Результаты клинического исследования эффективности и безопасности препарата для внутрипузырного введения на основе бактериофагов в терапии у пациентов с хроническим рецидивирующим циститом
Результаты клинического исследования эффективности и безопасности препарата для внутрипузырного введения на основе бактериофагов в терапии у пациентов с хроническим рецидивирующим циститом
Зайцев А.В., Арефьева О.А., Сазонова Н.А., Мельников В.Д., Ким Ю.А., Ширяев А.А., Васильев А.О., Грицков И.О., Говоров А.В., Пушкарь Д.Ю. Результаты клинического исследования эффективности и безопасности препарата для внутрипузырного введения на основе бактериофагов в терапии у пациентов с хроническим рецидивирующим циститом. Гинекология. 2021;23(6):578–585. DOI: 10.26442/20795696.2021.6.201286
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Zaitsev AV, Arefeva OA, Sazonova NA, Melnikov VD, Kim YuA, Shiryaev AA, Vasilyev AO, Gritskov IO, Govorov AV, Pushkar DYu. Results of a clinical study of the drug efficacy and safety for intravesical administration based on bacteriophages in therapy in patients with chronic recurrent cystitis. Gynecology. 2021;23(6):578–585.
DOI: 10.26442/20795696.2021.6.201286
Результаты клинического исследования эффективности и безопасности препарата для внутрипузырного введения на основе бактериофагов в терапии у пациентов с хроническим рецидивирующим циститом
Зайцев А.В., Арефьева О.А., Сазонова Н.А., Мельников В.Д., Ким Ю.А., Ширяев А.А., Васильев А.О., Грицков И.О., Говоров А.В., Пушкарь Д.Ю. Результаты клинического исследования эффективности и безопасности препарата для внутрипузырного введения на основе бактериофагов в терапии у пациентов с хроническим рецидивирующим циститом. Гинекология. 2021;23(6):578–585. DOI: 10.26442/20795696.2021.6.201286
________________________________________________
Zaitsev AV, Arefeva OA, Sazonova NA, Melnikov VD, Kim YuA, Shiryaev AA, Vasilyev AO, Gritskov IO, Govorov AV, Pushkar DYu. Results of a clinical study of the drug efficacy and safety for intravesical administration based on bacteriophages in therapy in patients with chronic recurrent cystitis. Gynecology. 2021;23(6):578–585.
DOI: 10.26442/20795696.2021.6.201286
Обоснование. Инфекции мочевыводящих путей остаются одной из актуальных проблем оказания квалифицированной медицинской помощи. Возбудители нозокомиальных инфекций становятся все более устойчивыми к используемым препаратам, в то время как темпы синтезирования новых лекарственных средств уступают скорости развития антибиотикорезистентности. Рутинная и подчас эмпирическая профилактика рецидивирующих инфекций мочевыводящих путей зачастую бывает неэффективной. Цель. Изучить эффективность и безопасность внутрипузырного применения препарата на основе бактериофагов в терапии у пациентов с хроническим рецидивирующим циститом. Материалы и методы. Проведено клиническое исследование по изучению эффективности и безопасности препарата для внутрипузырного введения на основе бактериофагов в терапии у пациентов с хроническим рецидивирующим циститом. В исследование включены 75 пациенток, которые были распределены в 3 группы в соотношении 1:1:1. В основной группе применялись препарат для внутрипузырного введения на основе бактериофагов, а также ректальные свечи с бактериофагами; в группе контроля – только препарат для внутрипузырного введения на основе бактериофагов или ректальные свечи с бактериофагами. Всем пациенткам на 1–4-м визите проведены клинический анализ крови, общий анализ мочи, бактериологический анализ мочи, а также анализ мочи методом полимеразной цепной реакции. Проведен анализ состояния пациентов в группах по динамике изменения основных клинических симптомов, данных валидизированных шкал оценки тазовой боли и ургентности/частоты мочеиспускания и оценки симптомов острого цистита (Acute Cystitis Symptom Score – ACSS), а также динамике изменения объективных параметров лабораторных исследований и возможного изменения чувствительности уропатогенов к антибактериальным препаратам. Результаты. Средний возраст пациенток, включенных в исследование, составил 50,6 года. Во всех 3 группах при бактериологическом исследовании мочи отмечен преимущественный рост Escherichia coli (≥104 КОЕ/мл). В ходе проведенного исследования отмечены хорошая переносимость терапии, уменьшение клинической симптоматики, а также значительное снижение суммарного балла по данным шкалы оценки тазовой боли и ургентности/частоты мочеиспускания и шкалы ACSS у всех пациенток. Заключение. Возникновение большого количества устойчивых к различным антибиотикам микроорганизмов и их быстрое распространение в окружающей среде привело к росту научного интереса к терапии бактериофагами в качестве альтернативного метода лечения. Общая субъективная эффективность проводимой терапии в нашем исследовании составила более 80%, безопасность – 100%. Проведение дальнейших исследований позволит осуществить персонализированный подход к терапии инфекционных заболеваний органов мочевыделительной системы.
