Bacteriophage therapy as an alternative technique for treatment of multidrug-resistant bacteria causing diabetic foot infection

International Microbiology - Tập 26 - Trang 343-359 - 2022
Amira Mohamed Ghanaim1, Mohammed Abdulaziz Foaad1, Eman Zakaria Gomaa1, Khalid Abdelfatah El Dougdoug2, Gamal Eldidamony Mohamed3, Ahmed Hamed Arisha4, Tarek Khamis5
1Department of Biological and Geological Sciences, Faculty of Education, Ain Shams University, Cairo, Egypt
2Department of Microbiology, Faculty of Agriculture, Ain Shams University, Cairo, Egypt
3Department of Microbiology, Faculty of Science, Zagazig University, Zagazig, Egypt
4Department of Physiology, Faculty of Veterinary Medicine, Zagazig University, Zagazig, Egypt
5Department of Pharmacology, Faculty of Veterinary Medicine, Zagazig University, Zagazig, Egypt

Tóm tắt

Diabetic foot ulcer (DFU) represented the most feared diabetic complication that caused the hospitalization of the diabetic patient. DFU was usually characterized with delayed healing as the diabetic neuropathy, angiopathy, and ulcer concomitant infections, among them, are multidrug-resistant (MDR) bacteria that emphasized the clinical importance for developing new therapeutic strategy with safe and effective alternatives for the antibiotics to overcome DFU-MDR bacterial infection. Bacteriophage therapy was considered a novel approach to eradicate the MDR, but its role in the polymicrobial infection of the DFU remains elusive. Thus, the current work was designed to investigate the effect of the topical application of the phage cocktail on the healing of the diabetic wound infected with clinical isolates of Staphylococcus aureus, Pseudomonas aeruginosa, Klebsiella variicola, Escherichia coli, and Proteus mirabilis. Bacterial isolation was performed from clinical hospitalized and non-hospitalized cases of DFU, identified morphologically, biochemically, molecularly via 16 s rRNA sequencing, and typed for the antibiotic resistance pattern. Moreover, phages were isolated from the aforementioned clinical isolates and identified with electron microscope. Forty-five adult male Sprague–Dawley rats were assigned in 3 groups (15 rats each), namely, the diabetic infected wound group, diabetic infected wound ceftriaxone-treated group, and the diabetic infected wound phage cocktail-treated group. The results revealed that phage cocktail had a superior effect over the ceftriaxone in wound healing parameters (wound size, wound index, wound bacterial load, and mRNA expression); wound healing markers (Cola1a, Fn1, MMP9, PCNA, and TGF-β); inflammatory markers (TNF-α, NF-κβ, IL-1β, IL-8, and MCP-1); anti-inflammatory markers (IL-10 and IL-4); and diabetic wound collagen deposition; and also the histomorphic picture of the diabetic infected wound. Based on the current findings, it could be speculated that phage therapy could be considered a novel antibiotic substitute in the DFU with MDR-polymicrobial infection therapeutic strategies.

