An Enzybiotic Regimen for the Treatment of Methicillin-Resistant Staphylococcus aureus Orthopaedic Device-Related Infection
Abstract
:1. Introduction
2. Materials and Methods
2.1. Bacterial Strains
2.2. Production and Purification of Enzybiotics
2.3. Cytotoxicity and Endotoxin Evaluation
2.4. In Vitro Evaluations
2.4.1. Planktonic Cell Assays
2.4.2. Peg Biofilm Assays
2.4.3. Titanium Device Biofilm Model
2.4.4. In Vitro SAC Model
2.4.5. Scanning Electron Microscopy
2.5. In Vivo Observations
2.5.1. Murine Model of Fracture-Related Infection
2.5.2. Computed Tomography
2.5.3. Histology
2.6. Statistics
3. Results
3.1. Purified Enzybiotics Demonstrate Rapid Bacterial Killing as Well as Antibiofilm Activity
3.2. Addition of the DA7 Polysaccharide Depolymerase and Antibiotics Enhances Antibiofilm Activity
3.3. Enzybiotics Are Highly Effective at Targeting Staphylococcal Abscess Communities In Vitro
3.4. Enzybiotics Are Effective at Treating ODRI In Vivo
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
- Moriarty, T.F.; Kuehl, R.; Coenye, T.; Metsemakers, W.J.; Morgenstern, M.; Schwarz, E.M.; Riool, M.; Zaat, S.A.J.; Khana, N.; Kates, S.L.; et al. Orthopaedic device-related infection: Current and future interventions for improved prevention and treatment. EFORT Open Rev. 2016, 1, 89–99. [Google Scholar] [CrossRef]
- Papakostidis, C.; Kanakaris, N.K.; Pretel, J.; Faour, O.; Morell, D.J.; Giannoudis, P.V. Prevalence of complications of open tibial shaft fractures stratified as per the Gustilo-Anderson classification. Injury 2011, 42, 1408–1415. [Google Scholar] [CrossRef]
- Metsemakers, W.-J.; Morgenstern, M.; Senneville, E.; Borens, O.; Govaert, G.A.M.; Onsea, J.; Depypere, M.; Richards, R.G.; Trampuz, A.; Verhofstad, M.H.J.; et al. General treatment principles for fracture-related infection: Recommendations from an international expert group. Arch. Orthop. Trauma Surg. 2019, 140, 1013–1027. [Google Scholar] [CrossRef] [Green Version]
- Czaja, S.A.; Rivara, P.F.; Wang, B.J.; Koepsell, J.T.; Nathens, J.A.; Jurkovich, J.G.; Mackenzie, J.E. Late Outcomes of Trauma Patients with Infections during Index Hospitalization. J. Trauma Inj. Infect. Crit. Care 2009, 67, 805–814. [Google Scholar] [CrossRef]
- Metsemakers, W.-J.; Smeets, B.; Nijs, S.; Hoekstra, H. Infection after fracture fixation of the tibia: Analysis of healthcare utilization and related costs. Injury 2017, 48, 1204–1210. [Google Scholar] [CrossRef]
- Steinmetz, S.; Wernly, D.; Moerenhout, K.; Trampuz, A.; Borens, O. Infection after fracture fixation. EFORT Open Rev. 2019, 4, 468–475. [Google Scholar] [CrossRef] [PubMed]
- Ovaska, M.T.; Makinen, T.J.; Madanat, R.; Vahlberg, T.; Hirvensalo, E.; Lindahl, J. Predictors of poor outcomes following deep infection after internal fixation of ankle fractures. Injury 2013, 44, 1002–1006. [Google Scholar] [CrossRef]
- Rittmann, W.W.; Perren, S.M. Cortical Bone Healing after Internal Fixation and Infection: Biomechanics and Biology; Springer: Berlin/Heidelberg, Germany, 1975. [Google Scholar]
- Kuiper, J.W.; Vos, S.J.; Saouti, R.; Vergroesen, D.A.; Graat, H.C.; Debets-Ossenkopp, Y.J.; Peters, E.J.; Nolte, P.A. Prosthetic joint-associated infections treated with DAIR (debridement, antibiotics, irrigation, and retention): Analysis of risk factors and local antibiotic carriers in 91 patients. Acta Orthop. 2013, 84, 380–386. [Google Scholar] [CrossRef] [Green Version]