Background. Urinary tract infections remain one of the urgent problems in the aspect of qualified medical care. The causative agents of nosocomial infections are becoming more and more resistant to the drugs used, while the rate of new drugs synthesis is lower than the rate of development of antibiotic resistance. Routine and empirical prevention of recurrent urinary tract infections is often ineffective. Aim. To study the efficacy and safety of intravesical application of the drug based on bacteriophages in therapy in patients with chronic recurrent cystitis.
Materials and methods. A clinical study was carried out to study the efficacy and safety of the drug for intravesical administration based on bacteriophages in therapy in patients with chronic recurrent cystitis. The study included 75 patients who were divided into 3 groups in a 1: 1: 1 ratio. In the main group, the drug for intravesical administration based on bacteriophages, as well as rectal suppositories with bacteriophages were used; in the control group – only a drug for intravesical administration based on bacteriophages or rectal suppositories with bacteriophages. On visits 1-4, all patients underwent a clinical blood test, general urine analysis, bacteriological urine analysis, as well as urine analysis by the polymerase chain reaction method. The analysis of the patients condition in groups was carried out according to the dynamics of main clinical symptoms changes, data from validated scales for assessing pelvic pain and urgency/frequency of urination and assessment of symptoms of acute cystitis (Acute Cystitis Symptom Score – ACSS), as well as the dynamics of changes in objective parameters of laboratory studies and possible changes in sensitivity uropathogens to antibacterial drugs. Results. The average age of the patients included in the study was 50.6 years. In all 3 groups, bacteriological examination of urine showed a predominant growth of Escherichia coli (3×104 CFU/ml). In the course of the study, there was a good tolerance to therapy, a decrease in clinical symptoms, as well as a significant decrease in the total score according to the pelvic pain scale and urgency/frequency of urination and the ACSS scale in all patients. Conclusion. The emergence of a large number of microorganisms resistant to various antibiotics and their rapid spread in the environment has led to an increase in scientific interest in bacteriophage therapy as an alternative method of treatment. The overall subjective effectiveness of the therapy in our study was more than 80%, safety - 100%. Further research will allow for a personalized approach to the treatment of infectious diseases of the urinary system.
1. Tandogdu Z, Wagenlehner FME. Global epidemiology of urinary tract infections. Curr Opin Infect Dis. 2016;29(1):73-9. DOI:10.1097/QCO.0000000000000228
2. Ikäheimo R, Siitonen A, Heiskanen T, et al. Recurrence of urinary tract infection in a primary care setting: analysis of a 1-year follow-up of 179 women. Clin Infect Dis. 1996(22):91-9. DOI:10.1093/clinids/22.1.91
3. Griebling TL. Urologic diseases in America project: trends in resource use for urinary tract infections in women. J Urol. 2005;173:1281-7.
