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9. Alginate microbeads and hydrogels delivering meropenem and bacteriophages to treat Pseudomonas aeruginosa fracture-related infections

Author

Chen, Baixing, Benavente, Luis Ponce, Chittò, Marco, Wychowaniec, Jacek K., Post, Virginia, D'Este, Matteo, Constant, Caroline, Zeiter, Stephan, Feng, Wenli, Moreno, Mercedes González, Trampuz, Andrej, Wagemans, Jeroen, Onsea, Jolien, Richards, R. Geoff, Lavigne, Rob, Moriarty, T. Fintan, and Metsemakers, Willem-Jan

Published
2023
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12. Treatment of Fracture-Related Infections

Author

Morgenstern, Mario, Clauss, Martin, Sendi, Parham, Cadosch, Dieter, Osinga, Rik, Metsemakers, Willem-Jan, Pape, Hans-Christoph, editor, Borrelli Jr., Joseph, editor, Moore, Ernest E., editor, Pfeifer, Roman, editor, and Stahel, Philip F., editor

Published
2022
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21. Fracture-related infection

Author

Moriarty, T. Fintan, Metsemakers, Willem-Jan, Morgenstern, Mario, Hofstee, Marloes I., Vallejo Diaz, Alejandro, Cassat, James E., Wildemann, Britt, Depypere, Melissa, Schwarz, Edward M., and Richards, R. Geoff

Published
2022
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28. Development of an ex vivo model to study Staphylococcus aureus invasion of the osteocyte lacuno‐canalicular network.

Author

Vanvelk, Niels, de Mesy Bentley, Karen L., Verhofstad, Michael H. J., Metsemakers, Willem‐Jan, Moriarty, Thomas F., and Siverino, Claudia

Abstract

Staphylococcus aureus has multiple mechanisms to evade the host's immune system and antibiotic treatment. One such mechanism is the invasion of the osteocyte lacuno‐canalicular network (OLCN), which may be particularly important in recurrence of infection after debridement and antibiotic therapy. The aim of this study was to develop an ex vivo model to facilitate further study of S. aureus invasion of the OLCN and early‐stage testing of antibacterial strategies against bacteria in this niche. The diameter of the canaliculi of non‐infected human, sheep, and mouse bones was measured microscopically on Schmorl's picrothionin stained sections, showing a large overlap in canalicular diameter. S. aureus successfully invaded the OLCN in all species in vitro as revealed by presence in osteocyte lacunae in Brown and Brenn‐stained sections and by scanning electron microscopy. Murine bones were then selected for further experiments, and titanium pins with either a wild‐type or ΔPBP4 mutant S. aureus USA300 were placed trans‐cortically and incubated for 2 weeks in tryptic soy broth. Wild‐type S. aureus readily invaded the osteocyte lacunae in mouse bones while the ΔPBP4 showed a significantly lower invasion of the OLCN (p = 0.0005). Bone specimens were then treated with gentamicin, sitafloxacin, R14 bacteriophages, or left untreated. Gentamicin (p = 0.0027) and sitafloxacin (p = 0.0280) significantly reduced the proportion of S. aureus‐occupied lacunae, whilst bacteriophage treatment had no effect. This study shows that S. aureus is able to invade the OLCN in an ex vivo model. This ex vivo model can be used for future early‐stage studies before proceeding to in vivo studies. [ABSTRACT FROM AUTHOR]

Published
2025
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30. Isolation and Antibiofilm Activity of Bacteriophages against Cutibacterium acnes from Patients with Periprosthetic Joint Infection.

Author

Chen, Baixing, Chittò, Marco, Tao, Siyuan, Wagemans, Jeroen, Lavigne, Rob, Richards, R. Geoff, Metsemakers, Willem-Jan, and Moriarty, T. Fintan

Subjects
PROSTHESIS-related infections, CUTIBACTERIUM acnes, BIOFILMS, BIOMASS, TITANIUM, BACTERIOPHAGES
Abstract