- Sukeik, M.; Patel, S.; Haddad, F.S. Aggressive early debridement for treatment of acutely infected cemented total hip arthroplasty. Clin. Orthop. Relat. Res. 2012, 470, 3164–3170. [Google Scholar] [CrossRef] [Green Version]
- Osmon, D.R.; Berbari, E.F.; Berendt, A.R.; Lew, D.; Zimmerli, W.; Steckelberg, J.M.; Rao, N.; Hanssen, A.; Wilson, W.R.; Infectious Diseases Society of, A. Diagnosis and management of prosthetic joint infection: Clinical practice guidelines by the Infectious Diseases Society of America. Clin. Infect. Dis. 2013, 56, e1–e25. [Google Scholar] [CrossRef] [Green Version]
- Holmberg, A.; Thorhallsdottir, V.G.; Robertsson, O.; W-Dahl, A.; Stefansdottir, A. 75% success rate after open debridement, exchange of tibial insert, and antibiotics in knee prosthetic joint infections. Acta Orthop. 2015, 86, 457–462. [Google Scholar] [CrossRef]
- Tsang, S.J.; Ting, J.; Simpson, A.; Gaston, P. Outcomes following debridement, antibiotics and implant retention in the management of periprosthetic infections of the hip: A review of cohort studies. Bone Jt. J. 2017, 99-B, 1458–1466. [Google Scholar] [CrossRef]
- Campoccia, D.; Montanaro, L.; Arciola, C.R. The significance of infection related to orthopedic devices and issues of antibiotic resistance. Biomaterials 2006, 27, 2331–2339. [Google Scholar] [CrossRef] [PubMed]
- Arciola, C.R.; An, Y.H.; Campoccia, D.; Donati, M.E.; Montanaro, L. Etiology of implant orthopedic infections: A survey on 1027 clinical isolates. Int. J. Artif. Organs 2005, 28, 1091–1100. [Google Scholar] [CrossRef] [PubMed]
- Masters, E.A.; Trombetta, R.P.; de Mesy Bentley, K.L.; Boyce, B.F.; Gill, A.L.; Gill, S.R.; Nishitani, K.; Ishikawa, M.; Morita, Y.; Ito, H.; et al. Evolving concepts in bone infection: Redefining “biofilm”, “acute vs. chronic osteomyelitis”, “the immune proteome” and “local antibiotic therapy”. Bone Res. 2019, 7, 20. [Google Scholar] [CrossRef] [Green Version]
- Costerton, J.W.; Post, J.C.; Ehrlich, G.D.; Hu, F.Z.; Kreft, R.; Nistico, L.; Kathju, S.; Stoodley, P.; Hall-Stoodley, L.; Maale, G.; et al. New methods for the detection of orthopedic and other biofilm infections. FEMS Immunol. Med. Microbiol. 2011, 61, 133–140. [Google Scholar] [CrossRef]
- Blanchette, K.A.; Wenke, J.C. Current therapies in treatment and prevention of fracture wound biofilms: Why a multifaceted approach is essential for resolving persistent infections. J. Bone Jt. Infect. 2018, 3, 50–67. [Google Scholar] [CrossRef] [Green Version]
- Flemming, H.C.; Wingender, J. The biofilm matrix. Nat. Rev. Microbiol. 2010, 8, 623–633. [Google Scholar] [CrossRef]
- Bryers, J.D. Medical biofilms. Biotechnol. Bioeng. 2008, 100, 1–18. [Google Scholar] [CrossRef]
- Veeh, R.H.; Shirtliff, M.E.; Petik, J.R.; Flood, J.A.; Davis, C.C.; Seymour, J.L.; Hansmann, M.A.; Kerr, K.M.; Pasmore, M.E.; Costerton, J.W. Detection of Staphylococcus aureus biofilm on tampons and menses components. J. Infect. Dis. 2003, 188, 519–530. [Google Scholar] [CrossRef] [Green Version]
- Post, J.C.; Preston, R.A.; Aul, J.J.; Larkins-Pettigrew, M.; Rydquist-White, J.; Anderson, K.W.; Wadowsky, R.M.; Reagan, D.R.; Walker, E.S.; Kingsley, L.A.; et al. Molecular analysis of bacterial pathogens in otitis media with effusion. JAMA 1995, 273, 1598–1604. [Google Scholar] [CrossRef]
