Terapevticheskii arkhivTerapevticheskii arkhivТерапевтический архив0040-36602309-5342LLC Obyedinennaya Redaktsiya31876Editorial articleПередовая статьяReview ArticleMicrobial dormancy and prevention of healthcare-associated infectionsДормантное состояние микроорганизмов и профилактика инфекций, связанных с оказанием медицинской помощиTutelyanA VТутельянА ВGaponovA MГапоновА МPisarevV MПисаревВ МEl-registanG IЭль-регистанГ И«ЦНИИ эпидемиологии» Роспотребнадзора, Москва«ФНКЦ ДГОИ им. Дмитрия Рогачева» Минздрава России, Москва«Первый МГМУ им. И.М. Сеченова» Минздрава России, Москва«ФНКЦ ДГОИ им. Дмитрия Рогачева» Минздрава России, Москва«НИИ общей реаниматологии им. В.А. Неговского» ФАНО России, Москва«ЦНИИ эпидемиологии» Роспотребнадзора, Москва«Институт микробиологии им. С.Н. Виноградского» РАН151120158711VOL 87, NO11 (2015)ТОМ 87, №11 (2015)10310810042020Copyright ©; 2015, Consilium MedicumCopyright ©; 2015, ООО "Консилиум Медикум"2015Consilium MedicumООО "Консилиум Медикум"https://creativecommons.org/licenses/by-nc-sa/4.0https://ter-arkhiv.ru/0040-3660/article/view/31876

Healthcare-associated infections (HCAI) remain one of the most challenges of modern health care and assume increasing social and medical significance. The specific features of HCAI are frequent recurrences and inefficiency of antibiotic therapy, a reason for which is antibiotic resistance in microorganisms. The review discusses antibiotic resistance, a form of antibiotic tolerance (AT), and its role in the development of HCAI. It also describes essential differences between AT and antibiotic tolerance at the cellular and molecular genetic levels. Relationships between AT and dormancy of microorganisms, pathogens of HCAI, are discussed. The paper gives the data available in the literature on how AT occurs in HCAI pathogens and discusses the diagnosis of this condition. It also analyzes the literature data on pharmacological attempts to overcome AT and discusses novel approaches to antibiotic therapy for HCAI.

Проблема инфекций, связанных с оказанием медицинской помощи (ИСМП), остается одной из острейших в современном здравоохранении и приобретает все большую социальную и медицинскую значимость. Особенностями течения ИСМП являются частое рецидивирование и неэффективность антибактериальной терапии, одна из причин которых — устойчивость микроорганизмов к антибиотикам. В обзоре обсуждается одна из форм антибиотикоустойчивости — антибиотикотолерантность (АР) и ее роль в развитии ИСМП. Описаны существенные отличия АР от антибиотикорезистентности на клеточном и молекулярно-генетическом уровне. Обсуждается взаимосвязь АР и состояния дормантности* у микроорганизмов — возбудителей ИСМП. Представлены данные литературы об условиях возникновения состояния АР у возбудителей ИСМП, обсуждаются вопросы диагностики подобного состояния. Кроме того, анализируются имеющиеся в литературе данные, касающиеся попыток фармакологического преодоления АР и обсуждаются новые подходы к антибактериальной терапии ИСМП.

healthcareassociated infectionsantibiotic toleranceantibiotic resistanceинфекциисвязанные с оказанием медицинской помощиантибиотикотолерантностьантибиотикорезистентностьKlevens RM, Edwards JR, Richards CL Jr. Estimating healthcare-associated infections and deaths in U.S. hospitals 2002. Public Health Rep. 2007;122:160-166.Матвеева А.И. Эпидемиологические особенности гнойно-воспалительных заболеваний у больных раком легкого. Казанский медицинскийжурнал. 2005;6:477-479.Румянцев А.Г., Масччан А.А., Самочатова Е.В. Сопроводительная терапия и контроль инфекций при гематологических и онкологических заболеваниях. М.: Медпрактика-М; 2009.Medscape/CDC Expert Commentaries, 2013.Roberts RR, Hota B, Ahmad I. Hospital and societal costs of antimicrobial-resistant infections in a Chicago teaching hospital: implications for antibiotic stewardship. Clin Infect Dis. 2009;49(8): 1175-1184.Stewart PS, Costerton JW. Antibiotic resistance of bacteria in biofilms. Lancet. 2001;358(9276):135-187.Lebeaux D, Ghigo JM, Lucet JC. Implanted medical device-related infections: pathophysiology and prevention. Rev Prat. 2014;64(5):620-625.Vandecandelaere I, Coenye T. Microbial composition and antibiotic resistance of biofilms recovered from endotracheal tubes of mechanically ventilated patients. Adv Exp Med Biol. 2015;830: 137-155.