Skip to main content
SpringerLink
Log in

The efficacy of mesenchymal stem cell therapy in experimental sepsis induced by carbapenem-resistant K. pneumoniae in neutropenic mice model

  • Original Article
  • Published:
European Journal of Clinical Microbiology & Infectious Diseases Aims and scope Submit manuscript

Abstract

Especially in recent years, the intensive use of antibiotics has caused multiple drug resistance in Klebsiella pneumoniae. In the absence of a new antibiotic, alternative treatment options have emerged. The aim of this study was to investigate the efficacy of mesenchymal stem cell (MSC) treatment of carbapenem-resistant K. pneumoniae sepsis in neutropenic murine model. BALB-c mice were divided into two groups as control (positive and negative) and treatment groups (colistin, colistin + MSC, MSC) after the development of neutropenia with cyclophosphamide. Sepsis was developed in mice by intraperitoneal injection of carbapenem-resistant K. pneumoniae. Three hours after inoculation of the bacteria, colistin and MSC were given in the treatment groups intraperitoneally. Colistin injection was repeated every 12 h, while MSC was administered as 2nd dose after 48 h. Mice were sacrificed at 48 and 96 h. The right lung and half of the liver were quantitatively cultured, and the bacterial load was calculated as cfu/g. The left lung, the other half of the liver tissue, and both kidneys were evaluated histopathologically. IL-6 and TNF-α cytokine levels in mouse sera were determined by ELISA. Bacterial loads in lung and liver tissues of neutropenic mice were lower in the MSC + colistin-treated group at 48 and 96 h compared to colistin and MSC monotherapy groups. Also, bacterial eradication was started the earliest in MSC + colistin group. It was concluded that combining colistin with MSC provided improved therapeutic effects compared to colistin or MSC monotherapy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Singer M, Deutschman CS, Seymour CW et al (2016) The third international consensus definitions for sepsis and septic shock (Sepsis-3). JAMA 315:801–810. https://doi.org/10.1001/jama.2016.0287

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Angus D, van der Poll T (2013) Severe sepsis and septic shock. New Engl J Med 369:840–851

    Article  CAS  PubMed  Google Scholar 

  3. Remick DG (2007) Pathophysiology of sepsis. Am J Pathol 170(5):1435–1444

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Alp E (2016) Right first time! Ann Transl Med 4(17):331. https://doi.org/10.21037/atm.2016.08.52

    Article  PubMed  PubMed Central  Google Scholar 

  5. Grande VM, Kumar A (2015) Optimizing antimicrobial therapy of Sepsis and septic shock: focus on antibiotic combination therapy. Semin Resp Crit Care 36:154–166

    Article  Google Scholar 

  6. Adhikari NK, Fowler RA, Bhagwanjee S, Rubenfeld GD (2010) Critical care and the global burden of critical illness in adults. Lancet 376(9749):1339–1346

    Article  PubMed  PubMed Central  Google Scholar 

  7. Genga KA, Russell JA (2017) Update of sepsis in the intensive care unit. J Innate Immun 9:441–455

    Article  PubMed  PubMed Central  Google Scholar 

  8. Zilberberg MD, Shorr AF, Micek ST, Vazquez-Guillamet C, Kollef MH (2014) Multidrug resistance, inappropriate initial antibiotic therapy and mortality in gram negative severe sepsis and septic shock: a retrospective cohort study. Crit Care 18(6):596

    Article  PubMed  PubMed Central  Google Scholar 

  9. Falagas ME, Lourida P, Poulikakos P, Rafailidis PI, Tansarli GSP (2014) Antibiotic treatment of infections due to carbapenem-resistant Enterobacteriaceae: systematic evaluation of the available evidence. Antimicrob Agents Chemother 58(2):654–663

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Donnenberg MS (2010) Enterobacteriaceae. In: Mandell GL, Bennett JE, Dolin R (eds) Principles and pratice of infectious diseas, 7th edn. Elsevier Churchill Livingstone, Philedelphia, pp 2815–2833

    Google Scholar 

  11. Bishara J, Leibovici L, Huminer D, Drucker M, Samra Z, Konisberger H, Pitlik S (1997) Five-year prospective study of bacteraemic urinary tract infection in a single institution. Eur J Clin Microbiol Infect Dis 16:563–567

    Article  CAS  PubMed  Google Scholar 

  12. Arnold RS, Thom KA, Sharma S, Phillips M, Johnson KJ, Morgan DJ (2011) Emergence of Klebsiella pneumoniae carbapenemase-producing bacteria. South Med J 104(1):40–45

    Article  PubMed  PubMed Central  Google Scholar 

  13. Nordmann P, Cuzon G, Naas T (2009) The real threat of Klebsiella pneumoniae carbapenemase-producing bacteria. Lancet Infect Dis 9:228–236