- Lewis, K. Multidrug tolerance of biofilms and persister cells. Curr. Top. Microbiol. Immunol. 2008, 322, 107–131. [Google Scholar] [CrossRef]
- Brown, M.R.; Allison, D.G.; Gilbert, P. Resistance of bacterial biofilms to antibiotics: A growth-rate related effect? J. Antimicrob. Chemother. 1988, 22, 777–780. [Google Scholar] [CrossRef]
- Lechner, S.; Lewis, K.; Bertram, R. Staphylococcus aureus persisters tolerant to bactericidal antibiotics. J. Mol. Microbiol. Biotechnol. 2012, 22, 235–244. [Google Scholar] [CrossRef] [Green Version]
- Lewis, K. Persister cells. Annu. Rev. Microbiol. 2010, 64, 357–372. [Google Scholar] [CrossRef]
- Brandt, S.L.; Putnam, N.E.; Cassat, J.E.; Serezani, C.H. Innate Immunity to Staphylococcus aureus: Evolving Paradigms in Soft Tissue and Invasive Infections. J. Immunol. 2018, 200, 3871–3880. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Farnsworth, C.W.; Schott, E.M.; Jensen, S.E.; Zukoski, J.; Benvie, A.M.; Refaai, M.A.; Kates, S.L.; Schwarz, E.M.; Zuscik, M.J.; Gill, S.R.; et al. Adaptive Upregulation of Clumping Factor A (ClfA) by Staphylococcus aureus in the Obese, Type 2 Diabetic Host Mediates Increased Virulence. Infect. Immun. 2017, 85, e01005-16. [Google Scholar] [CrossRef] [Green Version]
- Cheng, A.G.; DeDent, A.C.; Schneewind, O.; Missiakas, D. A play in four acts: Staphylococcus aureus abscess formation. Trends Microbiol. 2011, 19, 225–232. [Google Scholar] [CrossRef] [Green Version]
- Cheng, A.G.; McAdow, M.; Kim, H.K.; Bae, T.; Missiakas, D.M.; Schneewind, O. Contribution of coagulases towards Staphylococcus aureus disease and protective immunity. PLoS Pathog. 2010, 6, e1001036. [Google Scholar] [CrossRef] [Green Version]
- Thomer, L.; Schneewind, O.; Missiakas, D. Pathogenesis of Staphylococcus aureus Bloodstream Infections. Annu. Rev. Pathol. 2016, 11, 343–364. [Google Scholar] [CrossRef] [Green Version]
- Hofstee, M.I.; Riool, M.; Terjajevs, I.; Thompson, K.; Stoddart, M.J.; Richards, R.G.; Zaat, S.A.J.; Moriarty, T.F. Three-Dimensional In Vitro Staphylococcus aureus Abscess Communities Display Antibiotic Tolerance and Protection from Neutrophil Clearance. Infect. Immun. 2020, 88, e00293-20. [Google Scholar] [CrossRef]
- Kobayashi, S.D.; Malachowa, N.; DeLeo, F.R. Pathogenesis of Staphylococcus aureus abscesses. Am. J. Pathol. 2015, 185, 1518–1527. [Google Scholar] [CrossRef] [Green Version]
- Schmelcher, M.; Donovan, D.M.; Loessner, M.J. Bacteriophage endolysins as novel antimicrobials. Future Microbiol. 2012, 7, 1147–1171. [Google Scholar] [CrossRef] [Green Version]
- Fischetti, V.A. Bacteriophage endolysins: A novel anti-infective to control Gram-positive pathogens. Int. J. Med. Microbiol. 2010, 300, 357–362. [Google Scholar] [CrossRef] [Green Version]
- Lopetuso, L.R.; Giorgio, M.E.; Saviano, A.; Scaldaferri, F.; Gasbarrini, A.; Cammarota, G. Bacteriocins and Bacteriophages: Therapeutic Weapons for Gastrointestinal Diseases? Int. J. Mol. Sci. 2019, 20, 183. [Google Scholar] [CrossRef] [Green Version]
- Schindler, C.A.; Schuhardt, V.T. Lysostaphin: A New Bacteriolytic Agent for the Staphylococcus. Proc. Natl. Acad. Sci. USA 1964, 51, 414–421. [Google Scholar] [CrossRef] [Green Version]
