In Vitro and In Vivo Synergism of Fosfomycin in Combination with Meropenem or Polymyxin B against KPC-2-Producing <i>Klebsiella pneumoniae</i> Clinical Isolates
Fosfomycin disodium is a potential therapeutic option to manage difficult-to-treat infections, especially when combined with other antimicrobials. In this study, we evaluated the activity of fosfomycin in combination with meropenem or polymyxin B against contemporaneous KPC-2-producing <i>K. p...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-01-01
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| Series: | Antibiotics |
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| Online Access: | https://www.mdpi.com/2079-6382/12/2/237 |
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| author | Aghata Cardoso da Silva Ribeiro Yohanna Carvalho dos Santos Aoun Chikhani Tiago Barcelos Valiatti André Valêncio Mariana Neri Lucas Kurihara Fernanda Fernandes Santos Luciene Andrade da Rocha Minarini Ana Cristina Gales |
| author_facet | Aghata Cardoso da Silva Ribeiro Yohanna Carvalho dos Santos Aoun Chikhani Tiago Barcelos Valiatti André Valêncio Mariana Neri Lucas Kurihara Fernanda Fernandes Santos Luciene Andrade da Rocha Minarini Ana Cristina Gales |
| author_sort | Aghata Cardoso da Silva Ribeiro |
| collection | DOAJ |
| description | Fosfomycin disodium is a potential therapeutic option to manage difficult-to-treat infections, especially when combined with other antimicrobials. In this study, we evaluated the activity of fosfomycin in combination with meropenem or polymyxin B against contemporaneous KPC-2-producing <i>K. pneumoniae</i> clinical isolates (KPC-KPN). Synergistic activity was assessed by checkerboard (CKA) and time–kill (TKA) assays. TKA was performed using serum peak and trough concentrations. The activity of these combinations was also assessed in the <i>Galleria mellonella</i> model. Biofilm disruption was assessed by the microtiter plate technique. CKA resulted in an 8- to 2048-fold decrease in meropenem MIC, restoring meropenem activity for 82.4% of the isolates when combined with fosfomycin. For the fosfomycin + polymyxin B combination, a 2- to 128-fold reduction in polymyxin B MIC was achieved, restoring polymyxin B activity for 47% of the isolates. TKA resulted in the synergism of fosfomycin + meropenem (3.0–6.7 log<sub>10</sub> CFU/mL decrease) and fosfomycin + polymyxin B (6.0–6.2 log<sub>10</sub> CFU/mL decrease) at peak concentrations. All larvae treated with fosfomycin + meropenem survived. Larvae survival rate was higher with fosfomycin monotherapy (95%) than that observed for fosfomycin + polymyxin B (75%) (<i>p</i>-value < 0.0001). Finally, a higher biofilm disruption was observed under exposure to fosfomycin + polymyxin B (2.4–3.4-fold reduction). In summary, we observed a synergistic effect of fosfomycin + meropenem and fosfomycin + polymyxin B combinations, in vitro and in vivo, against KPC-KPN, as well as biofilm disruption. |
| first_indexed | 2024-03-11T09:15:30Z |
| format | Article |
| id | doaj.art-eaec63cf66c54445bdcd932ac923a2c5 |
| institution | Directory Open Access Journal |
| issn | 2079-6382 |
| language | English |
| last_indexed | 2024-03-11T09:15:30Z |
| publishDate | 2023-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antibiotics |
| spelling | doaj.art-eaec63cf66c54445bdcd932ac923a2c52023-11-16T18:42:08ZengMDPI AGAntibiotics2079-63822023-01-0112223710.3390/antibiotics12020237In Vitro and In Vivo Synergism of Fosfomycin in Combination with Meropenem or Polymyxin B against KPC-2-Producing <i>Klebsiella pneumoniae</i> Clinical IsolatesAghata Cardoso da Silva Ribeiro0Yohanna Carvalho dos Santos Aoun Chikhani1Tiago Barcelos Valiatti2André Valêncio3Mariana Neri Lucas Kurihara4Fernanda Fernandes Santos5Luciene Andrade da Rocha Minarini6Ana Cristina Gales7Laboratório Alerta, Division of Infectious Diseases, Department of Internal Medicine, Escola Paulista de Medicina, Universidade Federal de São Paulo—UNIFESP, São Paulo 04039-032, BrazilLaboratório Alerta, Division of Infectious Diseases, Department of Internal Medicine, Escola Paulista de Medicina, Universidade Federal de São Paulo—UNIFESP, São Paulo 04039-032, BrazilLaboratório Alerta, Division of Infectious Diseases, Department of Internal Medicine, Escola Paulista de Medicina, Universidade Federal de São Paulo—UNIFESP, São Paulo 04039-032, BrazilLaboratório Alerta, Division of Infectious Diseases, Department of Internal Medicine, Escola