. The magistral phage. Viruses. 2018;6;10(2):64.[Crossref] [PubMed] [PMC]
- Phage therapy unit of the medical centre of the institute of immunology and experimental therapy PAS. (Erişim tarihi: 15.9.2019)[Link]
- Schmidt C. Phage therapy's latest makeover. Nat Biotechnol. 2019;37(6):581-6.[Crossref] [PubMed]
- Wright A, Hawkins CH, Anggård EE, Harper DR. A controlled clinical trial of a therapeutic bacteriophage preparation in chronic otitis due to antibiotic-resistant Pseudomonas aeruginosa; a preliminary report of efficacy. Clin Otolaryngol. 2009;34(4):349-57.[Crossref] [PubMed]
- Dedrick RM, Guerrero-Bustamante CA, Garlena RA, Russell DA, Ford K, Harris K, et al. Engineered bacteriophages for treatment of a patient with a disseminated drug-resistant Mycobacterium abscessus. Nat Med. 2019;25(5):730-3.[Crossref] [PubMed] [PMC]
- Cooper CJ, Koonjan S, Nilsson AS. Enhancing whole phage therapy and their derived antimicrobial enzymes through complex formulation. Pharmaceuticals (Basel). 2018;19;11(2):34.[Crossref] [PubMed] [PMC]
- McCallin S, Sacher JC, Zheng J, Chan BK. Current State of Compassionate Phage Therapy. Viruses. 2019;11(4):343.[Crossref] [PubMed] [PMC]
- Ryan EM, Gorman SP, Donnelly RF, Gilmore BF. Recent advances in bacteriophage therapy: how delivery routes, formulation, concentration and timing influence the success of phage therapy. J Pharm Pharmacol. 2011;63(10):1253-64.[Crossref] [PubMed]
- Capparelli R, Parlato M, Borriello G, Salvatore P, Iannelli D. Experimental phage therapy against Staphylococcus aureus in mice. Antimicrob Agents Chemother. 2007;51(8):2765-73.[Crossref] [PubMed] [PMC]
- Chadha P, Katare OP, Chhibber S. Liposome loaded phage cocktail: enhanced therapeutic potential in resolving Klebsiella pneumoniae mediated burn wound infections. Burns. 2017;43(7):1532-43.[Crossref] [PubMed]
- Colom J, Cano-Sarabia M, Otero J, Arí-ez-Soriano J, Cortés P, Maspoch D, et al. Microencapsulation with alginate/CaCO3: a strategy for improved phage therapy. Sci Rep. 2017;25;7:41441.[Crossref] [PubMed] [PMC]
- Vinner GK, Vladisavljević GT, Clokie MRJ, Malik DJ. Microencapsulation of Clostridium difficile specific bacteriophages using microfluidic glass capillary devices for colon delivery using pH triggered release. PLoS One. 2017;12;12(10):e0186239.[Crossref] [PubMed] [PMC]
- Abdelsattar AS, Abdelrahman F, Dawoud A, Connerton IF, El-Shibiny A. Encapsulation of E.coli phage ZCEC5 in chitosan-alginate beads as a delivery system in phage therapy. AMB Express. 2019;17;9(1):87.[Crossref] [PubMed] [PMC]
- Łobocka MB, Głowacka A, Golec P. Methods for bacteriophage preservation. In: Azeredo J, Sillankorva S, editors. Bacteriophage therapy: From lab to clinical practice. New York: Springer New York; 2018. p.219-30.[Crossref] [PubMed]
- Brown TL, Petrovski S, Hoyle D, Chan HT, Lock P, Tucci J, et al. Characterization and formulation into solid dosage forms of a novel bacteriophage lytic against Klebsiella oxytoca. PLoS One. 2017;17;12(8):e0183510.[Crossref] [PubMed] [PMC]
- Brown TL, Thomas T, Odgers J, Petrovski S, Spark MJ, Tucci J, et al. Bacteriophage formulated into a range of semisolid and solid dosage forms maintain lytic capacity against isolated cutaneous and opportunistic oral bacteria. J Pharm Pharmacol. 2017;69(3):244-53.[Crossref] [PubMed]
- Bean JE, Alves DR, Laabei M, Esteban PP, Thet NT, Enright MC, et al. Triggered release of bacteriophage K from agarose/hyaluronan hydrogel matrixes by staphylococcus aureus virulence factors. Chem Mater. 2014;26(24):7201-8.[Crossref]