- Bastos, M.D.; Coutinho, B.G.; Coelho, M.L. Lysostaphin: A Staphylococcal Bacteriolysin with Potential Clinical Applications. Pharmaceuticals 2010, 3, 1139–1161. [Google Scholar] [CrossRef] [Green Version]
- Nelson, D.C.; Schmelcher, M.; Rodriguez-Rubio, L.; Klumpp, J.; Pritchard, D.G.; Dong, S.; Donovan, D.M. Endolysins as antimicrobials. Adv. Virus Res. 2012, 83, 299–365. [Google Scholar] [CrossRef] [Green Version]
- Cha, Y.; Son, B.; Ryu, S. Effective removal of staphylococcal biofilms on various food contact surfaces by Staphylococcus aureus phage endolysin LysCSA13. Food Microbiol. 2019, 84, 103245. [Google Scholar] [CrossRef]
- Gutierrez, D.; Ruas-Madiedo, P.; Martinez, B.; Rodriguez, A.; Garcia, P. Effective removal of staphylococcal biofilms by the endolysin LysH5. PLoS ONE 2014, 9, e107307. [Google Scholar] [CrossRef] [Green Version]
- Pennone, V.; Sanz-Gaitero, M.; O’Connor, P.; Coffey, A.; Jordan, K.; van Raaij, M.J.; McAuliffe, O. Inhibition of L. monocytogenes Biofilm Formation by the Amidase Domain of the Phage vB_LmoS_293 Endolysin. Viruses 2019, 11, 722. [Google Scholar] [CrossRef] [Green Version]
- Olsen, N.M.C.; Thiran, E.; Hasler, T.; Vanzieleghem, T.; Belibasakis, G.N.; Mahillon, J.; Loessner, M.J.; Schmelcher, M. Synergistic Removal of Static and Dynamic Staphylococcus aureus Biofilms by Combined Treatment with a Bacteriophage Endolysin and a Polysaccharide Depolymerase. Viruses 2018, 10, 438. [Google Scholar] [CrossRef] [Green Version]
- Mack, D.; Fischer, W.; Krokotsch, A.; Leopold, K.; Hartmann, R.; Egge, H.; Laufs, R. The intercellular adhesin involved in biofilm accumulation of Staphylococcus epidermidis is a linear beta-1,6-linked glucosaminoglycan: Purification and structural analysis. J. Bacteriol. 1996, 178, 175–183. [Google Scholar] [CrossRef] [Green Version]
- Gutierrez, D.; Briers, Y.; Rodriguez-Rubio, L.; Martinez, B.; Rodriguez, A.; Lavigne, R.; Garcia, P. Role of the Pre-neck Appendage Protein (Dpo7) from Phage vB_SepiS-phiIPLA7 as an Anti-biofilm Agent in Staphylococcal Species. Front. Microbiol. 2015, 6, 1315. [Google Scholar] [CrossRef] [Green Version]
- Schmelcher, M.; Loessner, M.J. Bacteriophage endolysins—Extending their application to tissues and the bloodstream. Curr. Opin. Biotechnol. 2021, 68, 51–59. [Google Scholar] [CrossRef]
- Schuch, R.; Nelson, D.; Fischetti, V.A. A bacteriolytic agent that detects and kills Bacillus anthracis. Nature 2002, 418, 884–889. [Google Scholar] [CrossRef]
- Fischetti, V.A. Development of Phage Lysins as Novel Therapeutics: A Historical Perspective. Viruses 2018, 10, 310. [Google Scholar] [CrossRef] [Green Version]
- Abdelrahman, F.; Easwaran, M.; Daramola, O.I.; Ragab, S.; Lynch, S.; Oduselu, T.J.; Khan, F.M.; Ayobami, A.; Adnan, F.; Torrents, E.; et al. Phage-Encoded Endolysins. Antibiotics 2021, 10, 124. [Google Scholar] [CrossRef]
- Haddad Kashani, H.; Schmelcher, M.; Sabzalipoor, H.; Seyed Hosseini, E.; Moniri, R. Recombinant Endolysins as Potential Therapeutics against Antibiotic-Resistant Staphylococcus aureus: Current Status of Research and Novel Delivery Strategies. Clin. Microbiol. Rev. 2018, 31, e00071-17. [Google Scholar] [CrossRef] [Green Version]