Paulista de Medicina, Universidade Federal de São Paulo—UNIFESP, São Paulo 04039-032, BrazilLaboratório Alerta, Division of Infectious Diseases, Department of Internal Medicine, Escola Paulista de Medicina, Universidade Federal de São Paulo—UNIFESP, São Paulo 04039-032, BrazilLaboratório Alerta, Division of Infectious Diseases, Department of Internal Medicine, Escola Paulista de Medicina, Universidade Federal de São Paulo—UNIFESP, São Paulo 04039-032, BrazilLaboratório Multidisciplinar em Saúde e Meio Ambiente, Departamento de Ciências Farmacêuticas, Instituto de Ciências Ambientais, Químicas e Farmacêuticas, Universidade Federal de São Paulo—UNIFESP, São Paulo 04039-032, BrazilLaboratório Alerta, Division of Infectious Diseases, Department of Internal Medicine, Escola Paulista de Medicina, Universidade Federal de São Paulo—UNIFESP, São Paulo 04039-032, BrazilFosfomycin disodium is a potential therapeutic option to manage difficult-to-treat infections, especially when combined with other antimicrobials. In this study, we evaluated the activity of fosfomycin in combination with meropenem or polymyxin B against contemporaneous KPC-2-producing <i>K. pneumoniae</i> clinical isolates (KPC-KPN). Synergistic activity was assessed by checkerboard (CKA) and time–kill (TKA) assays. TKA was performed using serum peak and trough concentrations. The activity of these combinations was also assessed in the <i>Galleria mellonella</i> model. Biofilm disruption was assessed by the microtiter plate technique. CKA resulted in an 8- to 2048-fold decrease in meropenem MIC, restoring meropenem activity for 82.4% of the isolates when combined with fosfomycin. For the fosfomycin + polymyxin B combination, a 2- to 128-fold reduction in polymyxin B MIC was achieved, restoring polymyxin B activity for 47% of the isolates. TKA resulted in the synergism of fosfomycin + meropenem (3.0–6.7 log<sub>10</sub> CFU/mL decrease) and fosfomycin + polymyxin B (6.0–6.2 log<sub>10</sub> CFU/mL decrease) at peak concentrations. All larvae treated with fosfomycin + meropenem survived. Larvae survival rate was higher with fosfomycin monotherapy (95%) than that observed for fosfomycin + polymyxin B (75%) (<i>p</i>-value < 0.0001). Finally, a higher biofilm disruption was observed under exposure to fosfomycin + polymyxin B (2.4–3.4-fold reduction). In summary, we observed a synergistic effect of fosfomycin + meropenem and fosfomycin + polymyxin B combinations, in vitro and in vivo, against KPC-KPN, as well as biofilm disruption.https://www.mdpi.com/2079-6382/12/2/237fosfomycinsynergism<i>Klebsiella pneumoniae</i>antimicrobial resistance<i>Galleria mellonella</i>biofilm |
| spellingShingle | Aghata Cardoso da Silva Ribeiro Yohanna Carvalho dos Santos Aoun Chikhani Tiago Barcelos Valiatti André Valêncio Mariana Neri Lucas Kurihara Fernanda Fernandes Santos Luciene Andrade da Rocha Minarini Ana Cristina Gales In Vitro and In Vivo Synergism of Fosfomycin in Combination with Meropenem or Polymyxin B against KPC-2-Producing <i>Klebsiella pneumoniae</i> Clinical Isolates Antibiotics fosfomycin synergism <i>Klebsiella pneumoniae</i> antimicrobial resistance <i>Galleria mellonella</i> biofilm |
| title | In Vitro and In Vivo Synergism of Fosfomycin in Combination with Meropenem or Polymyxin B against KPC-2-Producing <i>Klebsiella pneumoniae</i> Clinical Isolates |
| title_full | In Vitro and In Vivo Synergism of Fosfomycin in Combination with Meropenem or Polymyxin B against KPC-2-Producing <i>Klebsiella pneumoniae</i> Clinical Isolates |
| title_fullStr | In Vitro and In Vivo Synergism of Fosfomycin in Combination with Meropenem or Polymyxin B against KPC-2-Producing <i>Klebsiella pneumoniae</i> Clinical Isolates |
| title_full_unstemmed | In Vitro and In Vivo Synergism of Fosfomycin in Combination with Meropenem or Polymyxin B against KPC-2-Producing <i>Klebsiella pneumoniae</i> Clinical Isolates |
| title_short | In Vitro and In Vivo Synergism of Fosfomycin in Combination with Meropenem or Polymyxin B against KPC-2-Producing <i>Klebsiella pneumoniae</i> Clinical Isolates |
| title_sort | in vitro and in vivo synergism of fosfomycin in combination with meropenem or polymyxin b against kpc 2 producing i klebsiella pneumoniae i clinical isolates |
| topic | fosfomycin synergism <i>Klebsiella pneumoniae</i> antimicrobial resistance <i>Galleria mellonella</i> biofilm |
| url | https://www.mdpi.com/2079-6382/12/2/237 |
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