Generation of Antibiotic Tolerant Bacterial Persisters in Immunocompromized Patients with Hematologic and Malignant Diseases: A New Problem of Health-Care Associated Infections

Cover Page


Cite item

Full Text

Abstract

Background: Antibiotic tolerance (AT) represents one of the causes of the phenomenon of antibiotic resistance that allows escape of non-replicating metabolically inert microorganisms (persisters) from any antibiotics attack because molecular targets of antibiotics are lacking thereby creating the potential for chronic infections. 

Aims:Determine the heterogeneity of the strains of opportunistic pathogens E. coli and P. aeruginosa isolates from children with hematologic malignancies containing bacterial persisters that cause the AT phenomenon. 

Methods: Children with hematological malignancies were divided into 2 groups according to the intensity of antibiotic treatment of infectious complications. Ciprofloxacin-induced persisters were quantitatively determined in the biological materials obtained from sick children. 

Results: Within the clinical isolates of E. coli and P. aeruginosa, about a third of the strains belong to high-persisting. The numbers of persistent forms of bacteria did not correlate with a minimal inhibitory concentration values ciprofloxacin (r=0.148, n=25, p>0.05). Interestingly, higher level of formation of persistent E. coli and P. aeruginosa, is associated with higher frequencies of infection attacks, massive antibiotic use and unfavorable course of the disease in children. 

Conclusions: Therefore, detecting the persistent forms of bacterial pathogens including those associated with the health-care associated infection, specifically, in immunocompromised patients, should be included into the contemporary algorithms of microbiological observation and monitoring of patients and intrahospital environment.

About the authors

A. V. Tutelyan

Central Institute of Epidemiology, Moscow;
Dmitry Rogachev’s Federal Scientific and Clinical Centre of Pediatric Hematology, Oncology and Immunology, Moscow;
I.M. Sechenov First Moscow State Medical University

Author for correspondence.
Email: bio-tav@yandex.ru
Доктор медицинских наук, заведующий лабораторией инфекций, связанных с оказанием медицинской помощи, Центрального НИИ эпидемиологии Роспотребнадзора; профессор кафедры эпидемиологии ИПО Первого МГМУ им. И.М. Сеченова Россия

V. M. Pisarev

Central Institute of Epidemiology, Moscow;
Dmitry Rogachev’s Federal Scientific and Clinical Centre of Pediatric Hematology, Oncology and Immunology, Moscow;
V.A. Negovsky Research Institute of General Reanimatology, Moscow

Email: vpisarev@gmail.com
Доктор медицинских наук, профессор, заведующий лабораторией молекулярных механизмов критических состояний НИИ общей реаниматологии им. В.А. Неговского Россия

N. Z. Minaeva

Central Institute of Epidemiology, Moscow

Email: natm9797@ya.ru
Россия

A. M. Gaponov

Central Institute of Epidemiology, Moscow;
Dmitry Rogachev’s Federal Scientific and Clinical Centre of Pediatric Hematology, Oncology and Immunology, Moscow;
V.A. Negovsky Research Institute of General Reanimatology, Moscow

Email: zorba@yandex.ru
Кандидат медицинских наук, заведующий лабораторией инфекционной иммунологии ФНКЦ ДГОИ им. Дмитрия Рогачёва Россия

A. N. Gracheva

Dmitry Rogachev’s Federal Scientific and Clinical Centre of Pediatric Hematology, Oncology and Immunology, Moscow

Email: alnickgrach@mail.ru
Бактериолог отдела инфекционного контроля  Россия

G. G. Solopova

Dmitry Rogachev’s Federal Scientific and Clinical Centre of Pediatric Hematology, Oncology and Immunology, Moscow

Email: galigen@yahoo.co.uk
Кандидат медицинских наук, заведующая отделом инфекционного контроля Россия

