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Imaging of bacteria with radiolabeled ubiquicidin by SPECT and PET techniques

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Abstract

The ability to differentiate infection from sterile inflammation and monitor antimicrobial therapy against multidrug-resistant pathogens through imaging of bacteria with radiolabeled ubiquicidin (UBI 29-41) is a truly unique feature of the single photon emission computed tomography and positron emission tomography techniques, considering that conventional computed tomography; magnetic resonance imaging and ultrasound are not able to detect microorganisms. In this article, a systematic review of the reported diagnostic accuracy of 99mTc-UBI scintigraphy in detection of infections, as well as a review of the recent 68Ga-UBI studies for bacteria-targeted imaging, is presented. The results of 15 clinical studies (622 patients) carried out from 2004 to 2015 using 99mTc-UBI indicate a pooled sensitivity and specificity as high as 95.5 and 92.5 %, respectively, with an overall accuracy of 94.4 % (95 % confidence interval of 91.6–97.2 %). Preclinical studies reveal the same ability of 68Ga-UBI to identify bacteria by PET images. The reviewed studies demonstrated that radiolabeled UBI is a useful tracer for the accurate diagnosis of infections.

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References

  1. Holmes AH, Moore LS, Sundsfjord A, Steinbakk M, Regmi S, Karkey A, Guerin PJ, Piddock LJ (2016) Understanding the mechanisms and drivers of antimicrobial resistance. Lancet 387(10014):176–187

    Article  CAS  PubMed  Google Scholar 

  2. Ferro-Flores G, Ocampo-Garcia B, Melendez-Alafort L (2012) Development of specific radiopharmaceuticals for infection imaging by targeting infectious micro-organisms. Curr Pharm Des 18(8):1098–1106

    Article  CAS  PubMed  Google Scholar 

  3. Welling MM, Paulusma-Annema A, Balter HS, Pauwels EK, Nibbering PH (2000) Technetium-99m labelled antimicrobial peptides discriminate between bacterial infections and sterile inflammations. Eur J Nucl Med 27(3):292–301

    Article  CAS  PubMed  Google Scholar 

  4. Ferro-Flores G, de Murphy CA, Pedraza-López M, Meléndez-Alafort L, Zhang Y-M, Rusckowski M, Hnatowich DJ (2003) In vitro and in vivo assessment of 99mTc-UBI specificity for bacteria. Nucl Med Biol 30(6):597–603

    Article  CAS  PubMed  Google Scholar 

  5. Meléndez-Alafort L, de María Ramírez F, Ferro-Flores G, de Murphy CA, Pedraza-López M, Hnatowich DJ (2003) Lys and Arg in UBI: a specific site for a stable Tc-99m complex? Nucl Med Biol 30(6):605–615

    Article  PubMed  Google Scholar 

  6. Ferro-Flores G, de Murphy CA, Palomares-Rodriguez P, Melendez-Alafort L, Pedraza-Lopez M (2005) Kit for instant 99mTc labeling of the antimicrobial peptide ubiquicidin 29-41. J Radioanal Nucl Chem 266(2):307–311

    Article  CAS  Google Scholar 

  7. Ferro-Flores G, de María Ramírez F, Meléndez-Alafort L, de Murphy CA, Pedraza-López M (2004) Molecular recognition and stability of 99mTc-UBI 29-41 based on experimental and semiempirical results. Appl Radiat Isot 61(6):1261–1268

    Article  CAS  PubMed  Google Scholar 

  8. Nibbering PH, Welling MM, Paulusma-Annema A, Brouwer CP, Lupetti A, Pauwels EK (2004) 99mTc-Labeled UBI 29-41 peptide for monitoring the efficacy of antibacterial agents in mice infected with Staphylococcus aureus. J Nucl Med 45(2):321–326