Tài liệu tham khảo

Abbas M, Uc KI, Lipsky BA (2015) In diabetic foot infections antibiotics are to treat infection, not to heal wounds. Exper Opin Pharmaco 16(6):821–832 Adams MH (1959) Bacteriophages interscience Publishers Inc. N Y 74:164 Akhi MT, Shirinzadeh M, Ghotaslou R, Sorous MH, Pirzadeh T, Behzad MN (2013) Determination of antibiotic sensitivity of Bacteroid fragilis isolated from patients and healthy individuals in Imam Reza Center of Medical Teaching and Treatment Tabriz. Jund J Microbiol 6(9):1–5 Altschul SF, Gish W, Miller W, Myers EW, Lipmanl DJ (1990) Basic local alignment search tool. J Mol Biol 215:403–410 Angela VH, Rangel G, Clavijo V, Prada C, Mantilla M, Gomez MC, Kutter E, Taylor C, Fineran PC, Barrios AFG, Vives MJ (2015) Phage _Pan70, a putative temperate phage, controls Pseudomonas aeruginosa in planktonic, biofilm and burn mouse model assays. Viruses 7(8):4602–4623 Bancroft, JD Layton C (2019) Bancroft’s theory and practice of histological techniques E-Book. In: Kim Suvarna S, Layton C, Bancroft JD (eds) Elsevier Health Sciences, pp 126–137 Bauer A, Kirby W, Sherris J, Turck M (1966) Antibiotic susceptibility testing by a standardization single disk method. Am J Clin Pathol 45:493–496 Berlina AN, Zherdey AV, Dzantiev BB (2020) Monitoring antibiotics and inflammatory markers in human blood: impact in choice of antibiotic therapy and used methods. Biomed Pharm J 13(3):1–12 Bolocan AS, Callanan J, Forde A, Ross P, Hill C (2016) Phage therapy targeting Escherichia coli a story with no end? FEMS Microbiol Lett 3639(22):1–5 Bradley DE (1967) Ultrastructure of bacteriophage and bacteriocins. Bacteriol Rev 31(4):230–314 Butler MS, Blaskovich MAT, Cooper MA (2017) Antibiotics in the clinical pipeline at the end of 2015. J Antibiotic 70(1):3–24 Castillo DE, Nanda S, Keri JE (2019) Propionibacterium (Cutibacterium) acnes bacteriophage therapy in acne: current evidence and future perspectives. Dermatol Therapy 9(1):19–31 Centers for Disease Control and Prevention (CDC) (2013) National diabetes fact. Estimates of diabetes and its burden in the united states Cha K, Oh HK, Jang JY, Jo Y, Kim WK, Ha GU, Ko KS, Myung H (2018) Characterization of two novel bacteriophages infecting multidrug-resistant (MDR) Acinetobacter baumannii and evaluation of their therapeutic efficacy in vivo. Front Microbiol 9:696–608 Cha Y, Chun J, Son B, Ryu S (2019) Characterization and genome analysis of Staphylococcus aureus Podovirus CSA13 and its anti-biofilm capacity. Viruses 11(1):54–68 Chhibber S, Kaur T, Kaur S (2013) Co-therapy using lytic bacteriophage and linezolid: effective treatment in eliminating methicillin resistant Staphylococcus aureus (MRSA) from diabetic foot infections. PLoS ONE 8(2):1–11 Chhibber S, Kaur J, Kaur S (2018) Liposome entrapment of bacteriophages improves wound healing in a diabetic mouse MRSA infection. Front Microbiol 9:561–573 Citron DM, Goldstein EJ, Merriam CV, Lipsky BA, Abramson MA (2007) Bacteriology of moderate-to-severe diabetic foot infections and in vitro activity of antimicrobial agents. J Clin Microbiol 45(9):2819–2828 Dhar B, Singh B, Singh R, Singh R, SinghV SJ (1978) Isolation of a virus (RL1) infective on Rhizobium leguminosurum. Arch Microbiol 119(3):263–267 Domingo-Calap P, Beamud B, González-Candelas LMF, Sanjuán R (2020) Isolation and characterization of two Klebsiella pneumoniae phages encoding divergent depolymerases. Int J Mol Sci 21(9):3160–3175 El-Telbany M, El-Didamony G, Askora A, Ariny E, Abdallah D, Connerton F, El-Shibiny A (2021) Bacteriophages to control multi-drug