DOI:10.1097/01.ju.0000155596.98780.82
4. Foxman B, Gillespie B, Koopman J, et al. Risk factors for second urinary tract infection among college women. Am J Epidemiol. 2000;151(12):1194-205. DOI:10.1093/oxfordjournals.aje.a010170
5. Magistro G, Marcon J, Schubert S, et al. Pathogenese der harnwegsinfektion ein update. Der Urologe. 2017;56(6):720-7. DOI:10.1007/s00120-017-0391-7
6. Hooton TM, Scholes D, Hughes JP. A prospective study of risk factors for symptomatic urinary tract infection in young women. New Engl J Med. 1996;335(7):468-74. DOI:10.1056/NEJM199608153350703
7. Scholes D, Hawn TR, Roberts PL, et al. Family history and risk of recurrent cystitis and pyelonephritis in women. J Urol. 2010;184(2):564-9. DOI:10.1016/j.juro.2010.03.139
8. Hooton TM, Stapleton AE, Roberts PL Perineal anatomy and urine-voiding characteristics of young women with and without recurrent urinary tract infections. Clin Infect Dis. 1999;29(6):1600-1. DOI:10.1086/313528
9. Albert X, Huertas I, Pereiro´ II, et al. Antibiotics for preventing recurrent urinary tract infection in nonpregnant women. Cochrane Database Syst Rev. 2004;2004:CD001209. DOI;10.1002/14651858.CD001209.pub2
10. Ny S, Edquist P, Dumpis U, et al. Antimicrobial resistance of Escherichia coli isolates from outpatient urinary tract infections in women in six European countries including Russia. J Glob Antimicrob Resist. 2019;17:25-34. DOI:10.1016/j.jgar.2018.11.004
11. Wojno KJ, Baunoch D, Luke N, et al. Multiplex PCR Based Urinary Tract Infection (UTI) Analysis Compared to Traditional Urine Culture in Identifying Significant Pathogens in Symptomatic Patients. Urology. 2020;136:119-26. DOI:10.1016/j.urology.2019.10.018
12. Lee SJ, Choe HS, Na YG. Guidelines of the Korean association of urogenital tract infection and inflammation: recurrent urinary tract infection. Urogenit Tract Infect. 2017;12(1):7. DOI:10.14777/uti.2017.12.1.7
13. Hooton TM, Vecchio M, Iroz A, et al. Effect of increased daily water intake in premenopausal women with recurrent urinary tract infections: a randomized clinical trial. JAMA Intern Med. 2018;178(11):1509-15. DOI:10.1001/jamainternmed.2018.4204
14. Finh SD, Boyko EJ, Normand EH, et al. Association between use of spermicide-coated condoms and escherichia coli urinary tract infection in young women.
Am J Epidemiol. 1996;144(5):512-20. DOI:10.1093/oxfordjournals.aje.a008958
15. Schmidt DR, Sobota AE. An examination of the anti-adherence activity of cranberry juice on urinary and nonurinary bacterial isolates. Microbios. 1988;55(224-225):173-81.
16. Stapleton AE, Dziura J, Hooton TM, et al. Recurrent urinary tract infection and urinary escherichia coli in women ingesting cranberry juice daily: a randomized controlled trial. Mayo Clin Proc. 2012;87(2):143-50. DOI:10.1016/j.mayocp.2011.10.006
17. Beerepoot MAJ, ter Riet G, Nys S, et al. Cranberries vs antibiotics to prevent urinary tract infections: a randomized double-blind noninferiority trial in premenopausal women. Arch Intern Med. 2011;171(14):1270-8. DOI:10.1001/archinternmed.2011.306
18. Avorn J, Monane M, Gurwitz JH, et al. Reduction of bacteriuria and pyuria after ingestion of cranberry juice. JAMA. 1994;271(10):751-4.
DOI:10.1001/jama.1994.03510340041031
19. Lenger SM, Bradley MS, Thomas DA, et al. D-mannose vs other agents for recurrent urinary tract infection prevention in adult women: a systematic review and meta-analysis. Am J Gynecol. 2020;223(2):265.e1-265.e13. DOI:10.1016/j.ajog.2020.05.048
20. Kranjčec B, Papeš D, Altarac S. D-mannose powder for prophylaxis of recurrent urinary tract infections in women: a randomized clinical trial. World J Urol. 2014;32(1):79-84. DOI:10.1007/s00345-013-1091-6
21. Damiano R, Quarto G, Bava I, et al. Prevention of recurrent urinary tract infections by intravesical administration of hyaluronic acid and chondroitin sulphate: a placebo-controlled randomised trial. Eur Urology. 2011;59(4):645-51. DOI:10.1016/j.eururo.2010.12.039
22. Interdisziplinäre S3 leitlinie: epidemiologie, diagnostik, therapie, prevention und management unkomplizierter, bakterieller, ambulant erworbener harnwegsinfektionen bei erwachsenen patienten. AWMF-Register-Nr. 043/044 2017 (Version 1.1-2).
