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Efficacy of Ceragenins Alone and in Combinations with Antibiotics Against Multidrug-Resistant Gram Negative Pathogens from Bloodstream Infections

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Abstract

Ceragenins (CSAs) that mimic the activities of antimicrobial peptides may be new options for the treatment of infections caused by multidrug-resistant pathogens. This study investigated the antibacterial activities of eight different ceragenins against MDR pathogens and the synergistic effects of some ceragenins in combinations with antibiotics (meropenem-MEM, ceftazidime + avibactam-CZA, tigecycline-TIG). A disc diffusion method was used for antibiotic susceptibility tests, a broth microdilution, and checkerboard methods were used to detect minimum inhibitory concentrations (MICs) and the effects of combinations, respectively. While MIC90 values CSA-13, CSA-44, CSA-131 against Klebsiella pneumoniae isolates had similar effect with MEM (8 µg/ml); CSA-13, CSA-44, CSA-131, CSA-138, and CSA-144 had better activity than MEM against Acinetobacter baumannii and Pseudomonas aeruginosa isolates. In particular, CSA-44 and CSA-131 were effective against A. baumannii and P. aeruginosa isolates which resistant to both COL and MEM. CSA-44+MEM and CSA-131+CZA combinations showed synergistic activity against most (70%) of MDR- E. coli isolates. Although TIG is known to have weak activity in nonfermentative bacteria, CSA-44+TIG combination showed synergistic activity against two (17%) of the A. baumanni isolates. In addition, CSA-44+TIG and CSA-131+TIG combinations showed additive effects against all P. aeruginosa isolates. Antagonism was not detected in any of the combinations. CSA-44 and CSA-131 alone/or in combinations with MEM or CZA can be considered as new alternative treatments in serious infections caused by MDR pathogens.

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References

  1. Paphitou NI (2013) Antimicrobial resistance: action to combat the rising microbial challenges. Int J Antimicrob Agents 42:S25–S28 (https://www.sciencedirect.com/science/article/pii/S0924857913001337#:~:text=https%3A//doi.org/https://doi.org/10.1016/j.ijantimicag.2013.04.007)

  2. De Oliveira DM, Forde BM, Kidd TJ et al (2020) Antimicrobial resistance in ESKAPE pathogens. Clin Microbiol Rev 33:e00181-e219. https://doi.org/10.1128/CMR.00181-19

    Article  PubMed  PubMed Central  Google Scholar 

  3. Gandra S, Alvarez-Uria G, Turner P, Joshi J, Limmathurotsakul D, van Doorn HR (2020) Antimicrobial resistance surveillance in low-and middle-income countries: progress and challenges in eight South Asian and Southeast Asian countries. Clin Microbiol Rev 33:e00048-e119. https://doi.org/10.1128/CMR.00048-19

    Article  CAS  PubMed Central  Google Scholar 

  4. Theuretzbacher U, Gottwalt S, Beyer P et al (2019) Analysis of the clinical antibacterial and antituberculosis pipeline. Lancet Infect Dis 19:e40–e50. https://doi.org/10.1016/S1473-3099(18)30513-9

    Article  CAS  PubMed  Google Scholar 

  5. Chin JN, Rybak MJ, Cheung CM, Savage PB (2007) Antimicrobial activities of ceragenins against clinical isolates of resistant Staphylococcus aureus. Antimicrob Agents Chemother 51:1268–1273. https://doi.org/10.1128/AAC.01325-06

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Savage PB, Li C, Taotafa U, Ding B, Guan Q (2002) Antibacterial properties of cationic steroid antibiotics. FEMS Microbiol Lett 217:1–7. https://doi.org/10.1111/j.1574-6968.2002.tb11448.x

    Article  CAS  PubMed  Google Scholar 

  7. Surel U, Niemirowicz K, Marzec M, Savage PB, Bucki R (2014) Ceragenins—a new weapon to fight multidrug resistant bacterial infections. Med Stud/Studia Medyczne 30:207–213. https://doi.org/10.5114/ms.2014.45428

    Article  Google Scholar 

  8. Paprocka P, Durnaś B, Mańkowska A et al (2021) New β-lactam antibiotics and ceragenins–a study to assess their potential in treatment of infections caused by multidrug-resistant strains of Pseudomonas aeruginosa. Infect Drug Resist 14:5681. https://doi.org/10.2147/IDR.S338827