resistant Enterococcus faecalis infect Dent Root Canal. Microorgan 9(3):517–532 Fabijan AP, Lin RC, Ho J, Maddocks S, Zakour NLB, Iredell JR (2020) Safety of bacteriophage therapy in severe Staphylococcus aureus infection. Nat Microbiol 5(3):465–472 Funke G, Monnet D, Bernardis C, Graevenitz A, Freney J (1998) Evaluation of the VITEK2 system for rapid identification of medically relevant Gram–negative rods. J Clin Microbiol 36(7):1948–1952 Garbe J, Bunk B, Rohde M, Schobert M (2011) Sequencing and characterization of Pseudomonas aeruginosa phage JG004. BMC Microbiol 11(1):102–114 Guo Y, Chen P, Wang LZ, T, (2019) Characterization of two Pseudomonas aeruginosa viruses vB_PaeM_SCUT-S1 and vB_PaeM_SCUT-S2. Viruses 11(4):318–377 Hesse S, Rajaure M, Wall E, Johnson J, Bliskovsky V, Gottesman S, Adhyaa S (2020) Phage resistance in multidrug-resistant Klebsiella pneumonia ST258 evolves via diverse mutations that culminate in impaired adsorption. Mbio 11(1):1–14 Khamis T, Abdelalim AF, Abdallah SH, Saeed AA, Edress NM, Arisha AH (2020) Early intervention with breast milk mesenchymal stem cells attenuates the development of diabetic-induced testicular dysfunction via hypothalamic Kisspeptin/Kiss1r-GnRH/GnIH system in male rats. Biochim Biophys Acta (BBA) Mol Basis Dis 1866(1):165577 Kifelew LG, Warner MS, Morales S, Vaughan L, Woodman R, Fitridge R, Mitchell JG, Speck P (2020) Efficacy of phage cocktail AB-SA01 therapy in diabetic mouse wound infections caused by multidrug-resistant Staphylococcus aureus. BMC Microbiol 20(1):1–10 King AJ (2012) The use of animal models in diabetes research. Brit J Pharmacol 166(3):877–894 Kolanjiappan K, Manoharan S, Kayalvizhi M (2002) Measurement of erythrocyte lipids, lipid peroxidation, antioxidants and osmotic fragility in cervical cancer patients. Clin Chim Acta 326(1–2):143–149 Krumperman PH (1983) Multiple antibiotic resistance indexing Escherichia coli to identify risk sources of faecal contamination of foods. Appl Environ Microbiol 46:165–170 Kumari S, Harjaim K, Chhibber S (2010) Evidence to support the therapeutic potential of bacteriophage Kpn5 in burn wound infection caused by Klebsiella pneumoniae in BALB/c mice. J Microbiol Biotechnol 20(5):935–941 Loots MA, Lamme EN, Zeegelaar J, Mekkes JR, Bos JD, Middelkoop E (1998) Differences in cellular infiltrate and extracellular matrix of chronic diabetic and venous ulcers versus acute wounds. J Invest Dermatol 111(5):850–857 Luís DR, Veiga P, Cerca N, Kropinski AM, Almeida C, Azeredo J, Sillankorva S (2016) Development of a phage cocktail to control Proteus mirabilis catheter-associated urinary tract infections. Front Microbiol 7:1024–1036 Maciejewska B, Olszak T, Drulis-Kawa Z (2018) Applications of bacteriophages versus phage enzymes to combat and cure bacterial infections: an ambitious and also a realistic application. Appl Microbiol Biotechnol 102(6):2563–2581 Mahgoub EM, Elfatih M, Omer A (2015) Aerobic bacteria isolated from diabetic septic wounds. Am J Res Comm 3(10):1–14 Mahreen R, Mohsin M, Nashreen Z, Siraj M, Ishaq M (2010) Significantly increased levels of serum malondialdehyde in type 2 diabetics with myocardial infarction. Int J Diabet Develop Count 30(1):49–51 Malone M, Gosbell IB, Dickson HG, Vickery K, Espedido BA, Jensen SO (2017) Can molecular DNA-based techniques unravel the truth about diabetic foot infection?. Diabetes/metabolism Res Rev 33(1):1–7 Manoharan S, Kolanjiappan K, Suresh K, Panjamurthy K (2005) Lipid peroxidation and antioxidants status in patients with oral squamous cell carcinoma. Ind J Med Res 