23. Botros C, Lozo S, Iyer S, et al. Methenamine hippurate compared with trimethoprim for the prevention of recurrent urinary tract infections: a randomized clinical trial. Int Urogynecol J. 2021. DOI:10.1007/s00192-021-04849-0
24. Larsson B, Jonasson A, Fianu S. Prophylactic effect of UVA-E in women with recurrent cystitis: a preliminary report. Curr Ther Res. 1993;53(4):441-3.
DOI:10.1016/S0011-393X(05)80204-8
25. Albrecht U, Goos K-H, Schneider B. A randomised, double-blind, placebo-controlled trial of a herbal medicinal product containing Tropaeoli majoris herba (Nasturtium) and Armoraciae rusticanae radix (Horseradish) for the prophylactic treatment of patients with chronically recurrent lower urinary tract infections. Curr Med Res Opin. 2007;23(10):2415-22. DOI:10.1185/030079907X233089
26. Raz R, Stamm WE. A controlled trial of intravaginal estriol in postmenopausal women with recurrent urinary tract infections. New Engl J Med. 1993(329):753-6. DOI:10.1056/NEJM199309093291102
27. Eriksen BC. A randomized, open, parallel-group study on the preventive effect of an estradiol-releasing vaginal ring (Estring) on recurrent urinary tract infections in postmenopausal women. Am J Obstet Gynecol. 1999;180(5):1072-9. DOI:10.1016/s0002-9378(99)70597-1
28. Raz R, Colodner R, Rohana Y, et al. Effectiveness of estriol-containing vaginal pessaries and nitrofurantoin macrocrystal therapy in the prevention of recurrent urinary tract infection in postmenopausal women. Clin Infect Dis. 2003;36(11):1362-8. DOI:10.1086/374341
29. Bauer HW, Rahlfs VW, Lauener PA, Blessmann GS. Prevention of recurrent urinary tract infections with immuno-active E. coli fractions: a meta-analysis of five placebo-controlled double-blind studies. Int J Antimicrob Agents. 2002;19(6):451-6. DOI:10.1016/s0924-8579(02)00106-1
30. Nestler S, Grüne B, Schilchegger L, et al. Efficacy of vaccination with StroVac for recurrent urinary tract infections in women: a comparative single-centre study. Int Urol Nephrol. 2021;53(11):2267-72. DOI:10.1007/s11255-021-02987-4
31. Clarke AL, Soir S de, Jones JD. The safety and efficacy of phage therapy for bone and joint infections: a systematic review. Antibiotics (Basel, Switzerland). 2020;9(11):795. DOI:10.3390/antibiotics9110795.
32. Gibb BP, Hadjiargyrou M. Bacteriophage therapy for bone and joint infections. Bone Joint J. 2021;103-B(2):234-44. DOI:10.1302/0301-620X.103B2.BJJ-2020-0452.R2
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1. Tandogdu Z, Wagenlehner FME. Global epidemiology of urinary tract infections. Curr Opin Infect Dis. 2016;29(1):73-9. DOI:10.1097/QCO.0000000000000228
2. Ikäheimo R, Siitonen A, Heiskanen T, et al. Recurrence of urinary tract infection in a primary care setting: analysis of a 1-year follow-up of 179 women. Clin Infect Dis. 1996(22):91-9. DOI:10.1093/clinids/22.1.91
3. Griebling TL. Urologic diseases in America project: trends in resource use for urinary tract infections in women. J Urol. 2005;173:1281-7.