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Guan Q, Li C, Schmidt EJ et al (2000) Preparation and characterization of cholic acid-derived antimicrobial agents with controlled stabilities. Org Lett 2:2837–2840. https://doi.org/10.1021/ol0062704

    Article  CAS  PubMed  Google Scholar 

  10. Doi Y (2019) Treatment options for carbapenem-resistant gram-negative bacterial infections. Clin Infect Dis 69:565–575. https://doi.org/10.1093/cid/ciz830

    Article  CAS  Google Scholar 

  11. Gilligan PH, Alby K, York MK (2016) Blood cultures. In: Leber A (ed) Clinical microbiology procedures handsbook, 4th edn. ASM Press, Washington, pp 3.4.1

  12. Church DL. Biochemical tests for the identification of aerobic bacteria. In: Leber A (ed) Clinical microbiology procedures handsbook, 4th edn. ASM Press, Washington, pp 3.17

  13. Clinical Labortary and Standards Institute (CLSI) (2023) Performance standards for antimicrobial susceptibility testing CLSI Supplement M100. 33th edn. USA: Wayne Pa

  14. Clinical Labortary and Standards Institute (CLSI)(2006) Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically approved standard M7-A7. 7th edn. USA: Wayne, Pa.

  15. Pillai SK MRJ, Eliopoulos GM (2005) Antimicrobial combinations. In: Lorian V (ed) Antibiotics in laboratory medicine. Lippincott Williams and Wilkins, Philadelphia, 5th edn. pp 365–440.

  16. Leber AL (2016) Synergysm testing: broth microdilution checkerboard and broth macrodilution testing. In: Leber A (ed) Clinical microbiology procedures handsbook, 4th edn. ASM Press, Washington, pp 5.16.1

  17. Odds FC (2003) Synergy, antagonism, and what the chequerboard puts between them. J Antimicrob Chemother 52:1. https://doi.org/10.1093/jac/dkg301

    Article  PubMed  Google Scholar 

  18. Falagas ME, Karageorgopoulos DE (2008) Pandrug resistance (PDR), extensive drug resistance (XDR), and multidrug resistance (MDR) among Gram-negative bacilli: need for international harmonization in terminology. Clin Infect Dis 46:1121–1122. https://doi.org/10.1086/528867

    Article  PubMed  Google Scholar 

  19. Hashemi MM, Holden BS, Coburn J et al (2019) Proteomic analysis of resistance of Gram-negative bacteria to chlorhexidine and impacts on susceptibility to colistin, antimicrobial peptides and ceragenins. Front Microbiol 10:210. https://doi.org/10.3389/fmicb.2019.00210

    Article  PubMed  PubMed Central  Google Scholar 

  20. The World Health Organization (2022) Antimicrobial resistance surveillance in Europe 2022–2020 data. https://www.ecdc.europa.eu/en/publications-data/antimicrobial-resistance-surveillance-europe-2022-2020-data. Acceessed 15 Dec 2022

  21. Chin JN, Jones RN, Sader HS, Savage PB, Rybak MJ (2008) Potential synergy activity of the novel ceragenin, CSA-13, against clinical isolates of Pseudomonas aeruginosa, including multidrug-resistant P. aeruginosa. J Antimicrob Chemother 61:365–370. https://doi.org/10.1093/jac/dkm457

    Article  CAS  PubMed  Google Scholar 

  22. Bozkurt Guzel C, Oyardi OB, Savage P (2018) Comparative in vitro antimicrobial activities of CSA-142 and CSA-192, second-generation ceragenins, with CSA-13 against various microorganisms. J Chemother 30:332–337. https://doi.org/10.1080/1120009X.2018.