122(6):529–534 Mignon F, Piagnerelli M, van Nuffelen M, Vincent JL (2014) Effect of empiric antibiotic treatment on plasma endotoxin activity in septic patients. Infection 42(3):521–528 Miyan Z, Fawwad A, Sabir R, Basit A (2017) Microbiological pattern of diabetic foot infections at a tertiary care center in a developing country. Age Year 53:10–20 Molehin OR, Oloyede OI (2019) Attenuation of oxidative stress and hepatic damage by white butterfly (Clerodendrum volubile) leaves in streptozotocin-induced diabetes in rats. J Basic Clin Physiol Pharmacol 30(1):81–89 Muhammad AA, Arulselvan P, Cheah PS, Abas F, Fakurazi S (2016) Evaluation of wound healing properties of bioactive aqueous fraction from Moringa oleifera Lam on experimentally induced diabetic animal model. Drug Design Develop Ther 10:1715–1730 Nagini S, Saroja M (2001) Circulating lipid peroxides and antioxidants as biomarkers of tumor burden in patients with oral squamous cell carcinoma. Int J Biochem Biophys Mol Biol 5:55–59 Necel A, Bloch A, Nejman-Faleńczyk S, Grabski B, Topka M, Dydecka G, Kosznik-Kwaśnicka K, Grabowski Ł, Jurczak-Kurek A, Wołkowicz T, Węgrzyn G, Węgrzyn A (2020) Characterization of a bacteriophage, vB_Eco4M-7, that effectively infects many Escherichia coli O157 strains. Scientific Report 10(1):3743–3757 Noor S, Zubair M, Ahmad J (2015) Diabetic foot ulcer – a review on pathophysiology, classification and microbial etiology. Diab Metab Syndr 9:192–199 Pallavali RR, Degati VL, Lomada D, Reddy MC, Durbaka VRP (2017) Isolation and in vitro evaluation of bacteriophages against MDR-bacterial isolates from septic wound infections. PLoS ONE 12(7):1–16 Pan YJ, Lin TL, Chen CC, Tsai YT, Cheng YH, Chen YY, Hsieh PF, Lin YT, Wang JT (2017) Klebsiella phage ΦK64-1 encodes multiple depolymerases for multiple host capsular types. J Virol 91(6):1–16 Park S, Rich J, Hanses F, Lee JC (2009) Defects in innate immunity predispose C57BL/6J-Leprdb/Leprdb mice to infection by Staphylococcus aureus. Inf Immun 77(3):1008–1014 Philipson L, Albertson P, Frick G (1960) Purification and concentration of virus by aqueous polymer phase system. Virol 11(3):553–571 Pincus NB, Reckhow JD, Saleem D, Jammeh ML, Datta SK, Myles IA (2015) Strain specific phage treatment for Staphylococcus aureus infection is influenced by host immunity and site of infection. PLoS ONE 10(4):1–16 Pollack RM, Donath MY, LeRoith D, Leibowitz G (2016) Anti-inflammatory agents in the treatment of diabetes and its vascular complications. Diabet Care 39(2):S244–S252 Pondei K, Fente BG, Oladapo O (2013) Current microbial isolates from wound swabs, their culture and sensitivity pattern at the Niger Delta University Teaching Hospital, Okolobiri. Nigeria Trop Med Health 41(2):49–53 Rani PR, Degati D, Lakshmi DV, Vijaya D, Prasad R (2019) Lytic bacteriophages and phage cocktails seems to be a future alternative against multi-drug resistant bacterial infections. Preprint 2019:1–64 Roach DR, Debarbieux L (2017) Phage therapy: awakening a sleeping giant. Emerg Top Life Sci 1(1):93–103 Saltoglua N, Ergonulb O, Tulekc N, Yemisena M, Kadanalid A, Karagozd G, Batirele A et al (2018) Influence of multidrug resistant organisms on the outcome of diabetic foot infection. Int J Infec Dis 70:10–14 Sanchez CJ, Mende K, Beckius ML, Akers KS, Romano DR, Wenke JC, Murray C (2013) Biofilm formation by clinical isolates and the implications in chronic infections. BMC Infect Dis 13(1):1–12 Schmittgen TD, Livak KJ (2008) Analyzing real-time PCR data by the comparative CT method. Nat Protocol 3(6):1101–1108 Shang A, Liu Y, Wang