References

  1. Abraham EP, Chain E. An enzyme from bacteria able to destroy penicillin. Nature. 1940;146(3713):837. doi: 10.1038/146837a0.
  2. Bigger JW. Treatment of staphylococcal infections with penicillin by intermittent sterilization. Lancet. 1944,244(6320):497–500. doi: 10.1016/S0140-6736(00)74210-3.
  3. Levin BR. Microbiology: Noninherited resistance to antibiotics. Science. 2004;305(5690):1578–1579. doi: 10.1126/science.1103077.
  4. Gillings MR, Stokes HW. Are humans increasing bacterial evolvability? Trends Ecol Evol. 2012;27(6):346–352. doi: 10.1016/j.tree.2012.02.006.
  5. Kahrstrom CT. Antimicrobials: persisters come under fire. Nat Rev Microbiol. 2014;12(1):3. doi: 10.1038/nrmicro3181
  6. Mc Dermott W. Microbial persistence. Yale J Biol Med. 1958;30(4):257–229.
  7. Balaban NQ, Merrin J, Chait R, et al. Bacterial persistence as a phenotypic switch. Science. 2004;305(5690):1622–1625. doi: 10.1126/science.1099390.
  8. Lewis K. Persister cells. Annu Rev Microbiol. 2010;64:357–372. doi: 10.1146/annurev.micro.112408.134306.
  9. Balaban NQ. Persistence: mechanisms for triggering and enhancing phenotypic variability. Curr Opin Genet Dev. 2011;21(6):768–775. doi: 10.1016/j.gde.2011.10.001.
  10. Kint CI, Verstraeten N, Fauvart M, Michiels J. New-found fundamentals of bacterial persistence. Trends Microbiol. 2012;20(12):577–585. doi: 10.1016/j.tim.2012.08.009.
  11. Verstraeten N, Knapen W, Fauvart M, Michiels J. A historical perspective on bacterial persistence. Methods Mol Biol. 2016;1333:3–13. doi: 10.1007/978-1-4939-2854-5_1.
  12. Lewis K. Multidrug tolerance of biofilms and persister cells. Curr Top Microbiol Immunol. 2008;322:107–131. doi: 10.1007/978-3-540-75418-3_6.
  13. Römling U, Balsalobre C. Biofilm infections, their resilience to therapy and innovative treatment strategies. J Intern Med. 2012;272(6):541–561. doi: 10.1111/joim.12004.
  14. Эль-Регистан Г.И., Николаев Ю.А., Мулюкин А.Л., и др. Явление персистенции ― формы и механизмы выживаемости популяций // Медицинский алфавит. ― 2014. ― Т. 2. ― №10. ― С. 49–54. [El’-Registan GI, Nikolaev YuA, Mulyukin AL, et al. Yavlenie persistentsii ― formy i mekhanizmy vyzhivaemosti populyatsii. Meditsinskii alfavit. 2014;2(10):49–54. (In Russ).]
  15. Kim JS, Heo P, Yang TJ, et al. Bacterial persisters tolerate antibiotics by not producing hydroxyl radicals. Biochem Biophys Res Commun. 2011;413(1):105–110. doi: 10.1016/j.bbrc.2011.08.063.
  16. Lewis K. Persister cells: molecular mechanisms related to antibiotic tolerance. Handb Exp Pharmacol. 2012(211):121-133. doi: 10.1007/978-3-642-28951-4_8.
  17. Li Y, Zhang Y. PhoU is a persistence switch involved in persister formation and tolerance to multiple antibiotics and stresses in Escherichia coli. Antimicrob Agents Chemother. 2007;51(6):2092–2099. doi: 10.1128/aac.00052-07.
  18. Balaban NQ, Gerdes K, Lewis K, McKinney JD. A problem of persistence: still more questions than answers? Nat Rev Microbiol. 2013;11(8):587–591. doi: 10.1038/nrmicro3076.
  19. Conlon BP, Rowe SE, Lewis K. Persister cells in biofilm associated infections. Adv Exp Med Biol. 2015;831:1–9. doi: 10.1007/978-3-319-09782-4_1.
  20. Delarze E, Sanglard D. Defining the frontiers between antifungal resistance, tolerance and the concept of persistence. Drug Resist Updat. 2015;23:12−19. doi: 10.1016/j.drup.2015.10.001.