    CAS  PubMed  Google Scholar 

  9. Meléndez-Alafort L, Nadali A, Pasut G, Zangoni E, De Caro R, Cariolato L, Giron MC, Castagliuolo I, Veronese FM, Mazzi U (2009) Detection of sites of infection in mice using 99mTc-labeled PN 2 S-PEG conjugated to UBI and 99mTc-UBI: a comparative biodistribution study. Nucl Med Biol 36(1):57–64

    Article  PubMed  Google Scholar 

  10. Smith DL, Breeman WA, Sims-Mourtada J (2013) The untapped potential of Gallium 68-PET: the next wave of 68Ga-agents. Appl Radiat Isot 76:14–23

    Article  CAS  PubMed  Google Scholar 

  11. Mcphee JB, Hancock RE (2005) Function and therapeutic potential of host defence peptides. J Pept Sci 11(11):677–687

    Article  CAS  PubMed  Google Scholar 

  12. Hancock RE (1997) Peptide antibiotics. Lancet 349(9049):418–422

    Article  CAS  PubMed  Google Scholar 

  13. Otvos L (2005) Antibacterial peptides and proteins with multiple cellular targets. J Pept Sci 11(11):697–706

    Article  CAS  PubMed  Google Scholar 

  14. Ginsburg I (2002) The role of bacteriolysis in the pathophysiology of inflammation, infection and post-infectious sequelae. APMIS 110(11):753–770

    Article  PubMed  Google Scholar 

  15. Brogden KA (2005) Antimicrobial peptides: pore formers or metabolic inhibitors in bacteria? Nat Rev Microbiol 3(3):238–250

    Article  CAS  PubMed  Google Scholar 

  16. Welling MM, Hiemstra PS, van den Barselaar MT, Paulusma-Annema A, Nibbering PH, Pauwels E, Calame W (1998) Antibacterial activity of human neutrophil defensins in experimental infections in mice is accompanied by increased leukocyte accumulation. J Clin Invest 102(8):1583

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Cole AM, Hong T, Boo LM, Nguyen T, Zhao C, Bristol G, Zack JA, Waring AJ, Yang OO, Lehrer RI (2002) Retrocyclin: a primate peptide that protects cells from infection by T-and M-tropic strains of HIV-1. PNAS 99(4):1813–1818

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Lupetti A, Paulusma-Annema A, Welling MM, Senesi S, van Dissel JT, Nibbering PH (2000) Candidacidal activities of human lactoferrin peptides derived from the N terminus. Antimicrob Agents Chemother 44(12):3257–3263

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Sharma S, Verma I, Khuller G (2001) Therapeutic potential of human neutrophil peptide 1 against experimental tuberculosis. Antimicrob Agents Chemother 45(2):639–640

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Brouwer CP, Bogaards SJ, Wulferink M, Velders MP, Welling MM (2006) Synthetic peptides derived from human antimicrobial peptide ubiquicidin accumulate at sites of infections and eradicate (multi-drug resistant) Staphylococcus aureus in mice. Peptides 27(11):2585–2591

    Article  CAS  PubMed  Google Scholar 

  21. Welling MM, Lupetti A, Balter HS, Lanzzeri S, Souto B, Rey AM, Savio EO, Paulusma-Annema A, Pauwels EK, Nibbering PH (2001) 99mTc-labeled antimicrobial peptides for detection of bacterial and Candida albicans infections. J Nucl Med 42(5):788–794

    CAS  PubMed  Google Scholar 

  22. Lupetti A, Welling MM, Pauwels EK, Nibbering PH (2003) Radiolabelled antimicrobial peptides for infection detection. Lancet Infect Dis 3(4):223–229

    Article  CAS  PubMed  Google Scholar 

  23. Meléndez-Alafort L, Rodríguez-Cortés J, Ferro-Flores G, De Murphy CA, Herrera-Rodríguez R, Mitsoura E, Martínez-Duncker C (2004) Biokinetics of 99mTc-UBI 29-41 in humans. Nucl Med Biol 31(3):373–379

    Article  PubMed  Google Scholar 

  24. Akhtar MS, Qaisar A, Irfanullah J, Iqbal J, Khan B, Jehangir M, Nadeem MA, Khan MA, Afzal MS, Imran MB (2005) Antimicrobial peptide 99mTc-ubiquicidin 29-41 as human infection-imaging agent: clinical trial. J Nucl Med 46(4):567–573

    CAS  PubMed  Google Scholar 

  25. Ostovar A, Assadi M, Vahdat K, Nabipour I, Javadi H, Eftekhari M, Assadi M (2013) A pooled analysis of diagnostic value of 99mTc-ubiquicidin (UBI) scintigraphy in detection of an infectious process. Clin Nucl Med 38(6):413–416

    Article  PubMed  Google Scholar 

  26. Vallejo E, Martinez I, Tejero A, Hernandez S, Jimenez L, Bialostozky D, Sanchez G, Ilarraza H, Ferro-Flores G (2008) Clinical utility of 99m Tc-labeled ubiquicidin 29-41 antimicrobial peptide for the scintigraphic detection of mediastinitis after cardiac surgery. Arch Med Res 39(8):768–774

    Article  CAS  PubMed  Google Scholar 

  27. Gandomkar M, Najafi R, Shafiei M, Mazidi M, Goudarzi M, Mirfallah SH, Ebrahimi F, Heydarpor HR, Abdie N (2009) Clinical evaluation of antimicrobial peptide [99mTc/Tricine/HYNIC 0] ubiquicidin 29-41 as a human-specific infection imaging agent. Nucl Med Biol 36(2):199–205

    Article  CAS  PubMed  Google Scholar 

  28. de Murphy CA, Gemmel F, Balter J (2010) Clinical trial of specific imaging of infections. Nucl Med Commun 31(8):726–733

    Article  Google Scholar 

  29. Sepúlveda-Méndez J, de Murphy CA, Rojas-Bautista JC, Pedraza-López M (2010) Specificity of 99mTc-UBI for detecting infection foci in patients with fever in study. Nucl Med Commun 31(10):889–895

    PubMed  Google Scholar 

  30. Fard-Esfahani A, Beiki D, Fallahi B, Mohajeri-Tehrani MR, Gharaie MR, Dehghanian M, Saghari M, Emami-Ardekani A, Eftekhari M (2010) Evaluation of 99mTc-ubiquicidin 29-41 scintigraphyin in differentiation of bacterial infection from sterile inflammationin diabetic foot. Iran J Nucl Med 18(2):20–28

    CAS  Google Scholar 

  31. Dillmann-Arroyo C, Cantu-Leal R, Campa-Nunez H, López-Cavazos C, Bermúdez-Argüelles M, Mejía-Herrera J (2011) Application of the ubiquicidin 29-41 scan in the diagnosis of pyogenic vertebral osteomyelitis. Acta Ortop Mex 25(1):27–31

    CAS  PubMed  Google Scholar 

  32. Assadi M, Vahdat K, Nabipour I, Sehhat MR, Hadavand F, Javadi H, Tavakoli A, Saberifard J, Kalantarhormozi MR, Zakani A (2011) Diagnostic value of 99mTc-ubiquicidin scintigraphy for osteomyelitis and comparisons with 99mTc-methylene diphosphonate scintigraphy and magnetic resonance imaging. Nucl Med Commun 32(8):716–723

    Article  PubMed  Google Scholar 

  33. Nazari B, Azizmohammadi Z, Rajaei M, Karami M, Javadi H, Assadi M, Asli IN (2011) Role of 99mTc-ubiquicidin 29-41 scintigraphy to monitor antibiotic therapy in patients with orthopedic infection: a preliminary study. Nucl Med Commun 32(8):745–751

    Article  CAS  PubMed  Google Scholar 

  34. Aryana K, Hootkani A, Sadeghi R, Davoudi Y, Naderinasab M, Erfani M, Ayati N (2012) 99mTc-labeled ubiquicidin scintigraphy. Nuklearmedizin 51(4):133–139

    Article  CAS  PubMed  Google Scholar 

  35. Beiki D, Yousefi G, Fallahi B, Tahmasebi MN, Gholamrezanezhad A, Fard-Esfahani A, Erfani M, Eftekhari M (2013) 99mtc-Ubiquicidin [29-41], a promising radiopharmaceutical to differentiate orthopedic implant infections from sterile inflammation. Iran J Pharma Res 12(2):347–353

    CAS  Google Scholar 

  36. Saeed S, Zafar J, Khan B, Akhtar A, Qurieshi S, Fatima S, Ahmad N, Irfanullah J (2013) Utility of 99mTc-labelled antimicrobial peptide ubiquicidin (29-41) in the diagnosis of diabetic foot infection. Eur J Nucl Med Mol Imaging 40(5):737–743

    Article  CAS  PubMed  Google Scholar 

  37. Abbasian M, Salman Azarsina M (2015) Diagnostic efficacy of UBI scan in musculoskeletal infections. Arch Iran Med 18(6):371

    PubMed  Google Scholar 

  38. Doroudi A, Samaee H, Saadati SM, Ahmadi F, Kiasat A, Erfani M (2015) Clinical evaluation of 99mTc-MDP three phase bone scan and 99mTc-UBI 29-41 scintigraphy imaging in preferentially detection infection from sterile inflammation among diabetic patients with suspected foot infection. IOSR J Pharm 5(2):20–26

    CAS  Google Scholar 

  39. Verbruggen A, Coenen HH, Deverre J-R, Guilloteau D, Langstrom B, Salvadori PA, Halldin C (2008) Guideline to regulations for radiopharmaceuticals in early phase clinical trials in the EU. Eur J Nucl Med Mol Imaging 35(11):2144–2151

    Article  CAS  PubMed  Google Scholar 

  40. Wild SH, Roglic G, Green A, Sicree R, King H (2004) Global prevalence of diabetes: estimates for the year 2000 and projections for 2030 response to Rathman and Giani. Diabetes Care 27(10):2569

    Article  Google Scholar 

  41. Lavery LA, Armstrong DG, Wunderlich RP, Mohler MJ, Wendel CS, Lipsky BA (2006) Risk factors for foot infections in individuals with diabetes. Diabetes Care 29(6):1288–1293

    Article  PubMed  Google Scholar 

  42. Lipsky BA (1997) Osteomyelitis of the foot in diabetic patients. Clin Infect Dis 25(6):1318–1326

    Article  CAS  PubMed  Google Scholar 

  43. Lipsky BA, Berendt AR, Deery HG, Embil JM, Joseph WS, Karchmer AW, LeFrock JL, Lew DP, Mader JT, Norden C (2004) Diagnosis and treatment of diabetic foot infections. Clin Infect Dis 39(7):885–910

    Article  PubMed  Google Scholar 

  44. Ebenhan T, Chadwick N, Sathekge MM, Govender P, Govender T, Kruger HG, Marjanovic-Painter B, Zeevaart JR (2014) Peptide synthesis, characterization and 68Ga-radiolabeling of NOTA-conjugated ubiquicidin fragments for prospective infection imaging with PET/CT. Nucl Med Biol 41(5):390–400

    Article  CAS  PubMed  Google Scholar 

  45. Ebenhan T, Zeevaart JR, Venter JD, Govender T, Kruger GH, Jarvis NV, Sathekge MM (2014) Preclinical evaluation of 68Ga-labeled 1, 4, 7-triazacyclononane-1, 4, 7-triacetic acid-ubiquicidin as a radioligand for PET infection imaging. J Nucl Med 55(2):308–314

    Article  CAS  PubMed  Google Scholar 

  46. Vilche MB, Reyes AL, Vasilskis E, Oliver P, Balter HS, Engler HW (2016) 68Ga-NOTA-UBI 29-41 as a PET tracer for detection of bacterial infection. J Nucl Med. doi:10.2967/jnumed.115.161265