Background: Infections following shoulder surgery, particularly periprosthetic joint infection (PJI), are challenging to treat. Cutibacterium acnes is the causative pathogen in 39% to 76% of these cases. This study explores the efficacy of bacteriophage therapy as an alternative to conventional antibiotics for treating such infections. Methods: Nine phages with lytic activity were isolated from the skin of humans using C. acnes ATCC 6919 as the indicator host. These phages were tested individually or in combination to assess host range and antibiofilm activity against clinical strains of C. acnes associated with PJIs. The phage cocktail was optimized for broad-spectrum activity and tested in vitro against biofilms formed on titanium discs to mimic the prosthetic environment. Results: The isolated phages displayed lytic activity against a range of C. acnes clinical isolates. The phage cocktail significantly reduced the bacterial load of C. acnes strains 183, 184, and GG2A, as compared with untreated controls (p < 0.05). Individual phages, particularly CaJIE7 and CaJIE3, also demonstrated significant reductions in bacterial load with respect to specific strains. Moreover, phages notably disrupted the biofilm structure and reduced biofilm biomass, confirming the potential of phage therapy in targeting biofilm-associated infections. Conclusions: Our preclinical findings support the potential of phage therapy as a viable adjunct to traditional antibiotics for treating C. acnes infections in orthopedic device-related infections. The ability of phages to disrupt biofilms may be particularly beneficial for managing infections associated with prosthetic implants. [ABSTRACT FROM AUTHOR]

Published
2024
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31. Optimization of bacteriophage therapy for difficult-to-treat musculoskeletal infections: a bench-to-bedside perspective.

Author

Bessems, Laura, Baixing Chen, Uyttebroek, Saartje, Devolder, David, Lood, Ce' dric, Verwimp, Stefaan, De Munter, Paul, Debaveye, Yves, Depypere, Melissa, Spriet, Isabel, Van Gerven, Laura, Dupont, Lieven, Wagemans, Jeroen, van Noort, Vera, Lavigne, Rob, Metsemakers, Willem-Jan, and Onsea, Jolien

Subjects
MOLECULAR kinetics, NUCLEOTIDE sequencing, DRUG resistance in microorganisms, MOLECULAR interactions, DATA quality
Abstract

Given the increasing threat of antimicrobial resistance, scientists are urgently seeking adjunct antimicrobial strategies, such as phage therapy (PT). However, despite promising results for the treatment of musculoskeletal infections in our center, crucial knowledge gaps remain. Therefore, a prospective observational study (PHAGEFORCE) and a multidisciplinary approach was set up to achieve and optimize standardized treatment guidelines. At our center, PT is strictly controlled and monitored by a multidisciplinary taskforce. Each phage treatment follows the same pathway to ensure standardization and data quality. Within the PHAGEFORCE framework, we established a testing platform to gain insight in the safety and efficacy of PT, biodistribution, phage kinetics and the molecular interaction between phages and bacteria. The draining fluid is collected to determine the phage titer and bacterial load. In addition, all bacterial isolates are fully characterized by genome sequencing to monitor the emergence of phage resistance. We hereby present a standardized bench-to-bedside protocol to gain more insight in the kinetics and dynamics of PT for musculoskeletal infections. [ABSTRACT FROM AUTHOR]

Published
2024
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35. Personalized bacteriophage therapy outcomes for 100 consecutive cases:a multicentre, multinational, retrospective observational study