- Pastagia, M.; Euler, C.; Chahales, P.; Fuentes-Duculan, J.; Krueger, J.G.; Fischetti, V.A. A novel chimeric lysin shows superiority to mupirocin for skin decolonization of methicillin-resistant and -sensitive Staphylococcus aureus strains. Antimicrob. Agents Chemother. 2011, 55, 738–744. [Google Scholar] [CrossRef] [Green Version]
- Totte, J.E.E.; van Doorn, M.B.; Pasmans, S. Successful Treatment of Chronic Staphylococcus aureus-Related Dermatoses with the Topical Endolysin Staphefekt SA.100: A Report of 3 Cases. Case Rep. Dermatol. 2017, 9, 19–25. [Google Scholar] [CrossRef]
- Hathaway, H.; Ajuebor, J.; Stephens, L.; Coffey, A.; Potter, U.; Sutton, J.M.; Jenkins, A.T. Thermally triggered release of the bacteriophage endolysin CHAPK and the bacteriocin lysostaphin for the control of methicillin resistant Staphylococcus aureus (MRSA). J. Control Release 2017, 245, 108–115. [Google Scholar] [CrossRef] [PubMed]
- Hathaway, H.; Milo, S.; Sutton, J.M.; Jenkins, T.A. Recent advances in therapeutic delivery systems of bacteriophage and bacteriophage-encoded endolysins. Ther. Deliv. 2017, 8, 543–556. [Google Scholar] [CrossRef] [PubMed]
- Daniel, A.; Euler, C.; Collin, M.; Chahales, P.; Gorelick, K.J.; Fischetti, V.A. Synergism between a novel chimeric lysin and oxacillin protects against infection by methicillin-resistant Staphylococcus aureus. Antimicrob. Agents Chemother. 2010, 54, 1603–1612. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Johnson, C.T.; Wroe, J.A.; Agarwal, R.; Martin, K.E.; Guldberg, R.E.; Donlan, R.M.; Westblade, L.F.; Garcia, A.J. Hydrogel delivery of lysostaphin eliminates orthopedic implant infection by Staphylococcus aureus and supports fracture healing. Proc. Natl. Acad. Sci. USA 2018, 115, E4960–E4969. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Sosa, B.R.; Niu, Y.; Turajane, K.; Staats, K.; Suhardi, V.; Carli, A.; Fischetti, V.; Bostrom, M.; Yang, X. 2020 John Charnley Award: The antimicrobial potential of bacteriophage-derived lysin in a murine debridement, antibiotics, and implant retention model of prosthetic joint infection. Bone Jt. J. 2020, 102-B, 3–10. [Google Scholar] [CrossRef]
- Sobieraj, A.M.; Huemer, M.; Zinsli, L.V.; Meile, S.; Keller, A.P.; Röhrig, C.; Eichenseher, F.; Shen, Y.; Zinkernagel, A.S.; Loessner, M.J.; et al. Engineering of Long-Circulating Peptidoglycan Hydrolases Enables Efficient Treatment of Systemic Staphylococcus aureus Infection. mBio 2020, 11, e01781-20. [Google Scholar] [CrossRef]
- Verbree, C.T.; Datwyler, S.M.; Meile, S.; Eichenseher, F.; Donovan, D.M.; Loessner, M.J.; Schmelcher, M. Corrected and Republished from: Identification of Peptidoglycan Hydrolase Constructs with Synergistic Staphylolytic Activity in Cow’s Milk. Appl. Environ. Microbiol. 2018, 84, e02134-17. [Google Scholar] [CrossRef] [Green Version]
- Gu, J.; Xu, W.; Lei, L.; Huang, J.; Feng, X.; Sun, C.; Du, C.; Zuo, J.; Li, Y.; Du, T.; et al. LysGH15, a novel bacteriophage lysin, protects a murine bacteremia model efficiently against lethal methicillin-resistant Staphylococcus aureus infection. J. Clin. Microbiol. 2011, 49, 111–117. [Google Scholar] [CrossRef] [Green Version]
- Lu, J.Z.; Fujiwara, T.; Komatsuzawa, H.; Sugai, M.; Sakon, J. Cell wall-targeting domain of glycylglycine endopeptidase distinguishes among peptidoglycan cross-bridges. J. Biol. Chem. 2006, 281, 549–558. [Google Scholar] [CrossRef] [Green Version]
- Rohrig, C.; Huemer, M.; Lorge, D.; Luterbacher, S.; Phothaworn, P.; Schefer, C.; Sobieraj, A.M.; Zinsli, L.V.; Mairpady Shambat, S.; Leimer, N.; et al. Targeting Hidden Pathogens: Cell-Penetrating Enzybiotics Eradicate Intracellular Drug-Resistant Staphylococcus aureus. mBio 2020, 11, e00209-20. [Google Scholar] [CrossRef] [Green Version]
- Boles, B.R.; Thoendel, M.; Roth, A.J.; Horswill, A.R. Identification of genes involved in polysaccharide-independent Staphylococcus aureus biofilm formation. PLoS ONE 2010, 5, e10146. [Google Scholar] [CrossRef] [Green Version]
- Copin, R.; Sause, W.E.; Fulmer, Y.; Balasubramanian, D.; Dyzenhaus, S.; Ahmed, J.M.; Kumar, K.; Lees, J.; Stachel, A.; Fisher, J.C.; et al. Sequential evolution of virulence and resistance during clonal spread of community-acquired methicillin-resistant Staphylococcus aureus. Proc. Natl. Acad. Sci. USA 2019, 116, 1745–1754. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Schulz, M.; Calabrese, S.; Hausladen, F.; Wurm, H.; Drossart, D.; Stock, K.; Sobieraj, A.M.; Eichenseher, F.; Loessner, M.J.; Schmelcher, M.; et al. Point-of-care testing system for digital single cell detection of MRSA directly from nasal swabs. Lab Chip 2020, 20, 2549–2561. [Google Scholar] [CrossRef] [PubMed]
- Seijsing, J.; Sobieraj, A.M.; Keller, N.; Shen, Y.; Zinkernagel, A.S.; Loessner, M.J.; Schmelcher, M. Improved Biodistribution and Extended Serum Half-Life of a Bacteriophage Endolysin by Albumin Binding Domain Fusion. Front. Microbiol. 2018, 9, 2927. [Google Scholar] [CrossRef] [PubMed]
- Schmelcher, M.; Loessner, M.J. Use of bacteriophage cell wall-binding proteins for rapid diagnostics of Listeria. Methods Mol. Biol. 2014, 1157, 141–156. [Google Scholar] [CrossRef]
- Sabate Bresco, M.; O’Mahony, L.; Zeiter, S.; Kluge, K.; Ziegler, M.; Berset, C.; Nehrbass, D.; Richards, R.G.; Moriarty, T.F. Influence of fracture stability on Staphylococcus epidermidis and Staphylococcus aureus infection in a murine femoral fracture model. Eur. Cells Mater. 2017, 34, 321–340. [Google Scholar] [CrossRef]
- Hofstee, M.I.; Riool, M.; Gieling, F.; Stenger, V.; Constant, C.; Nehrbass, D.; Zeiter, S.; Richards, R.G.; Zaat, S.A.; Moriarty, T.F. A murine Staphylococcus aureus fracture-related infection model characterised by fracture non-union, staphylococcal abscess communities and myeloid-derived suppressor cells. Eur. Cells Mater. 2021, 41, 774–792. [Google Scholar] [CrossRef]
- Coraca-Huber, D.C.; Fille, M.; Hausdorfer, J.; Pfaller, K.; Nogler, M. Staphylococcus aureus biofilm formation and antibiotic susceptibility tests on polystyrene and metal surfaces. J. Appl. Microbiol. 2012, 112, 1235–1243. [Google Scholar] [CrossRef]
- Brady, R.A.; Leid, J.G.; Calhoun, J.H.; Costerton, J.W.; Shirtliff, M.E. Osteomyelitis and the role of biofilms in chronic infection. FEMS Immunol. Med. Microbiol. 2008, 52, 13–22. [Google Scholar] [CrossRef] [Green Version]
- Gaeng, S.; Scherer, S.; Neve, H.; Loessner, M.J. Gene cloning and expression and secretion of Listeria monocytogenes bacteriophage-lytic enzymes in Lactococcus lactis. Appl. Environ. Microbiol. 2000, 66, 2951–2958. [Google Scholar] [CrossRef] [Green Version]
- Otto, M. Staphylococcal biofilms. Curr. Top. Microbiol. Immunol. 2008, 322, 207–228. [Google Scholar] [CrossRef]