    PubMed  Google Scholar 

  47. Máté G, Šimeček J, Pniok M, Kertész I, Notni J, Wester H-J, Galuska L, Hermann P (2015) The influence of the combination of carboxylate and phosphinate pendant arms in 1, 4, 7-triazacyclononane-based chelators on their 68Ga labelling properties. Molecules 20(7):13112–13126

    Article  PubMed  Google Scholar 

  48. Mukai T, Suwada J, Sano K, Okada M, Yamamoto F, Maeda M (2009) Design of Ga–DOTA-based bifunctional radiopharmaceuticals: two functional moieties can be conjugated to radiogallium–DOTA without reducing the complex stability. Bioorg Med Chem 17(13):4285–4289

    Article  CAS  PubMed  Google Scholar 

  49. Rösch F (2013) Past, present and future of 68Ge/68Ga generators. Appl Radiat Isot 76:24–30

    Article  PubMed  Google Scholar 

  50. Vis R, Lavalaye J, van de Garde EM (2015) GMP-compliant 68Ga radiolabelling in a conventional small-scale radiopharmacy: a feasible approach for routine clinical use. EJNMMI Res 5(1):1–7

    Article  CAS  Google Scholar 

  51. Ebenhan T, Gheysens O, Kruger HG, Zeevaart JR, Sathekge MM (2014) Antimicrobial peptides: their role as infection-selective tracers for molecular imaging. BioMed Res Int 2014:867381. doi:10.1155/2014/867381

    Article  PubMed  PubMed Central  Google Scholar 

  52. van Oosten M, Hahn M, Crane LM, Pleijhuis RG, Francis KP, van Dijl JM, van Dam GM (2015) Targeted imaging of bacterial infections: advances, hurdles and hopes. FEMS Microbiol Rev 39(6):892–916

    Article  PubMed  Google Scholar 

  53. Bunschoten A, Welling M, Termaat M, Sathekge M, Van Leeuwen F (2013) Development and prospects of dedicated tracers for the molecular imaging of bacterial infections. Bioconjugate Chem 24(12):1971–1989

    Article  CAS  Google Scholar 

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Acknowledgments

The authors acknowledge the funding provided by the National Council of Science and Technology-Mexico (CONACYT-SEP-CB-2014-01-242443) and the International Atomic Energy Agency (RC16467).

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Authors and Affiliations

  1. Departamento de Materiales Radiactivos, Instituto Nacional de Investigaciones Nucleares, Carretera México-Toluca S/N. La Marquesa, C.P. 52750, Ocoyoacac, Estado de México, Mexico

    Guillermina Ferro-Flores

  2. Unidad Radiofarmacia-Ciclotrón, Facultad de Medicina, Universidad Nacional Autónoma de México, 04510, Mexico City, Mexico

    Miguel A. Avila-Rodríguez

  3. Departamento de Medicina Nuclear, Instituto Nacional de Cancerología, Mexico City, Mexico

    Francisco O. García-Pérez

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  1. Guillermina Ferro-Flores
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  2. Miguel A. Avila-Rodríguez
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  3. Francisco O. García-Pérez
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Correspondence to Guillermina Ferro-Flores.

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Ethical approval

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008. Informed consent was obtained from all patients for being included in the study.

Conflict of interest

Ferro-Flores G, Avila-Rodriguez MA and Garcia-Perez OF declare that they have no conflict of interest.

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Ferro-Flores, G., Avila-Rodríguez, M.A. & García-Pérez, F.O. Imaging of bacteria with radiolabeled ubiquicidin by SPECT and PET techniques. Clin Transl Imaging 4, 175–182 (2016). https://doi.org/10.1007/s40336-016-0178-7

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  • DOI: https://doi.org/10.1007/s40336-016-0178-7

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