Author

Pirnay, Jean Paul, Djebara, Sarah, Steurs, Griet, Griselain, Johann, Cochez, Christel, De Soir, Steven, Glonti, Tea, Spiessens, An, Vanden Berghe, Emily, Green, Sabrina, Wagemans, Jeroen, Lood, Cédric, Schrevens, Eddie, Chanishvili, Nina, Kutateladze, Mzia, de Jode, Mathieu, Ceyssens, Pieter Jan, Draye, Jean Pierre, Verbeken, Gilbert, De Vos, Daniel, Rose, Thomas, Onsea, Jolien, Van Nieuwenhuyse, Brieuc, Soentjens, Patrick, Lavigne, Rob, Merabishvili, Maya, Pang, Kim Win, Metsemakers, Willem Jan, Van der Linden, Dimitri, Chatzis, Olga, Eskenazi, Anaïs, Lopez, Angel, De Voeght, Adrien, Rousseau, Anne Françoise, Tilmanne, Anne, Vens, Daphne, Gérain, Jean, Layeux, Brice, Vlieghe, Erika, Baar, Ingrid, Van Ierssel, Sabrina, Van Laethem, Johan, Guiot, Julien, De Roock, Sophie, Jennes, Serge, Uyttebroek, Saartje, Van Gerven, Laura, Hellings, Peter W., Dupont, Lieven, Debaveye, Yves, Devolder, David, Spriet, Isabel, De Munter, Paul, Depypere, Melissa, Vanfleteren, Michiel, Cornu, Olivier, Verhulst, Stijn, Boiy, Tine, Lamote, Stoffel, Van Zele, Thibaut, Wieërs, Grégoire, Courtin, Cécile, Lebeaux, David, Sartre, Jacques, Ferry, Tristan, Laurent, Frédéric, Paul, Kevin, Di Luca, Mariagrazia, Gottschlich, Stefan, Tkhilaishvili, Tamta, Cesta, Novella, Racenis, Karlis, Barbosa, Telma, López-Cortés, Luis Eduardo, Tomás, Maria, Hübner, Martin, Pham, Truong Thanh, Nagtegaal, Paul, Ten Oever, Jaap, Daniels, Johannes, Loubert, Maartje, Iheb, Ghariani, Jones, Joshua, Hall, Lesley, Young, Matthew, Balarjishvili, Nana, Tediashvili, Marina, Tong, Yigang, Rohde, Christine, Wittmann, Johannes, Hazan, Ronen, Nir-Paz, Ran, Azeredo, Joana, Krylov, Victor, Cameron, David, Pitton, Melissa, Que, Yok Ai, Resch, Gregory, McCallin, Shawna, Dunne, Matthew, Kilcher, Samuel, Pirnay, Jean Paul, Djebara, Sarah, Steurs, Griet, Griselain, Johann, Cochez, Christel, De Soir, Steven, Glonti, Tea, Spiessens, An, Vanden Berghe, Emily, Green, Sabrina, Wagemans, Jeroen, Lood, Cédric, Schrevens, Eddie, Chanishvili, Nina, Kutateladze, Mzia, de Jode, Mathieu, Ceyssens, Pieter Jan, Draye, Jean Pierre, Verbeken, Gilbert, De Vos, Daniel, Rose, Thomas, Onsea, Jolien, Van Nieuwenhuyse, Brieuc, Soentjens, Patrick, Lavigne, Rob, Merabishvili, Maya, Pang, Kim Win, Metsemakers, Willem Jan, Van der Linden, Dimitri, Chatzis, Olga, Eskenazi, Anaïs, Lopez, Angel, De Voeght, Adrien, Rousseau, Anne Françoise, Tilmanne, Anne, Vens, Daphne, Gérain, Jean, Layeux, Brice, Vlieghe, Erika, Baar, Ingrid, Van Ierssel, Sabrina, Van Laethem, Johan, Guiot, Julien, De Roock, Sophie, Jennes, Serge, Uyttebroek, Saartje, Van Gerven, Laura, Hellings, Peter W., Dupont, Lieven, Debaveye, Yves, Devolder, David, Spriet, Isabel, De Munter, Paul, Depypere, Melissa, Vanfleteren, Michiel, Cornu, Olivier, Verhulst, Stijn, Boiy, Tine, Lamote, Stoffel, Van Zele, Thibaut, Wieërs, Grégoire, Courtin, Cécile, Lebeaux, David, Sartre, Jacques, Ferry, Tristan, Laurent, Frédéric, Paul, Kevin, Di Luca, Mariagrazia, Gottschlich, Stefan, Tkhilaishvili, Tamta, Cesta, Novella, Racenis, Karlis, Barbosa, Telma, López-Cortés, Luis Eduardo, Tomás, Maria, Hübner, Martin, Pham, Truong Thanh, Nagtegaal, Paul, Ten Oever, Jaap, Daniels, Johannes, Loubert, Maartje, Iheb, Ghariani, Jones, Joshua, Hall, Lesley, Young, Matthew, Balarjishvili, Nana, Tediashvili, Marina, Tong, Yigang, Rohde, Christine, Wittmann, Johannes, Hazan, Ronen, Nir-Paz, Ran, Azeredo, Joana, Krylov, Victor, Cameron, David, Pitton, Melissa, Que, Yok Ai, Resch, Gregory, McCallin, Shawna, Dunne, Matthew, and Kilcher, Samuel