J, Mo Z, Li G, Mou H (2015) Complete nucleotide sequence of Klebsiella phage P13 and prediction of an EPS depolymerase gene. Virus Genes 50(1):118–128 Shanmugam P, Jeya M, Linda SS (2013) The bacteriology of diabetic foot ulcers, with a special reference to multidrug resistant strains. J Clin Diagn Res 7(3):441–445 Shi Y, Shu B, Yang R, Xu Y, Xing B, Liu J, Wang P, Tang J, Xie J (2015) Wnt and Notch signaling pathway involved in wound healing by targeting separately c-Myc and Hes1. Stem Cell Res Therapy 6(1):1–13 Shigehisa R, Uchiyama J, Kato SI, Takemura-Uchiyama I, Yamaguchi K, Miyata R, Ujihara T, Sakaguchi Y, Okamoto N, Shimakura H, Daibata M, Sakaguchi M, Matsuzaki S (2016) Characterization of Pseudomonas aeruginosa phage KPP21 belonging to family Podoviridae genus N4-like viruses isolated in Japan. Microbiol Immunol 60(1):64–67 Solarek W, Koper M, Lewicki S, Szczylik C, Czarnecka AM (2019) Insulin and insulin-like growth factors act as renal cell cancer intratumoral regulators. J Cell Comm Signal 13(3):381–394 Son JS, Lee SJ, Jun SY, Yoon SJ, Kang SH, Paik HR, Kang JO, Choi YJ (2010) Antibacterial and biofilm removal activity of a podoviridae Staphylococcus aureus bacteriophage SAP-2 and a derived recombinant cell-wall-degrading enzyme. Appl Microbiol Biotechnol 86(5):1439–1449 Soothill JS (1992) Treatment of experimental infections of mice with bacteriophages. J Med Microbiol 37(4):258–261 Speck P, Smithyman A (2016) Safety and efficacy of phage therapy via the intravenous route. FEMS Microbiol Lett 363(3):1–5 Spichler A, Hurwitz B, David GA, Lipsky BA (2015) Microbiology of diabetic foot infections: from Louis Pasteur to ‘crime scene investigation.’ BMC Med 13(1):1–13 Sulakvelidze A, Alavidze Z, Morris JG (2001) Bacteriophage therapy. Antimicrob Agents Chemother 45(3):649–659 Suvik A, Effendy AWM (2012) The use of modified Masson’s trichrome staining in collagen evaluation in wound healing study. Mal J Vet Res 3(1):39–47 Sweere JM, Van Belleghem JD, Ishak H, Bach MS, Popescu M, Sunkari V, Kaber G, Manasherob R, Suh GA, Cao X (2019) Bacteriophage trigger antiviral immunity and prevent clearance of bacterial infection. Sci 363(6434):1–13 Teng T, Li Q, Liu Z, Li X, Liu Z, Liu H, Liu F, Xie L, Wang H, Zhang L, Wu D, Chen M, Li Y, Ji A (2019) Characterization and genome analysis of novel Klebsiella phage Henu1 with lytic activity against clinical strains of Klebsiella pneumoniae. Arch Virol 164(9):2389–2393 Van Belleghem JD, Clement F, Merabishvili M, Lavigne R, Vaneechoutte M (2017) Pro-and anti-inflammatory responses of peripheral blood mononuclear cells induced by Staphylococcus aureus and Pseudomonas aeruginosa phages. Sci Report 7(1):1–13 Xavier W, Sukumaran MT, Varma AK, Kumar H, Chellan G (2014) Emergence of multi drug resistant bacteria in diabetic patients with lower limb wounds. Ind J Med Res 140(3):435–437 Zakaria AS, Afifi SA, Elkhodairy KA (2016) Newly developed topical cefotaxime sodium hydrogels: antibacterial activity and in vivo evaluation. BioMed Res Int 2016:1–16 Zaman SB, Hussain MA, Nye R, Mehta V, Mamun KT, Hossain N (2017) A review on antibiotic resistance: alarm bells are ringing. Cureus 9(6):1–9 Zhang M, Jiang Z, Li D, Jiang D, Wu Y, Ren H, Peng H, Lai Y (2014) Oral antibiotic treatment induces skin microbiota dysbiosis and influences wound healing. Micro Ecol 69(2):415–421 Zhang Z, Jiang D, Wang C, Garzotto M, Kopp R, Wilmot B, Thuillier P, Dang A, Palma A, Farris PE, Shannon J (2019) Polymorphisms in oxidative stress pathway genes and prostate cancer risk. Cancer Causes Cont 30(12):1365–1375