Карпун Н.А., Мороз В.В., Климова Г.М., Акимкин В.Г., Журавлев А.Г., Колесник А.В. Профилактика нозокомиальных инфекций дыхательных путей. Общая реаниматология. 2007;3(3):100-104.Голубев А.М., Мороз В.В., Сундуков Д.В. Патогенез острого респираторного дистресс-синдрома. Общая реаниматология. 2012;8(4):13-21.Нозокомиальная пневмония у взрослых. Национальные рекомендации. Под ред. Чучалина А.Г. М.; 2009.Blot S, Koulenti D, Dimopoulos G, Martin C, Komnos A, Krueger WA, Spina G, Armaganidis A, Rello J; EU-VAP Study Investigators. /Prevalence, risk factors, and mortality for ventilator-associated pneumonia in middle-aged, old, and very old critically ill patients. Crit Care Med. 2014;42(3):601-609.Mihai MM, Holban AM, Giurcăneanu C, Popa LG, Buzea M, Filipov M, Lazăr V, Chifiriuc MC, Popa MI. Identification and phenotypic characterization of the most frequent bacterial etiologies in chronic skin ulcers. Rom J Morphol Embryol. 2014;55(4):1401-1408.Percival SL, McCarty SM, Lipsky B. Biofilms and Wounds: An Overview of the Evidence. Advances in Wound Care. 2015;373-381.Lewis K. Persister cells, dormancy and infectious disease. Nat RevMicrobiol. 2007;5:48-56.Gefen O, Balaban N. The importance of being persistent: heterogeneity of bacterial populations under antibiotic stress. FEMS Microbiol Rev. 2009;33:704-717.Balaban NQ, Gerdes K, Lewis K, McKinney JD. A problem of persistence: still more questions than answers? Nature Rev Microbiol. 2013;11:587-591.Hobby GL, Meyer K, Chaffee E. Observation on the mechanism of action of penicillin. Proc Soc Exp Biol NY. 1942;50:281-285.Lewis K. Persister cells. Ann Rev Microbiol. 2010;64:357-372.Bigger JW. Treatment of staphylococcal infections with penicillin by intermittent sterilization. Lancet. 1944;244:497-500.Balaban NQ, Merrin J, Chait R, Kowalik L, Leibler S. Bacterial persistence as a phenotypic switch. Science. 2004;305:1622-1625.Guilfoile PG. Antibiotic-resistant bacteria. Chelsea House. NY. 2007; 128.Antonopoulos DA, Huse SM, Morrison HG, Schmidt TM, Sogin ML, Young VB. Reproducible community dynamics of the gastrointestinal microbiota following antibiotic perturbation. Inf Immun. 2009;77:2367-2375.Ying Zhang. Persisters, persistent infections and the Yin-Yang model Emerging. Microbes & Infections. 2014;3:e3. doi:10.1038/emi.2014.3.Wayne LG, Lin KY. Glyoxylate metabolism and adaptation of Mycobacterium tuberculosis to survival under anaerobic conditions. Inf Immun. 1982;37:1042-1049.Gengenbacher M, Kaufmann SH. Mycobacterium tuberculosis: success through dormancy. FEMS Microbiol Rev. 2012;36(3): 514-532.Lewis K. Persister cells: molecular mechanisms related to antibiotic tolerance. Handb Exp Pharmacol. 2012;211:121-133.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(Pt 6):699-709.Rosen DA, Hooton TM, Stamm WE, Humphrey PA, Hultgren SJ. Detection of intracellular bacterial communities in human urinary tract infection. PLoS Med. 2007;4:e329.Helaine S, Thompson JA, Watson KG, Liu M, Boyle C, Holden DW. Dynamics of intracellular bacterial replication at the single cell level. Proc Natl Acad Sci USA. 2010;107:3746-3751.Lafond RE, Lukehart SA. Biological basis for syphilis. Clin MicrobiolRev. 2006;19:29-49.Kent ME, Romanelli F. Reexamining syphilis: an update on epidemiology, clinical manifestations, and management. Ann Pharmacother. 2008;42:226-236.Monack DM, Mueller A, Falkow S. Persistent bacterial infections: the interface of the pathogen and the host immune system. Nat Rev Microbiol. 2004;2:747-765.Caygill CP, Hill MJ, Braddick M, Sharp JC. Cancer mortality in chronic typhoid and paratyphoid carriers. Lancet. 1994;343: 83-84.Chronic and acute infection of the gall bladder by Salmonella Typhi: understanding the carrier state. Nat Rev Microbiol. 2011;9: 9-14.Wotherspoon AC, Ortiz-Hidalgo C, Falzon MR, Isaacson PG. Helicobacter pylori-associated gastritis and primary B-cell gastric lymphoma. Lancet 1991;338:1175-1176.LaFleur MD, Kumamoto CA, Lewis K. Candida albicans biofilms produce antifungal-tolerant persister cells. Antimicrob Agents Chemother. 2006;50(11):3839-3846.Mulcahy LR, Burns JL, Lory S, Lewis K. Emergence of Pseudomonas aeruginosa strains producing high levels of persister cells in patients with cystic fibrosis. J Bacteriol. 2010;192: 6191-6199.Singh PK, Schaefer AL, Parsek MR, Moninger TO, Welsh MJ, Greenberg EP. Quorum-sensing signals indicate that cystic fibrosis lungs are infected with bacterial biofilms. Nature. 2000;407(6805):762-764.Whiteley M, Bangera MG, Bumgarner RE, Parsek MR, Teitzel GM, Lory S, Greenberg EP. Gene expression in Pseudomonas aeruginosa biofilms. Nature. 2001;413(6858):860-864.Foley I, Marsh P, Wellington EM, Smith AW, Brown MR. General stress response master regulator rpoS is expressed in human infection: a possible role in chronicity. J Antimicrob Chemother. 1999;43(1):164-165.Roszak DB, Colwell RR. Metabolic activity of bacterial cells enumerated by direct viable count. Appl Environ Microbiol. 1987;53:2889-2893.Эль-Регистан Г.И., Мулюкин А.Л., Николаев Ю.А., Сузина Н.Е., Гальченко В.Ф., Дуда В.И. Адаптогенные функции внеклеточных ауторегуляторов микроорганизмов. Микробиология. 2006;75(4):446-456.Shah D, Zhang Z, Khodursky AB, Kaldalu N, Kurg K, Lewis K. Persisters: a distinct physiological state of E. coli. BMC Microbiol. 2006;6:53-61.Levin BR, Rozen DE. Non-inherited antibiotic resistance. Nat Rev Microbiol. 2006;4:556-562.Grant SS, Hung DT. Persistent bacterial infections, antibiotic tolerance, and the oxidative stress response. Virulence. 2013;4: 273-283.Fernandez L, Hancock RE. Adaptive and mutation resistance: Role of porin and efflux pumps in drug resistence. Clin Microbiol Rev. 2012;25:661-681.Nguyen D, Joshi-Datar A, Lepine F, Bauerle E, Olakanmi O, Beer K, McKay G, Siehnel R, Schafhauser J, Wang Y, Britigan BE, Singh PK. Active starvation responses mediate antibiotic tolerance in biofilms and nutrient-limited bacteria. Science. 2011;334:982-986.Wayne LG, Lin KY. Glyoxylate metabolism and adaptation of Mycobacterium tuberculosis to survival under anaerobic conditions. Infect Immun. 1982;37:1042-1049.Maisonneuve E, Gerdes K. Molecular mechanisms underlying bacterial persisters. Cell. 2014;157:539-548.Kolodkin-Gal I, Sat B, Keshet A, Engelberg-Kulka H. The communication factor EDF and the toxin-antitoxin module mazEF determine the mode of action of antibiotics. PLoS Biol. 2008;6:e319.Бухарин О.В., Гинцбург А.Л., Романова Ю.Н., Эль-Регистан Г.И. Механизмы выживания бактерий. М.: Медицина; 2005.Moker N, Dean CR, Tao J. Pseudomonas aeruginosa Increases Formation of Multidrug-Tolerant Persister Cells in Response to Quorum-Sensing Signaling Molecules. J Biotechnol. 2010;192(7): 1946-1955.Lakshmana GK, John J, Marie MA, Sangeetha G, Bindurani SR. Isolation and characterization of quorum-sensing signaling molecules in Pseudomonas aeruginosa isolates recovered from nosocomial infections. APMIS. 2013;121(9):886-889.Glucksam-Galnoy Y, Sananes R, Silberstein N, Krief P, Kravchenko VV, Meijler MM, Zor T. The bacterial quorum-sensing signal molecule N-3-oxo-dodecanoyl-L-homoserine lactone reciprocally modulates pro- and anti-inflammatory cytokines in activated macrophages. J Immunol. 2013;191(1): 337-344. doi:10.4049/jimmunol.1300368.Garner AL, Yu J, Struss AK, Kaufmann GF, Kravchenko VV, Janda KD. Immunomodulation and the quorum sensing molecule 3-oxo-C12-homoserine lactone: the importance of chemical scaffolding for probe development. Chem Commun (Camb). 2013;49(15):1515-1517.Monack DM, Hultgren SJ. The complex interactions of bacterial pathogens and host defenses. Curr Opin Microbiol. 2013;16(1):1-3. doi:10.1016/j.mib.2013.03.001.Эль-Регистан Г.И., Николаев Ю.А., Мулюкин А.Л., Н.Г. Лойко, Е.В. Демкина, В.М. Писарев, А.М. Гапонов, А.В. Тутельян Явление персистенции — формы и механизмы выживаемости популяций. Медицинскийалфавит. 2014;10(2): 49-54.Conlon B, Nakayasu E, Fleck L, LaFleur M, Isabella V, Coleman K. Activated ClpP kills persisters and eradicates a chronic biofilm infection. Nature. 2013;503(7476):365-370.Ling L, Schneider T, Peoples A, Spoering A, Engels I, Conlon B. A novel antibiotic kills pathogens without detectable resistance. Nature. 2015;517(7535):455-459.