DOI:10.1097/01.ju.0000155596.98780.82
4. Foxman B, Gillespie B, Koopman J, et al. Risk factors for second urinary tract infection among college women. Am J Epidemiol. 2000;151(12):1194-205. DOI:10.1093/oxfordjournals.aje.a010170
5. Magistro G, Marcon J, Schubert S, et al. Pathogenese der harnwegsinfektion ein update. Der Urologe. 2017;56(6):720-7. DOI:10.1007/s00120-017-0391-7
6. Hooton TM, Scholes D, Hughes JP. A prospective study of risk factors for symptomatic urinary tract infection in young women. New Engl J Med. 1996;335(7):468-74. DOI:10.1056/NEJM199608153350703
7. Scholes D, Hawn TR, Roberts PL, et al. Family history and risk of recurrent cystitis and pyelonephritis in women. J Urol. 2010;184(2):564-9. DOI:10.1016/j.juro.2010.03.139
8. Hooton TM, Stapleton AE, Roberts PL Perineal anatomy and urine-voiding characteristics of young women with and without recurrent urinary tract infections. Clin Infect Dis. 1999;29(6):1600-1. DOI:10.1086/313528
9. Albert X, Huertas I, Pereiro´ II, et al. Antibiotics for preventing recurrent urinary tract infection in nonpregnant women. Cochrane Database Syst Rev. 2004;2004:CD001209. DOI;10.1002/14651858.CD001209.pub2
10. Ny S, Edquist P, Dumpis U, et al. Antimicrobial resistance of Escherichia coli isolates from outpatient urinary tract infections in women in six European countries including Russia. J Glob Antimicrob Resist. 2019;17:25-34. DOI:10.1016/j.jgar.2018.11.004
11. Wojno KJ, Baunoch D, Luke N, et al. Multiplex PCR Based Urinary Tract Infection (UTI) Analysis Compared to Traditional Urine Culture in Identifying Significant Pathogens in Symptomatic Patients. Urology. 2020;136:119-26. DOI:10.1016/j.urology.2019.10.018
12. Lee SJ, Choe HS, Na YG. Guidelines of the Korean association of urogenital tract infection and inflammation: recurrent urinary tract infection. Urogenit Tract Infect. 2017;12(1):7. DOI:10.14777/uti.2017.12.1.7
13. Hooton TM, Vecchio M, Iroz A, et al. Effect of increased daily water intake in premenopausal women with recurrent urinary tract infections: a randomized clinical trial. JAMA Intern Med. 2018;178(11):1509-15. DOI:10.1001/jamainternmed.2018.4204
14. Finh SD, Boyko EJ, Normand EH, et al. Association between use of spermicide-coated condoms and escherichia coli urinary tract infection in young women.
Am J Epidemiol. 1996;144(5):512-20. DOI:10.1093/oxfordjournals.aje.a008958
15. Schmidt DR, Sobota AE. An examination of the anti-adherence activity of cranberry juice on urinary and nonurinary bacterial isolates. Microbios. 1988;55(224-225):173-81.
16. Stapleton AE, Dziura J, Hooton TM, et al. Recurrent urinary tract infection and urinary escherichia coli in women ingesting cranberry juice daily: a randomized controlled trial. Mayo Clin Proc. 2012;87(2):143-50. DOI:10.1016/j.mayocp.2011.10.006
17. Beerepoot MAJ, ter Riet G, Nys S, et al. Cranberries vs antibiotics to prevent urinary tract infections: a randomized double-blind noninferiority trial in premenopausal women. Arch Intern Med. 2011;171(14):1270-8. DOI:10.1001/archinternmed.2011.306
18. Avorn J, Monane M, Gurwitz JH, et al. Reduction of bacteriuria and pyuria after ingestion of cranberry juice. JAMA. 1994;271(10):751-4.
DOI:10.1001/jama.1994.03510340041031
19. Lenger SM, Bradley MS, Thomas DA, et al. D-mannose vs other agents for recurrent urinary tract infection prevention in adult women: a systematic review and meta-analysis. Am J Gynecol. 2020;223(2):265.e1-265.e13. DOI:10.1016/j.ajog.2020.05.048
20. Kranjčec B, Papeš D, Altarac S. D-mannose powder for prophylaxis of recurrent urinary tract infections in women: a randomized clinical trial. World J Urol. 2014;32(1):79-84. DOI:10.1007/s00345-013-1091-6
21. Damiano R, Quarto G, Bava I, et al. Prevention of recurrent urinary tract infections by intravesical administration of hyaluronic acid and chondroitin sulphate: a placebo-controlled randomised trial. Eur Urology. 2011;59(4):645-51. DOI:10.1016/j.eururo.2010.12.039
22. Interdisziplinäre S3 leitlinie: epidemiologie, diagnostik, therapie, prevention und management unkomplizierter, bakterieller, ambulant erworbener harnwegsinfektionen bei erwachsenen patienten. AWMF-Register-Nr. 043/044 2017 (Version 1.1-2).
23. Botros C, Lozo S, Iyer S, et al. Methenamine hippurate compared with trimethoprim for the prevention of recurrent urinary tract infections: a randomized clinical trial. Int Urogynecol J. 2021. DOI:10.1007/s00192-021-04849-0
24. Larsson B, Jonasson A, Fianu S. Prophylactic effect of UVA-E in women with recurrent cystitis: a preliminary report. Curr Ther Res. 1993;53(4):441-3.
DOI:10.1016/S0011-393X(05)80204-8
25. Albrecht U, Goos K-H, Schneider B. A randomised, double-blind, placebo-controlled trial of a herbal medicinal product containing Tropaeoli majoris herba (Nasturtium) and Armoraciae rusticanae radix (Horseradish) for the prophylactic treatment of patients with chronically recurrent lower urinary tract infections. Curr Med Res Opin. 2007;23(10):2415-22. DOI:10.1185/030079907X233089
26. Raz R, Stamm WE. A controlled trial of intravaginal estriol in postmenopausal women with recurrent urinary tract infections. New Engl J Med. 1993(329):753-6. DOI:10.1056/NEJM199309093291102
27. Eriksen BC. A randomized, open, parallel-group study on the preventive effect of an estradiol-releasing vaginal ring (Estring) on recurrent urinary tract infections in postmenopausal women. Am J Obstet Gynecol. 1999;180(5):1072-9. DOI:10.1016/s0002-9378(99)70597-1
28. Raz R, Colodner R, Rohana Y, et al. Effectiveness of estriol-containing vaginal pessaries and nitrofurantoin macrocrystal therapy in the prevention of recurrent urinary tract infection in postmenopausal women. Clin Infect Dis. 2003;36(11):1362-8. DOI:10.1086/374341
29. Bauer HW, Rahlfs VW, Lauener PA, Blessmann GS. Prevention of recurrent urinary tract infections with immuno-active E. coli fractions: a meta-analysis of five placebo-controlled double-blind studies. Int J Antimicrob Agents. 2002;19(6):451-6. DOI:10.1016/s0924-8579(02)00106-1
30. Nestler S, Grüne B, Schilchegger L, et al. Efficacy of vaccination with StroVac for recurrent urinary tract infections in women: a comparative single-centre study. Int Urol Nephrol. 2021;53(11):2267-72. DOI:10.1007/s11255-021-02987-4
31. Clarke AL, Soir S de, Jones JD. The safety and efficacy of phage therapy for bone and joint infections: a systematic review. Antibiotics (Basel, Switzerland). 2020;9(11):795. DOI:10.3390/antibiotics9110795.
32. Gibb BP, Hadjiargyrou M. Bacteriophage therapy for bone and joint infections. Bone Joint J. 2021;103-B(2):234-44. DOI:10.1302/0301-620X.103B2.BJJ-2020-0452.R2
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1 ФГБОУ ВО «Московский государственный медико-стоматологический университет им. А.И. Евдокимова» Минздрава России, Москва, Россия;
2 ГБУЗ «Городская клиническая больница им. С.И. Спасокукоцкого» Департамента здравоохранения г. Москвы, Москва, Россия;
3 ГБУ «Научно-исследовательский институт организации здравоохранения и медицинского менеджмента» Департамента здравоохранения г. Москвы, Москва, Россия
*rickoff@mail.ru
________________________________________________
Andrei V. Zaitsev1,2, Oksana A. Arefeva1–3, Natalia A. Sazonova1,2, Vladimir D. Melnikov1,2, Yuriy A. Kim1,2, Arseniy A. Shiryaev1,2, Alexander O. Vasilyev1–3, Igor O. Gritskov 1, Alexander V. Govorov1,2, Dmitry Yu. Pushkar1,2
1 Yevdokimov Moscow State University of Medicine and Dentistry, Moscow, Russia;
2 Spasokukotsky City Clinical Hospital, Moscow, Russia;
3 Research Institute of Health Organization and Medical Management, Moscow, Russia
*rickoff@mail.ru