  21. Kaldalu N, Joers A, Ingelman H, Tenson T. A general method for measuring persister levels in Escherichia coli cultures. Methods Mol Biol. 2016;1333:29–42. doi: 10.1007/978-1-4939-2854-5_3.
  22. Moker N, Dean CR, Tao J. Pseudomonas aeruginosa increases formation of multidrug-tolerant persister cells in response to quorum-sensing signaling molecules. J Bacteriol. 2010;192(7):1946–1955. doi: 10.1128/JB.01231-09.
  23. Keilin D. The problem of anabiosis or latent life: history and current concept. Proc R Soc Lond B Biol Sci. 1959;150(939):149–191. doi: 10.1098/rspb.1959.0013.
  24. Potgieter M, Bester J, Kell DB, Pretorius E. The dormant blood microbiome in chronic, inflammatory diseases. FEMS Microbiol Rev. 2015;39(4):567–591. doi: 10.1093/femsre/fuv013.
  25. Fauvart M, De Groote VN, Michiels J. Role of persister cells in chronic infections: clinical relevance and perspectives on anti-persister therapies. J Med Microbiol. 2011;60(6):699–709. doi: 10.1099/jmm.0.030932-0.
  26. Wayne LG, Sohaskey CD. Nonreplicating persistence of mycobacterium tuberculosis. Annu Rev Microbiol. 2001;55:139–163. doi: 10.1146/annurev.micro.55.1.139.
  27. Trecarichi EM, Tumbarello M. Antimicrobial-resistant Gram-negative bacteria in febrile neutropenic patients with cancer: current epidemiology and clinical impact. Curr Opin Infect Dis. 2014;27(2):200–210. doi: 10.1097/QCO.0000000000000038.25.
  28. Khurana M, Lee B, Feusner JH. Fever at diagnosis of pediatric acute lymphoblastic leukemia: are antibiotics really necessary? J Pediatr Hematol Oncol. 2015;37(7):498–501. doi: 10.1097/MPH.0000000000000417.
  29. Nolt D, Lindemulder S, Meyrowitz J, et al. Preventive antibiotics in pediatric patients with acute myeloid leukemia (AML). Pediatr Blood Cancer. 2015;62(7):1149–1154. doi: 10.1002/pbc.25463.
  30. Blennow O, Ljungman P. The challenge of antibiotic resistance in haematology patients. Br J Haematol. 2016;172(4):497–511. doi: 10.1111/bjh.13816.
  31. Cohen NR, Lobritz MA, Collins JJ. Microbial persistence and the road to drug resistance. Cell Host Microbe. 2013;13(6):632–642. doi: 10.1016/j.chom.2013.05.009.
  32. Lewis K. Persister cells, dormancy and infectious disease. Nat Rev Microbiol. 2007;5(1):48–56. doi: 10.1038/nrmicro1557.
  33. Grant SS, Hung DT. Persistent bacterial infections, antibiotic tolerance, and the oxidative stress response. Virulence. 2013;4(4):273–283. doi: 10.4161/viru.23987.
  34. Fothergill JL, Winstanley C, James CE. Novel therapeutic strategies to counter Pseudomonas aeruginosa infections. Expert Rev Anti Infect Ther. 2012;10(2):219–235. doi: 10.1586/eri.11.168.
  35. Тутельян А.В., Гапонов А.М., Писарев В.М., Эльрегистан Г.И. Дормантное состояние микроорганизмов и профилактика инфекций, связанных с оказанием медицинской помощи // Терапевтический архив. ― 2015. ― Т. 87. ― №11. ― С. 103–108. [Tutelyan AV, Gaponov AM, Pisarev VM, Elregistan GI. Microbial dormancy and prevention of healthcare-associated infections. Ter Arkh. 2015;87(11):103–108. (In Russ).]

Supplementary files

Supplementary Files
Action
1. JATS XML

Copyright (c) 2016 "Paediatrician" Publishers LLC



This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies