Araştırma Makalesi
Genel Pediatri Ünitesinde Empirik Mono/Kombine Antibiyoterapi Uygulamaları ve İlişkili Faktörlerin Değerlendirilmesi: Kesitsel Retrospektif Çalışma
Öz
Giriş; Pediyatrik
çağda uygunsuz antibiyotik kullanımı 70-80%’lere ulaşabilmektedir. Bu durum ek
mali yük ve antimikrobiyal direnç gibi sorunları da beraberinde getirmektedir.
Bu çalışmada genel pediyatri ünitesinde ampirik mono/kombine antibiyotik
kullanımı ve ilişkili faktörler araştırılmıştır.
Gereç ve yöntemler; Çalışmanın
kesim noktasından geriye dönük olarak son 8 aylık dönemde toplam yatan hasta
sayısına göre ampirik mono/kombine antibiyotik kullanım oranları belirlendi.
Yaş, yaş aralığı (1-5, 6-10 ve 11-18 yaş), ön tanılar, kantitatif C-reaktif
protein, kan beyaz küre sayısı, eritrosit sedimantasyon hızı, idrar tetkiki,
akciğer grafisi ve hospitalizasyon sürelerinin mono/kombine antibiyoterapi ile
ilişkileri regresyon analizi ile incelendi.
Bulgular; Antibiyotik
kullanımı yatan hastalarda %60,4 (529/875) idi ve bunların %47,5’i (416/529)
mono, %12,4%’ü (113/529) kombine antibiyoterapiydi. Antibiyoterapi uygulanan
hastaların yaş ortalaması 5,08±4,4 yıl ve yaş aralıklarına göre %66,7’si 1-5
yaş, %20,2’si 6-10 yaş ve %13’ü de 11-18 yaş aralığında bulundu. Hastaların
büyük çoğunluğu üst ve alt solunum yolu (%27,4 ve %35,3), üriner sistem (%16,6)
ve gastrointestinal sistem (%9,1) enfeksiyonu tanısı aldı. Eritrosit sedimantasyon
hızı ortalama 33,3±24,6 mm/saat, hastane yatış süresi ortalama 4,5±4,08 gün
idi. Ampirik mono antibiyoterapide en çok penisilinler (%48,7) ve
sefalosporinler (%45,4) tercih edildi. Regresyon analizinde çocuk servisine
yatırılan hastanın solunum yolu enfeksiyonu dışında bir ön tanıya sahip
olmasının, yüksek sedimantasyon hızı ve akciğer grafisi çektirmiş olmasının
kombine antibiyoterapi riskini arttırdığı görüldü.
Sonuç;
Solunum yolu dışı enfeksiyon hastalıkları ve yüksek sedimantasyon hızı, kombine
antibiyotik tercihi için hekimi etkileyen önemli faktörlerdir. Genel çocuk
servislerinde akılcı antibiyoterapi stratejileri geliştirmek için tüm süreci
kapsayan mevsimsel dönem, hasta ve hastalıkla ile ilgili faktörler gibi birçok
değişkeni hesaba katabilen daha gelişmiş yöntemlere ihtiyaç olduğu
gözükmektedir.
Anahtar Kelimeler
Destekleyen Kurum
yok
Teşekkür
yok
Kaynakça
- 1.Fleming A. On the antibacterial action of the culture of a penicillium, with special reference to their use in the isolation of B.Influenza. Br J Exp Pathol 1929;10(3):226-36.
- 2.Aminov R. History of antimicrobial drug discovery: major classes and health impact. Biochem Pharmacol 2017;133:4-19.
- 3.Goossens H, Ferech M, Stichele Vander R, Elseviers M. Outpatient antibiotic use in Europe and association with resistance: a cross-national database study. Lancet 2005; 365:579-87.
- 4.Shorr AF. Epidemiology and economic impact of methicillin-resistant Staphylococcus aureus: review and analysis of the literature. Pharmacoeconomics 2007;25:751-68.
- 5.Fernandes P, Martens E. Antibiotics in late clinical development. Biochem Pharmacol 2017;133:152-163.
- 6.Theuretzbacher U. Antibiotic innovation for future public health needs. Clin Microbiol Infect 2017;23(10):713-17.
- 7.Akılcı ilaç kullanımı Ulusal eylem planı 2014-2017 [internet]. Health Ministry of Turkey Republic. [cited 2019 February 10]. Available from: www.akilciilac.gov.tr/wp-content/uploads/2014/11/aik-ulusal-eylem-plani.pdf.
- 8. Devrim İ, Gülfidan G, Tavlı V, Dizdarer C, Yaşar N, Oruç Y et al. Dr. Behçet Uz Çocuk Hastanesinde antibiyotik kullanımına ilişkin nokta prevalans çalışması. J Pediatr Inf 2009;3:11-3.
- 9.Ergül AB, Gokcek I, Çelik T, Torun YA. Assessment of inappropriate antibiotic use in pediatric patients: point-prevalence study. Turk Pediatri Ars 2018;53(1):17-23.
- 10.Chiotos K, Gerber JS, Himebauch AS. How can we optimize antibiotic use in the PICU? Pediatr Crit Care Med 2017;18(9):903-04.
- 11.Abbas Q, Ul Haq A, Kumar R, Ali SA, Hussain K, Shakoor S. Evaluation of antibiotic use in pediatric intensive care unit of developing country. Indian J Crit Care Med 2016;20(5):291-4.
- 12.WHO Collaborating Centre for Drug Statistics Methodology. Anatomical Therapeutic Chemical (ATC) classification system: Guidelines for ATC classification and DDD assignment. http://www.whocc.no/atc_ddd_methodology/purpose_of_the_atc_ddd_system/.
- 13.Antimicrobial resistance: global report on surveillance 2014 [Internet]. World Health Organization [cited 2019 February 10]. Available from: http://apps.who.int/iris/bitstream/handle/10665/112642/9789241564748_eng.pdf?sequence=1.
- 14.Hiltunen T, Virta M, Laine AL. Antibiotic resistance in the wild: an eco-evolutionary perspective. Philos Trans R Soc Lond B Biol Sci 2017;B 372(1712):20160039.15.Baker S. A return to the pre-antimicrobial era? Science 2015;347(6226):1064-66.
- 16.Hersh AL, De Lurgio SA, Thurm C, Lee BR, Weissman SJ, Courter JD, et al. Antimicrobial stewardship programs in freestanding children's hospitals. Pediatrics 2015;135(1):33-9.
- 17.Schrier L, Hadjipanayis A, Del Torso S, Stiris T, Emonts M, Dornbusch HJ. European antibiotic awareness day 2017: training the next generation of health care professionals in antibiotic stewardship. Eur J Pediatr 2018;177(2):279-83.
- 18.Godbout EJ, Pakyz AL, Markley JD, Noda AJ, Stevens MP. Pediatric antimicrobial stewardship: state of the art. Curr Infect Dis Rep 2018;20:39:1-13.19.Nguyen-Ha PT, Howrie D, Crowley K, Vetterly CG, McGhee W, Berry D, et al. A quality assessment of a collaborative model of a pediatric antimicrobial stewardship program. Pediatrics 2016;137(5). pii:e20150316.
- 20.Dolgner SJ, Arya B, Kronman MP, Chan T. Effect of congenital heart disease status on trends in pediatric infective endocarditis hospitalizations in the United States between 2000 and 2012. Pediatr Cardiol 2018. https://doi.org/10.1007/s00246-018-2020-7. 21.Langton Hewer SC, Smyth AR. Antibiotic strategies for eradicating pseudomonas aeruginosa in people with cystic fibrosis. Cochrane Database Syst Rev 2017;4:CD004197.
- 22.Kuruvilla M, de la Morena MT. Antibiotic prophylaxis in primary immune deficiency disorders. J Allergy Clin Immunol Pract 2013;1(6):573-82.
- 23.Hersh AL, Olson J, Stockmann C, Thorell EA, Knackstedt ED, Esquibel L, and et al. Impact of antimicrobial stewardship for pediatric outpatient parenteral antibiotic therapy. J Pediatric Infect Dis Soc 2018;7(2):e34-e36.
- 24.Vaz LE, Farnstrom CL, Felder KK, Guzman-Cottrill J, Rosenberg H, Antonelli RC. Utilizing a modified care coordination measurement tool to capture value for a pediatric outpatient parenteral and prolonged oral antibiotic therapy program. J Pediatric Infect Dis Soc 2018;7(2):136-42.
- 25.Watson JR, Wang L, Klima J, Moore-Clingenpeel P, Gleeson S, Kelleher K and et al. Healthcare claims data: an underutilized tool for pediatric outpatient antimicrobial stewardship. Clin Infect Dis 2017;64(11):1479-85.
- 26.Fahimzad A, Eydian Z, Karimi A, Shiva F, Sayyahfar S, Kahbazi M, and et al. Surveillance of antibiotic consumption point prevalence survey 2014: Antimicrobial prescribing in pediatrics wards of 16 Iranian hospitals. Arch Iran Med 2016;19(3):204-09.
- 27.Labi AK, Obeng-Nkrumah N, Sunkwa-Mills G, Bediako-Bowan A, Akufo C, Bjerrum S and et al. Antibiotic prescribing in pediatric inpatients in Ghana: a multi-center point prevalence survey. BMC Pediatrics 2018;18(1):391. doi:10.1186/s12887-018-1367-5.
- 28.Gharbi M, Doerholt K, Vergnano S, Bielicki JA, Paulus S, Menson E and et al. Using a simple point-prevalence survey to define appropriate antibiotic prescribing in hospitalized children across the UK. BMJ Open 2016;6(11):e012675. doi:10.1136/bmjopen-2016-012675.
- 29.Versporten A, Bielicki J, Drapier N, Sharland M, Goossens H; ARPEC project group. The Worldwide Antibiotic Resistance and Prescribing in European Children (ARPEC) point prevalence survey: developing hospital-quality indicators of antibiotic prescribing for children. J Antimicrob Chemother 2016; 71: 1106-17.
- 30.Gerber JS, Newland JG, Coffin SE, Hall M, Thurm C, Prasad PA et al. Variability in antibiotic use at children’s hospital throughout the United States. Pediatrics 2010;126(6):1067-73. doi:10.1542/peds.2010-1275.
- 31.Goossens H. Antibiotic consumption and link to resistance. Clin Microbiol Infect 2009; 15(3):12-5.
- 32.Rutledge-Taylor K, Matlow A, Gravel D, Embree J, Le Saux N, Johnston L, and et al. A point prevalence survey of healthcare-associated infections in Canadian pediatric inpatients. Am J Infect Control 2012;40(6):491-6.
- 33.Pakyz AL, Gurgle HE, Ibrahim OM, Oinonen MJ, Polk RE. Trends in antibacterial use in hospitalized pediatric patients in the United States academic health centers. Infect Control Hosp Epidemiol 2009;30(6):600-3.
- 34.Sviestina I, Mozgis D. Observational study of antibiotic usage at the children’s clinical university hospital in Riga, Latvia. Medicina (Kaunas) 2018;54(5). piiE74. doi: 10.3390/medicina54050074.
- 35.Gerber JS, Prasad PA, Russell Localio A, Fiks AG, Grundmeier RW, Bell LM, et al. Variation in antibiotic prescribing across a pediatric primary care network. J Pediatric Infect Dis Soc 2015;4(4):297-304. doi: 10.1093/jpids/piu086.
- 36.Adriaenssens N, Coenen S, Versporten A, Muller A, Minalu G, Faes C, and et al. European Surveillance of Antimicrobial Consumption (ESAC): outpatient antibiotic use in Europe (1997–2009). J Antimicrob Chemother 2011;66(6):vi3-12. doi: 10.1093/jac/dkr453.
- 37.Akkerman AE, Kuyvenhoven MM, van der Wouden JC, Verheij TJ. Determinants of antibiotic overprescribing in respiratory tract infections in general practice. J Antimicrob Chemother 2005;56(5):930-6. doi:10.1093/jac/dki283.
- 38.Nasimfar A, Sadeghi E, Karamyyar M, Manesh LJ. Comparison of serum procalcitonin level with erythrocytes sedimentation rate, C-reactive protein, white blood cell count, and blood culture in the diagnosis of bacterial infections in patients hospitalized in Montahhari hospital of Urmia (2016). J Adv Pharm Technol Res 2018;9(4):147-52. doi: 10.4103/japtr.JAPTR_319_18.
- 39.Akın F, Yazar A, Doğan M. Determining the infectious pathogens and their resistance to antibiotics in a pediatric intensive care unit. J Pediatr Infect Dis 2018;13(01):42-5. doi:10.1055/s-0037-1607236. 40.Kreitmeyri K, von Both U, Pecar A, Borde JP, Mikolajczyk R, Huebner J. Pediatric antibiotic stewardship: successful interventions in reduce broad-spectrum antibiotic use on general pediatric wards. Infection 2017;45 (4):493-504. doi: 10.1007/s15010-017-1009-0.
- 40.Kreitmeyri K, von Both U, Pecar A, Borde JP, Mikolajczyk R, Huebner J. Pediatric antibiotic stewardship: successful interventions in reduce broad-spectrum antibiotic use on general pediatric wards. Infection 2017;45 (4):493-504.
Evaluation of Empirical Mono / Combined Antibiotherapy Consumption and Related Factors in General Pediatric Ward: a Cross-Sectional Retrospactive Study
Öz
Introduction; Inappropriate
antibiotic use in the pediatric period reaches up to 70-80%. This situation
brings problems such as additional financial cost and antimicrobial resistance.
In this study, the empirical mono/combined antibiotic consumption and related
factors were researched in a general pediatric ward.
Material
and methods; This study
was carried out retrospectively on the inpatiens from the cut-off point and was
determined the rate of empirical mono/combined antibiotic use. The relation of
age, age interval (1-5, 6-10 and 11-18 years), preliminary diagnosis,
quantitative C-reactive protein, white blood cell count, erythrocyte sedimentation
rate, urinalysis, chest x-ray and hospitalization duration with mono/combined
antibiotherapy were investigated.
Results;
Of inpatients,
60.4% used antibiotics (529/875) and of these 47.5% (416/529) used mono and
12.4% (113/529) used combined antibiotherapy. The mean age of patients administered
antibiotherapy was 5.0±4.4 years and according to age interval 66.7% were 1-5
years, 20.2% were 6-10 years and 13% were 11-18 years. The majority of patients
had upper and lower respiratory tract (27.4% and 35.3%), urinary system (16.6%)
and gastrointestinal system (9.1%) infection diagnosis. Erythrocyte
sedimentation rate was mean 33.3±24.6 mm/h and hospital stay was mean 4.5±4.08
days. For empirical mono antibiotherapy mainly penicillin (48.7%) and cephalosporin
(45.4%) were chosen. Regression analysis observed that other preliminary diagnoses
except for respiratory tract infection, elevated sedimentation rate and chest
x-ray increased the combined antibiotherapy rate.
Conclusion;
It is considered
there is a need for more developed methods accounting for many variables like
seasonal periods and factors relating to the patient and disease during the
whole process to develop rationale antibiotherapy strategies for general
pediatric wards.
Anahtar Kelimeler
Kaynakça
- 1.Fleming A. On the antibacterial action of the culture of a penicillium, with special reference to their use in the isolation of B.Influenza. Br J Exp Pathol 1929;10(3):226-36.
- 2.Aminov R. History of antimicrobial drug discovery: major classes and health impact. Biochem Pharmacol 2017;133:4-19.
- 3.Goossens H, Ferech M, Stichele Vander R, Elseviers M. Outpatient antibiotic use in Europe and association with resistance: a cross-national database study. Lancet 2005; 365:579-87.
- 4.Shorr AF. Epidemiology and economic impact of methicillin-resistant Staphylococcus aureus: review and analysis of the literature. Pharmacoeconomics 2007;25:751-68.
- 5.Fernandes P, Martens E. Antibiotics in late clinical development. Biochem Pharmacol 2017;133:152-163.
- 6.Theuretzbacher U. Antibiotic innovation for future public health needs. Clin Microbiol Infect 2017;23(10):713-17.
- 7.Akılcı ilaç kullanımı Ulusal eylem planı 2014-2017 [internet]. Health Ministry of Turkey Republic. [cited 2019 February 10]. Available from: www.akilciilac.gov.tr/wp-content/uploads/2014/11/aik-ulusal-eylem-plani.pdf.
- 8. Devrim İ, Gülfidan G, Tavlı V, Dizdarer C, Yaşar N, Oruç Y et al. Dr. Behçet Uz Çocuk Hastanesinde antibiyotik kullanımına ilişkin nokta prevalans çalışması. J Pediatr Inf 2009;3:11-3.
- 9.Ergül AB, Gokcek I, Çelik T, Torun YA. Assessment of inappropriate antibiotic use in pediatric patients: point-prevalence study. Turk Pediatri Ars 2018;53(1):17-23.