    Article  CAS  PubMed  Google Scholar 

  14. Ko WC, Paterson DL, Sagnimeni AJ, Hansen DS, Von Gottberg A, Mohapatra S, Casellas JM, Goossens H, Mulazimoglu L, Trenholme G, Klugman KP, McCormack JG, Yu VL (2002) Community-acquired Klebsiella pneumoniae bacteremia: global differences in clinical patterns. Emerg Infect Dis 8:160–166

    Article  PubMed  PubMed Central  Google Scholar 

  15. Wu K, Wang F, Sun J, Wang Q, Chen Q, Yu S, Rui Y (2012) Class 1 integron gene cassettes in multidrug-resistant gram-negative bacteria in southern China. Int J Antimicrob Agents 40(3):264–267

    Article  CAS  PubMed  Google Scholar 

  16. Naas T, Cuzon G, Villegas MV, Lartigue MF, Quinn JP, Nordmann P (2008) Genetic structures at the origin of acquisition of the beta-lactamase Bla KPC gene. Antimicrob Agents Chemother 52:1257–1263

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Giamarellou H, Poulakou G (2009) Multidrug-resistant gram-negative infections: what are the treatment options? Drugs 69(14):1879–1901

    Article  CAS  PubMed  Google Scholar 

  18. Saeedi P, Halabian R, Fooladi AAI (2018) Mesenchymal stem cells preconditioned by staphylococcal enterotoxin B enhance survival and bacterial clearance in murine sepsis model. Cytotherapy 21(1):41–53

    Article  CAS  PubMed  Google Scholar 

  19. Bouglé A, Rocheteau P, Hivelin M, Haroche A, Briand D, Tremolada C, Mantz J, Chrétien F (2018) Micro-fragmented fat injection reduces sepsis-induced acute inflammatory response in a mouse model. Br J Anaesth 121(6):1249–1259

    Article  PubMed  Google Scholar 

  20. Ko HF, Tsui SS, Tse JW, Kwong WY, Chan OY, Wong GC (2015) Improving the emergency department management of post-chemotherapy sepsis in haematological malignancy patients. Hong Kong Med J 21(1):10–15

    CAS  PubMed  Google Scholar 

  21. Lombardo E, van der Poll T, DelaRosa O, Dalemans W (2015) Mesenchymal stem cells as a therapeutic tool to treat sepsis. World J Stem Cells 7(2):368–379

    Article  PubMed  PubMed Central  Google Scholar 

  22. Martinez-Gonzalez I, Roca O, Masclans JR, Moreno R, Salcedo MT, Baekelandt V, Cruz MJ, Rello J, Aran JM (2013) Human mesenchymal stem cells overexpressing the IL-33 antagonist soluble IL-1 receptor-like-1 attenuate endotoxin-induced acute lung injury. Am J Respir Cell Mol Biol 49(4):552–562

    Article  CAS  PubMed  Google Scholar 

  23. Luo CJ, Zhang FJ, Zhang L, Geng YQ, Li QG, Hong Q, Fu B, Zhu F, Cui SY, Feng Z, Sun XF, Chen XM (2014) Mesenchymal stem cells ameliorate sepsis-associated acute kidney injury in mice. Shock 41(2):123–129

    Article  CAS  PubMed  Google Scholar 

  24. Castro-Manrreza ME, Montesinos JJ (2015) Immunoregulation by mesenchymal stem cells: biological aspects and clinical applications. J Immunol Res 2015:394917. https://doi.org/10.1155/2015/394917

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Pedrazza L, Lunardelli A, Luft C, Cruz CU, de Mesquita FC, Bitencourt S, Nunes FB, de Oliveira JR (2014) Mesenchymal stem cells decrease splenocytes apoptosis in a sepsis experimental model. Inflamm Res 63(9):719–728

    Article  CAS  PubMed  Google Scholar 

  26. Yang J, Jia Z (2014) Cell-based therapy in lung regenerative medicine. Regen Med Res 2(1):7. https://doi.org/10.1186/2050-490X-2-7

    Article  PubMed  PubMed Central  Google Scholar 

  27. Demiraslan H, Dinc G, Ahmed SS, Elmali F, Metan G, Alp E, Doganay M (2014) Carbapenem-resistant Klebsiella pneumoniae sepsis in corticosteroid receipt mice: tigecycline or colistin monotherapy versus tigecycline/colistin combination. J Chemother 26(5):276–281

    Article  CAS  PubMed  Google Scholar 

  28. Zeng D, Sun M, Lin Z, Li M, Gehring R, Zeng Z (2018) Pharmacokinetics and pharmacodynamics of Tildipirosin against Pasteurella multocida in a murine lung infection model. Front Microbiol. https://doi.org/10.3389/fmicb.2018.01038

  29. Zuluaga AF, Salazar BE, Rodriguez CA, Zapata AX, Agudelo M, Vesga O (2006) Neutropenia induced in outbred mice by a simplified low-dose cyclophosphamide regimen: characterization and applicability to diverse experimental models of infectious diseases. BMC Infect Dis. https://doi.org/10.1186/1471-2334-6-55

  30. Soleimani M, Nadri S (2009) A protocol for isolation and culture of mesenchymal stem cells from mouse bone marrow. Nat Protoc 4(1):102–106