Abstract

In contrast to the many reports of successful real-world cases of personalized bacteriophage therapy (BT), randomized controlled trials of non-personalized bacteriophage products have not produced the expected results. Here we present the outcomes of a retrospective observational analysis of the first 100 consecutive cases of personalized BT of difficult-to-treat infections facilitated by a Belgian consortium in 35 hospitals, 29 cities and 12 countries during the period from 1 January 2008 to 30 April 2022. We assessed how often personalized BT produced a positive clinical outcome (general efficacy) and performed a regression analysis to identify functional relationships. The most common indications were lower respiratory tract, skin and soft tissue, and bone infections, and involved combinations of 26 bacteriophages and 6 defined bacteriophage cocktails, individually selected and sometimes pre-adapted to target the causative bacterial pathogens. Clinical improvement and eradication of the targeted bacteria were reported for 77.2% and 61.3% of infections, respectively. In our dataset of 100 cases, eradication was 70% less probable when no concomitant antibiotics were used (odds ratio = 0.3; 95% confidence interval = 0.127–0.749). In vivo selection of bacteriophage resistance and in vitro bacteriophage–antibiotic synergy were documented in 43.8% (7/16 patients) and 90% (9/10) of evaluated patients, respectively. We observed a combination of antibiotic re-sensitization and reduced virulence in bacteriophage-resistant bacterial isolates that emerged during BT. Bacteriophage immune neutralization was observed in 38.5% (5/13) of screened patients. Fifteen adverse events were reported, including seven non-serious adverse drug reactions suspected to be linked to BT. While our analysis is limited by the uncontrolled nature of these data, it indicates that BT can be effective in combination with antibiotics and can inform the design of future controlled clinical trials. B

Published
2024

40. SYNERGISTIC ACTION OF BACTERIOPHAGE AND VANCOMYCIN IN A CO-DELIVERY HYDROGEL FOR LOCALIZED TREATMENT OF FRACTURE-RELATED INFECTION CAUSED BY METHICILLIN-RESISTANT STAPHYLOCOCCUS AUREUS

Author

Chen, Baixing, primary, Chittò, Marco, additional, Benavente, Luis Ponce, additional, Post, Virginia, additional, Moreno, Mercedes González, additional, Zeiter, Stephan, additional, Trampuz, Andrej, additional, Wagemans, Jeroen, additional, Lavigne, Rob, additional, Onsea, Jolien, additional, Metsemakers, Willem-Jan, additional, and Moriarty, Fintan, additional

Published
2023
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42. The global burden of fracture-related infection: can we do better?

Author

Metsemakers, Willem-Jan, primary, Moriarty, T Fintan, additional, Morgenstern, Mario, additional, Marais, Leonard, additional, Onsea, Jolien, additional, O'Toole, Robert V, additional, Depypere, Melissa, additional, Obremskey, William T, additional, Verhofstad, Michael H J, additional, McNally, Martin, additional, Morshed, Saam, additional, Wouthuyzen-Bakker, Marjan, additional, and Zalavras, Charalampos, additional

Published
2023
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44. Musculoskeletal Infection in Orthopaedic Trauma: Assessment of the 2018 International Consensus Meeting on Musculoskeletal Infection

Author

Obremskey, William T., Metsemakers, Willem-Jan, Schlatterer, Daniel R., Tetsworth, Kevin, Egol, Kenneth, Kates, Stephen, McNally, Martin, Gibbons, John, Kenny, Paddy, Obremskey, William T., Stangl, Paul, Patzakis, Michael J., Ferreira, Nando, Tornetta, Paul, III, Suda, Arnold J., O’Hara, Nathan, Costa Salles, Mauro Jose, Bhashyam, Abhiram R., Morgenstern, Mario, Manrique, Jorge, Malizos, Konstantinos N., Giannoudis, Peter, Egol, Kenneth A., Kleftouris, George, Reyes, Francisco, Klement, Mitchell R., Bautista, Maria, Linke, Philip, Citak, Mustafa, Abdelaziz, Hussein, Ecker, Niklas Unter, Suero, Eduardo, Caba, Pedro, Marais, Leonard, Haasper, Carl, Papakostidis, Costas, Natoli, Roman M., Aldahamsheh, Osama, Abuodeh, Yousef, Quinnan, Stephen, Suarez, Cristina, Conway, Janet D., Sánchez Correa, Carlos A., Leal, Jaime A., Zalavras, Charalampos, Komnos, Georgios, Shope, Alexander J., Saxena, Arjun, Fram, Brianna, Åkesson, Per, Haggard, Warren O., Vahedi, Hamed, Athanaselis, Efstratios, Pesantez, Rodrigo, Lowenberg, David W., Gleason, Brendan, Hendershot, Edward F., Amaris, Gerson, Metsemakers, Willem-Jan, Kates, Stephen L., Chang, Gerard, Archdeacon, Michael T., Pinzón, Andrés, Shetty, Rajendra Prasad, Chan, James, McNally, Martin A., Shaffer, Andre, Schlatterer, Daniel R., Harris, Mitchel, Tetsworth, Kevin, Matsushita, Kazuhiko, Kvederas, Giedrius, Garcia, Maria Fernanda, Swiontkowski, Marc F., Kallel, Sofiene, Gutierrez, Vicky, Alt, Volker, O’Toole, Robert V., and Watson, J. Tracy

Published
2020
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