- 10.Chiotos K, Gerber JS, Himebauch AS. How can we optimize antibiotic use in the PICU? Pediatr Crit Care Med 2017;18(9):903-04.
- 11.Abbas Q, Ul Haq A, Kumar R, Ali SA, Hussain K, Shakoor S. Evaluation of antibiotic use in pediatric intensive care unit of developing country. Indian J Crit Care Med 2016;20(5):291-4.
- 12.WHO Collaborating Centre for Drug Statistics Methodology. Anatomical Therapeutic Chemical (ATC) classification system: Guidelines for ATC classification and DDD assignment. http://www.whocc.no/atc_ddd_methodology/purpose_of_the_atc_ddd_system/.
- 13.Antimicrobial resistance: global report on surveillance 2014 [Internet]. World Health Organization [cited 2019 February 10]. Available from: http://apps.who.int/iris/bitstream/handle/10665/112642/9789241564748_eng.pdf?sequence=1.
- 14.Hiltunen T, Virta M, Laine AL. Antibiotic resistance in the wild: an eco-evolutionary perspective. Philos Trans R Soc Lond B Biol Sci 2017;B 372(1712):20160039.15.Baker S. A return to the pre-antimicrobial era? Science 2015;347(6226):1064-66.
- 16.Hersh AL, De Lurgio SA, Thurm C, Lee BR, Weissman SJ, Courter JD, et al. Antimicrobial stewardship programs in freestanding children's hospitals. Pediatrics 2015;135(1):33-9.
- 17.Schrier L, Hadjipanayis A, Del Torso S, Stiris T, Emonts M, Dornbusch HJ. European antibiotic awareness day 2017: training the next generation of health care professionals in antibiotic stewardship. Eur J Pediatr 2018;177(2):279-83.
- 18.Godbout EJ, Pakyz AL, Markley JD, Noda AJ, Stevens MP. Pediatric antimicrobial stewardship: state of the art. Curr Infect Dis Rep 2018;20:39:1-13.19.Nguyen-Ha PT, Howrie D, Crowley K, Vetterly CG, McGhee W, Berry D, et al. A quality assessment of a collaborative model of a pediatric antimicrobial stewardship program. Pediatrics 2016;137(5). pii:e20150316.
- 20.Dolgner SJ, Arya B, Kronman MP, Chan T. Effect of congenital heart disease status on trends in pediatric infective endocarditis hospitalizations in the United States between 2000 and 2012. Pediatr Cardiol 2018. https://doi.org/10.1007/s00246-018-2020-7. 21.Langton Hewer SC, Smyth AR. Antibiotic strategies for eradicating pseudomonas aeruginosa in people with cystic fibrosis. Cochrane Database Syst Rev 2017;4:CD004197.
- 22.Kuruvilla M, de la Morena MT. Antibiotic prophylaxis in primary immune deficiency disorders. J Allergy Clin Immunol Pract 2013;1(6):573-82.
- 23.Hersh AL, Olson J, Stockmann C, Thorell EA, Knackstedt ED, Esquibel L, and et al. Impact of antimicrobial stewardship for pediatric outpatient parenteral antibiotic therapy. J Pediatric Infect Dis Soc 2018;7(2):e34-e36.
- 24.Vaz LE, Farnstrom CL, Felder KK, Guzman-Cottrill J, Rosenberg H, Antonelli RC. Utilizing a modified care coordination measurement tool to capture value for a pediatric outpatient parenteral and prolonged oral antibiotic therapy program. J Pediatric Infect Dis Soc 2018;7(2):136-42.
- 25.Watson JR, Wang L, Klima J, Moore-Clingenpeel P, Gleeson S, Kelleher K and et al. Healthcare claims data: an underutilized tool for pediatric outpatient antimicrobial stewardship. Clin Infect Dis 2017;64(11):1479-85.
- 26.Fahimzad A, Eydian Z, Karimi A, Shiva F, Sayyahfar S, Kahbazi M, and et al. Surveillance of antibiotic consumption point prevalence survey 2014: Antimicrobial prescribing in pediatrics wards of 16 Iranian hospitals. Arch Iran Med 2016;19(3):204-09.