    Article  CAS  PubMed  Google Scholar 

  23. Bozkurt-Guzel C, Inci G, Oyardi O, Savage PB (2020) Synergistic activity of ceragenins against carbapenem-resistant Acinetobacter baumannii strains in both checkerboard and dynamic time-kill assays. Curr Microbiol 77:1419–1428. https://doi.org/10.1007/s00284-020-01949-w

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Ozbek-Celik B, Damar-Celik D, Mataraci-Kara E, Bozkurt-Guzel C, Savage PB (2019) Comparative in vitro activities of first and second-generation ceragenins alone and in combination with antibiotics against multidrug-resistant Klebsiella pneumoniae strains. Antibiotics 8:130. https://doi.org/10.3390/antibiotics8030130

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. European Committee on Antimicrobial Susceptibility Testing-EUCAST (2022). Tigecycline: Rationale for EUCAST Clinical Breakpoints: EUCAST Available from: https://www.eucast.org/fileadmin/src/media/PDFs/EUCAST_files/Rationale_documents/Tigecycline_Rationale_Document_2.0_20220720.pdf. Accessed 15 Dec 2022

  26. Lai X-Z, Feng Y, Pollard J et al (2008) Ceragenins: cholic acid-based mimics of antimicrobial peptides. Acc Chem Res 41:1233–1240. https://doi.org/10.1021/ar700270t

    Article  CAS  PubMed  Google Scholar 

  27. Paprocka P, Mańkowska A, Skłodowski K et al (2022) Bactericidal activity of ceragenin in combination with ceftazidime, levofloxacin, Co-trimoxazole, and colistin against the opportunistic pathogen Stenotrophomonas maltophilia. Pathogens 11:621. https://doi.org/10.3390/pathogens11060621

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Güzel ÇB, Hacioğlu M, Gözde İ, Savage PB (2019) Antibacterial and antibiofilm activities of ceragenins against Pseudomonas aeruginosa clinical isolates. Turk J Pharm Sci 16:444. https://doi.org/10.4274/tjps.galenos.2018.59023

    Article  CAS  Google Scholar 

  29. Chmielewska SJ, Skłodowski K, Piktel E et al (2020) NDM-1 carbapenemase-producing Enterobacteriaceae are highly susceptible to ceragenins CSA-13, CSA-44, and CSA-131. Infect Drug Resist 13:3277. https://doi.org/10.2147/IDR.S261579

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Vila-Farrés X, Callarisa AE, Gu X, Savage PB, Giralt E, Vila J (2015) CSA-131, a ceragenin active against colistin-resistant Acinetobacter baumannii and Pseudomonas aeruginosa clinical isolates. Int J Antimicrob Agents 46:568–571. https://doi.org/10.1016/j.ijantimicag.2015.08.003

    Article  CAS  PubMed  Google Scholar 

  31. Oyardi Ö, Savage PB, Erturan Z, Bozkurt-Guzel C (2021) In vitro assessment of CSA-131 and CSA-131 poloxamer form for the treatment of Stenotrophomonas maltophilia infections in cystic fibrosis. J Antimicrob Chemother 76:443–450. https://doi.org/10.1093/jac/dkaa434

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Pharmaceutical Microbiology, Faculty of Pharmacy, Istanbul University, Istanbul, Türkiye

    Fatima Nur Yilmaz, Elif Sena Demir, Sibel Döşler & Çağla Bozkurt Güzel

  2. Department of Medical Microbiology, Istanbul Faculty of Medicine, Istanbul University, 34093-Capa-Fatih, Istanbul, Türkiye

    Lütfiye Öksüz

  3. Department of Chemistry and Biochemistry, Brigham Young University, Provo, UT, 84602, USA

    Paul B. Savage

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  1. Fatima Nur Yilmaz
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Contributions

Concept–LO, CBG, SD; Design– LO, CBG, SD; Supervision– LO, CBG, SD, PBS; Resources– LO, CBG, SD; Materials– LO, CBG, SD, PBS; Data Collection and/orProcessing– LO, CBG, SD, FNY, ED; Analysis and/or Interpretation– LO CBG, SD,_FNY, ED, PBS; Literature Search– LO CBG, SD; Writing Manuscript– LO, CBG, SD; Critical Review– LO, CBG, SD, PBS.

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Correspondence to Lütfiye Öksüz.

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Yilmaz, F.N., Öksüz, L., Demir, E.S. et al. Efficacy of Ceragenins Alone and in Combinations with Antibiotics Against Multidrug-Resistant Gram Negative Pathogens from Bloodstream Infections. Curr Microbiol 80, 327 (2023). https://doi.org/10.1007/s00284-023-03443-5

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