    Article  CAS  PubMed  Google Scholar 

  31. Saeedi P, Halabian R, Fooladi AAI (2018) Antimicrobial effects of mesenchymal stem cells primed by modified LPS on bacterial clearance in sepsis. J Cell Physiol. https://doi.org/10.1002/jcp.27298

  32. Laroye C, Gibot S, Reppel L, Bensoussan D (2017) Concise review: mesenchymal stromal/stem cells: a new treatment for sepsis and septic shock? Stem Cells 35(12):2331–2339

    Article  PubMed  Google Scholar 

  33. Mei SH, Haitsma JJ, Dos Santos CC, Deng Y, Lai PF, Slutsky AS, Liles WC, Stewart DJ (2010) Mesenchymal stem cells reduce inflammation while enhancing bacterial clearance and improving survival in sepsis. Am J Res Crit Care Med 182(8):1047–1057

    Article  CAS  Google Scholar 

  34. Kim H, Darwish I, Monroy MF, Prockop DJ, Liles WC, Kain KC (2014) Mesenchymal stromal (stem) cells suppress pro-inflammatory cytokine production but fail to improve survival in experimental staphylococcal toxic shock syndrome. BMC Immunol 14(15):1. https://doi.org/10.1186/1471-2172-15-1

    Article  CAS  Google Scholar 

  35. Mei S, Wang S, Jin S, Zhao X, Shao Z, Zhang R, Yu X, Tong Y, Chen S, Chen Z, Li Q (2019) Human adipose tissue-derived stromal cells attenuate the multiple organ injuries induced by sepsis and mechanical ventilation in mice. Inflammation 42(2):485–495

    Article  CAS  PubMed  Google Scholar 

  36. Behjani ZZ, Ai J, Soleimani M, Atashi A, Taheri B, Ebrahimi-Barough S, Siavashi V, Shirian S, Hamidieh AA (2019) Human unrestricted somatic stem cells ameliorate sepsis-related acute lung injury in mice. J Cell Physiol 234(4):4970–4986

    Article  CAS  Google Scholar 

  37. Michail G, Labrou M, Pitiriga V, Manousaka S, Sakellaridis N, Tsakris A, Pournaras S (2013) Activity of tigecycline in combination with colistin, meropenem, rifampin, or gentamicin against KPC-producing Enterobacteriaceae in a murine thigh infection model. Antimicrob Agents Chemother 57(12):6028–6033

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Docobo-Pérez F, Nordmann P, Domínguez-Herrera J, López-Rojas R, Smani Y, Poirel L, Pachón J (2012) Efficacies of colistin and tigecycline in mice with experimental pneumonia due to NDM-1-producing strains of Klebsiella pneumoniae and Escherichia coli. Int J Antimicrob Agents 39(3):251–254

    Article  CAS  PubMed  Google Scholar 

  39. Luo G, Spellberg B, Gebremariam T, Bolaris M, Lee H, Fu Y, French SW, Ibrahim AS (2012) Diabetic murine models for Acinetobacter baumannii infection. J Antimicrob Chemother 67(6):1439–1445

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

The present study was funded by a grant from the Scientific and Technological Research Council of Turkey (TUBITAK, Project No: 216S893).

Author information

Authors and Affiliations

  1. Department of Medical Microbiology, Faculty of Medicine, Erciyes University, 38039, Kayseri, Turkey

    Gokcen Dinc

  2. Department of Molecular Microbiology, Genome and Stem Cell Centre, Erciyes University, Kayseri, Turkey

    Gokcen Dinc

  3. Department of Infectious Diseases and Clinical Microbiology, Kayseri City Hospital, Kayseri, Turkey

    Esma Eren

  4. Department of Medical Pathology, Faculty of Medicine, Erciyes University, Kayseri, Turkey

    Olgun Kontas

  5. Department of Infectious Diseases and Clinical Microbiology, Faculty of Medicine, Erciyes University, Kayseri, Turkey

    Mehmet Doganay

Authors
  1. Gokcen Dinc
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Esma Eren
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Olgun Kontas
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mehmet Doganay
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Gokcen Dinc.

Ethics declarations

Conflict of interest

The authors declare that they have no conflicts of interest.

Ethical approval

The animal experiments of this study were approved by the Animal Experiments Local Ethics Committee of Erciyes University (Permit number: 16/063). This study was carried out in accordance with the recommendations of the National board of Erciyes University Animal Experiments Local Ethics Committee and also animal studies were conducted in accordance with the recommendations of the European Community (Directive 86/609/EEC).

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Dinc, G., Eren, E., Kontas, O. et al. The efficacy of mesenchymal stem cell therapy in experimental sepsis induced by carbapenem-resistant K. pneumoniae in neutropenic mice model. Eur J Clin Microbiol Infect Dis 39, 1739–1744 (2020). https://doi.org/10.1007/s10096-020-03910-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10096-020-03910-y

Keywords

Search

Navigation