- 27.Labi AK, Obeng-Nkrumah N, Sunkwa-Mills G, Bediako-Bowan A, Akufo C, Bjerrum S and et al. Antibiotic prescribing in pediatric inpatients in Ghana: a multi-center point prevalence survey. BMC Pediatrics 2018;18(1):391. doi:10.1186/s12887-018-1367-5.
- 28.Gharbi M, Doerholt K, Vergnano S, Bielicki JA, Paulus S, Menson E and et al. Using a simple point-prevalence survey to define appropriate antibiotic prescribing in hospitalized children across the UK. BMJ Open 2016;6(11):e012675. doi:10.1136/bmjopen-2016-012675.
- 29.Versporten A, Bielicki J, Drapier N, Sharland M, Goossens H; ARPEC project group. The Worldwide Antibiotic Resistance and Prescribing in European Children (ARPEC) point prevalence survey: developing hospital-quality indicators of antibiotic prescribing for children. J Antimicrob Chemother 2016; 71: 1106-17.
- 30.Gerber JS, Newland JG, Coffin SE, Hall M, Thurm C, Prasad PA et al. Variability in antibiotic use at children’s hospital throughout the United States. Pediatrics 2010;126(6):1067-73. doi:10.1542/peds.2010-1275.
- 31.Goossens H. Antibiotic consumption and link to resistance. Clin Microbiol Infect 2009; 15(3):12-5.
- 32.Rutledge-Taylor K, Matlow A, Gravel D, Embree J, Le Saux N, Johnston L, and et al. A point prevalence survey of healthcare-associated infections in Canadian pediatric inpatients. Am J Infect Control 2012;40(6):491-6.
- 33.Pakyz AL, Gurgle HE, Ibrahim OM, Oinonen MJ, Polk RE. Trends in antibacterial use in hospitalized pediatric patients in the United States academic health centers. Infect Control Hosp Epidemiol 2009;30(6):600-3.
- 34.Sviestina I, Mozgis D. Observational study of antibiotic usage at the children’s clinical university hospital in Riga, Latvia. Medicina (Kaunas) 2018;54(5). piiE74. doi: 10.3390/medicina54050074.
- 35.Gerber JS, Prasad PA, Russell Localio A, Fiks AG, Grundmeier RW, Bell LM, et al. Variation in antibiotic prescribing across a pediatric primary care network. J Pediatric Infect Dis Soc 2015;4(4):297-304. doi: 10.1093/jpids/piu086.
- 36.Adriaenssens N, Coenen S, Versporten A, Muller A, Minalu G, Faes C, and et al. European Surveillance of Antimicrobial Consumption (ESAC): outpatient antibiotic use in Europe (1997–2009). J Antimicrob Chemother 2011;66(6):vi3-12. doi: 10.1093/jac/dkr453.
- 37.Akkerman AE, Kuyvenhoven MM, van der Wouden JC, Verheij TJ. Determinants of antibiotic overprescribing in respiratory tract infections in general practice. J Antimicrob Chemother 2005;56(5):930-6. doi:10.1093/jac/dki283.
- 38.Nasimfar A, Sadeghi E, Karamyyar M, Manesh LJ. Comparison of serum procalcitonin level with erythrocytes sedimentation rate, C-reactive protein, white blood cell count, and blood culture in the diagnosis of bacterial infections in patients hospitalized in Montahhari hospital of Urmia (2016). J Adv Pharm Technol Res 2018;9(4):147-52. doi: 10.4103/japtr.JAPTR_319_18.
- 39.Akın F, Yazar A, Doğan M. Determining the infectious pathogens and their resistance to antibiotics in a pediatric intensive care unit. J Pediatr Infect Dis 2018;13(01):42-5. doi:10.1055/s-0037-1607236. 40.Kreitmeyri K, von Both U, Pecar A, Borde JP, Mikolajczyk R, Huebner J. Pediatric antibiotic stewardship: successful interventions in reduce broad-spectrum antibiotic use on general pediatric wards. Infection 2017;45 (4):493-504. doi: 10.1007/s15010-017-1009-0.
- 40.Kreitmeyri K, von Both U, Pecar A, Borde JP, Mikolajczyk R, Huebner J. Pediatric antibiotic stewardship: successful interventions in reduce broad-spectrum antibiotic use on general pediatric wards. Infection 2017;45 (4):493-504.
Toplam 37 adet kaynakça vardır.
Kaynak Göster
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