- Gotz, F. Staphylococcus and biofilms. Mol. Microbiol. 2002, 43, 1367–1378. [Google Scholar] [CrossRef]
- Kaplan, J.B. Therapeutic potential of biofilm-dispersing enzymes. Int. J. Artif. Organs 2009, 32, 545–554. [Google Scholar] [CrossRef] [PubMed]
- Kaplan, J.B.; LoVetri, K.; Cardona, S.T.; Madhyastha, S.; Sadovskaya, I.; Jabbouri, S.; Izano, E.A. Recombinant human DNase I decreases biofilm and increases antimicrobial susceptibility in staphylococci. J. Antibiot. 2012, 65, 73–77. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Hogan, S.; O’Gara, J.P.; O’Neill, E. Novel Treatment of Staphylococcus aureus Device-Related Infections Using Fibrinolytic Agents. Antimicrob. Agents Chemother. 2018, 62, e02008-17. [Google Scholar] [CrossRef] [Green Version]
- Talan, D.A.; Krishnadasan, A.; Gorwitz, R.J.; Fosheim, G.E.; Limbago, B.; Albrecht, V.; Moran, G.J.; Group, E.M.I.N.S. Comparison of Staphylococcus aureus from skin and soft-tissue infections in US emergency department patients, 2004 and 2008. Clin. Infect. Dis. 2011, 53, 144–149. [Google Scholar] [CrossRef] [PubMed]
- Rauch, S.; DeDent, A.C.; Kim, H.K.; Bubeck Wardenburg, J.; Missiakas, D.M.; Schneewind, O. Abscess formation and alpha-hemolysin induced toxicity in a mouse model of Staphylococcus aureus peritoneal infection. Infect. Immun. 2012, 80, 3721–3732. [Google Scholar] [CrossRef] [Green Version]
- Winstel, V.; Schneewind, O.; Missiakas, D. Staphylococcus aureus Exploits the Host Apoptotic Pathway to Persist during Infection. mBio 2019, 10, e02270-19. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Schmelcher, M.; Shen, Y.; Nelson, D.C.; Eugster, M.R.; Eichenseher, F.; Hanke, D.C.; Loessner, M.J.; Dong, S.; Pritchard, D.G.; Lee, J.C.; et al. Evolutionarily distinct bacteriophage endolysins featuring conserved peptidoglycan cleavage sites protect mice from MRSA infection. J. Antimicrob. Chemother. 2015, 70, 1453–1465. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Singh, P.K.; Donovan, D.M.; Kumar, A. Intravitreal injection of the chimeric phage endolysin Ply187 protects mice from Staphylococcus aureus endophthalmitis. Antimicrob. Agents Chemother. 2014, 58, 4621–4629. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Abdelkader, K.; Gerstmans, H.; Saafan, A.; Dishisha, T.; Briers, Y. The Preclinical and Clinical Progress of Bacteriophages and Their Lytic Enzymes: The Parts are Easier than the Whole. Viruses 2019, 11, 96. [Google Scholar] [CrossRef] [Green Version]
- Windolf, C.D.; Logters, T.; Scholz, M.; Windolf, J.; Flohe, S. Lysostaphin-coated titan-implants preventing localized osteitis by Staphylococcus aureus in a mouse model. PLoS ONE 2014, 9, e115940. [Google Scholar] [CrossRef] [Green Version]
- Johnson, C.T.; Sok, M.C.P.; Martin, K.E.; Kalelkar, P.P.; Caplin, J.D.; Botchwey, E.A.; Garcia, A.J. Lysostaphin and BMP-2 co-delivery reduces S. aureus infection and regenerates critical-sized segmental bone defects. Sci. Adv. 2019, 5, eaaw1228. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Wu, J.A.; Kusuma, C.; Mond, J.J.; Kokai-Kun, J.F. Lysostaphin disrupts Staphylococcus aureus and Staphylococcus epidermidis biofilms on artificial surfaces. Antimicrob. Agents Chemother. 2003, 47, 3407–3414. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Walencka, E.; Sadowska, B.; Rozalska, S.; Hryniewicz, W.; Rozalska, B. Lysostaphin as a potential therapeutic agent for staphylococcal biofilm eradication. Pol. J. Microbiol. 2005, 54, 191–200. [Google Scholar]