- Hathaway H, Alves DR, Bean J, Esteban PP, Ouadi K, Sutton JM, et al. Poly(N-isopropylacrylamide-co-allylamine) (PNIPAM-co-ALA) nanospheres for the thermally triggered release of Bacteriophage K. Eur J Pharm Biopharm. 2015;96:437-41.[Crossref] [PubMed]
- Abdulamir AS, Jassim SA, Abu Bakar F. Novel approach of using a cocktail of designed bacteriophages against gut pathogenic E. coli for bacterial load biocontrol. Ann Clin Microbiol Antimicrob. 2014;26;13:39.[Crossref] [PubMed] [PMC]
- Dai M, Senecal A, Nugen SR. Electrospun water-soluble polymer nanofibers for the dehydration and storage of sensitive reagents. Nanotechnology. 2014;6;25(22):225101.[Crossref] [PubMed]
- Salalha W, Kuhn J, Dror Y, Zussman E. Encapsulation of bacteria and viruses in electrospun nanofibres. Nanotechnology. 2006;28;17(18):4675-81.[Crossref] [PubMed]
- Kim S, Jo A, Ahn J. Application of chitosan-alginate microspheres for the sustained release of bacteriophage in simulated gastrointestinal conditions. Int J Food Sci Technol. 2015;50(4):913-8.[Crossref]
- Kaikabo AA, AbdulKarim SM, Abas F. Evaluation of the efficacy of chitosan nanoparticles loaded ΦKAZ14 bacteriophage in the biological control of colibacillosis in chickens. Poult Sci. 2017;1;96(2):295-302.[Crossref] [PubMed] [PMC]
- Tang Z, Huang X, Sabour PM, Chambers JR, Wang Q. Preparation and characterization of dry powder bacteriophage K for intestinal delivery through oral administration. LWT - Food Science and Technology. 2015;60(1):263-70.[Crossref]
- Dini C, Islan GA, Castro GR. Characterization and stability analysis of biopolymeric matrices designed for phage-controlled release. Appl Biochem Biotechnol. 2014;174(6):2031-47.[Crossref] [PubMed]
- Şenel S. Current status and future of chitosan in drug and vaccine delivery. React Funct Polym. 2020;147:104452.[Crossref]
- Vinner GK, Richards K, Leppanen M, Sagona AP, Malik DJ. Microencapsulation of enteric bacteriophages in a ph-responsive solid oral dosage formulation using a scalable membrane emulsification process. Pharmaceutics. 2019;14;11(9):475.[Crossref] [PubMed] [PMC]
- Hoffman AS. Hydrogels for biomedical applications. Adv Drug Deliv Rev. 2012;64:18-23.[Crossref]
- Brown TL, Petrovski S, Dyson ZA, Seviour R, Tucci J. The formulation of bacteriophage in a semi solid preparation for control of propionibacterium acnes growth. PLoS One. 2016;10;11(3):e0151184.[Crossref] [PubMed] [PMC]
- Shakeel F, Ramadan W, Faisal MS, Rizwan M, Faiyazuddin M, Mustafa G, et al. Transdermal and topical delivery of anti-inflammatory agents using nanoemulsion/ microemulsion: an updated review. Curr Nanosci. 2010;6(2):184-98.[Crossref]
- Torchilin VP. Recent advances with liposomes as pharmaceutical carriers. Nat Rev Drug Discov. 2005;4(2):145-60.[Crossref] [PubMed]
- Jaiswal M, Dudhe R, Sharma PK. Nanoemulsion: an advanced mode of drug delivery system. 3 Biotech. 2015;5(2):123-7.[Crossref] [PubMed] [PMC]
- Cinquerrui S, Mancuso F, Vladisavljević GT, Bakker SE, Malik DJ. Nanoencapsulation of bacteriophages in liposomes prepared using microfluidic hydrodynamic flow focusing. Front Microbiol. 2018;12;9:2172.[Crossref] [PubMed] [PMC]
- Pattni BS, Chupin VV, Torchilin VP. New developments in liposomal drug delivery. Chem Rev. 2015;14;115(19):10938-66.[Crossref] [PubMed]
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