- Climo, M.W.; Ehlert, K.; Archer, G.L. Mechanism and suppression of lysostaphin resistance in oxacillin-resistant Staphylococcus aureus. Antimicrob. Agents Chemother. 2001, 45, 1431–1437. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Grundling, A.; Missiakas, D.M.; Schneewind, O. Staphylococcus aureus mutants with increased lysostaphin resistance. J. Bacteriol. 2006, 188, 6286–6297. [Google Scholar] [CrossRef] [Green Version]
- Thabit, A.K.; Fatani, D.F.; Bamakhrama, M.S.; Barnawi, O.A.; Basudan, L.O.; Alhejaili, S.F. Antibiotic penetration into bone and joints: An updated review. Int. J. Infect. Dis. 2019, 81, 128–136. [Google Scholar] [CrossRef] [Green Version]
- Loeffler, J.M.; Djurkovic, S.; Fischetti, V.A. Phage lytic enzyme Cpl-1 as a novel antimicrobial for pneumococcal bacteremia. Infect. Immun. 2003, 71, 6199–6204. [Google Scholar] [CrossRef] [Green Version]
Number of Mice Survived until Day 13 and Evaluated | Treatment | Additional Vancomycin Treatment | Frequency | |
---|---|---|---|---|
Untreated | 9 for bacteriology 3 for CT/Histo | 50 µL sterile saline | none | 1× per day directly into infected soft tissue |
Enzybiotics | 8 for bacteriology 3 for CT/Histo | 50 µL equimolar enzybiotics (M23, GH15, DA7). 1 mg/mL total enzyme concentration | none | 1× per day directly into infected soft tissue |
Enzybiotics + Vanc/Gent | 7 for bacteriology 2 for CT/Histo | 50 µL equimolar enzybiotics (M23, GH15, DA7). 1 mg/mL total enzyme concentration; supplemented with 200 µg gentamicin | 110 mg/kg delivered subcutaneously | Enzybiotics/gentamicin 1× per day directly into infected soft tissue vancomycin 2× per day |
Vanc/Gent | 7 for bacteriology 2 for CT/Histo | 50 µL saline containing 200 µg gentamicin | 110 mg/kg delivered subcutaneously | Gentamicin 1× per day directly into infected soft tissue vancomycin 2× per day |
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. |
© 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Sumrall, E.T.; Hofstee, M.I.; Arens, D.; Röhrig, C.; Baertl, S.; Gehweiler, D.; Schmelcher, M.; Loessner, M.J.; Zeiter, S.; Richards, R.G.; et al. An Enzybiotic Regimen for the Treatment of Methicillin-Resistant Staphylococcus aureus Orthopaedic Device-Related Infection. Antibiotics 2021, 10, 1186. https://0-doi-org.brum.beds.ac.uk/10.3390/antibiotics10101186
Sumrall ET, Hofstee MI, Arens D, Röhrig C, Baertl S, Gehweiler D, Schmelcher M, Loessner MJ, Zeiter S, Richards RG, et al. An Enzybiotic Regimen for the Treatment of Methicillin-Resistant Staphylococcus aureus Orthopaedic Device-Related Infection. Antibiotics. 2021; 10(10):1186. https://0-doi-org.brum.beds.ac.uk/10.3390/antibiotics10101186
Chicago/Turabian StyleSumrall, Eric T., Marloes I. Hofstee, Daniel Arens, Christian Röhrig, Susanne Baertl, Dominic Gehweiler, Mathias Schmelcher, Martin J. Loessner, Stephan Zeiter, R. Geoff Richards, and et al. 2021. "An Enzybiotic Regimen for the Treatment of Methicillin-Resistant Staphylococcus aureus Orthopaedic Device-Related Infection" Antibiotics 10, no. 10: 1186. https://0-doi-org.brum.beds.ac.uk/10.3390/antibiotics10101186