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Evaluation of the Efficacy of Colistin Therapy with or without Loading Dose in the Treatment of Multi Drug Resistant Gram-negative Bacterial Infections

Yıl 2022, Cilt 12, Sayı 2, 312 - 318, 15.03.2022
https://doi.org/10.16899/jcm.1058903

Öz

Aim: Colistin (Col) is an agent used in the treatment of multidrug-resistant gram-negative (MDRGN) bacterial infections. This drug has been administered with a loading dose in recent years to provide rapid clinical response and therapeutic blood levels. In our study, we aimed to evaluate whether there is a relationship between the efficacy of the loading dose of Col treatment, mortality, microbiological clearance during treatment, nephrotoxicity, and neurotoxicity side effects for the treatment of MDRGN bacterial infections. Material method: In this retrospective study, which included a control group, 6-years data was analyzed. Totally, 323 patients who received Col treatment with or without loading dose (LD) were included in the study. Patients were divided into two groups; I: without Col-LD regimen (those who were hospitalized in 2011-2014), II: with Col-LD regimen (those who were hospitalized in 2015-2017). Demographic characteristics such as age, gender, microbiological cultures, laboratory results, side effects, and mortality of the patients were evaluated. Results: A statistically significant relationship was found between with Col-LD regimen and nephrotoxicity. However, it was determined that there was no statistically significant relationship between microbiological clearance without a Col-LD regimen. Nephrotoxicity was found to be decreased with the Col-LD regimen. Neurotoxicity was observed more frequently (3.7%) in with Col-LD regimen. Initial and final C-reactive protein (CRP) and procalcitonin (PCT) levels were statistically significantly lower in with Col-LD regimen. Conclusion: It was found that with Col-LD regimen had a statistically significant effect on nephrotoxicity, neurotoxicity, and treatment outcome, but had no effect on microbiological clearance. In addition, with Col-LD regimen was effective in decreasing CRP and PCT values.

Kaynakça

  • 1. Aydın M, Azak E, Bilgin H, Menekse S, Asan A, Mert HTE, et al. Changes in antimicrobial resistance and outcomes of health careassociated infections. Eur J Clin Microbiol Infect Dis. 2021. doi: 10.1007/s10096-020-04140-y.
  • 2. LaPlante K, Cusumano J, Tillotson G. Colistin for the treatment of multidrug-resistant infections. Lancet Infect Dis. 2018;18(11):1174-1175. doi: 10.1016/S1473-3099(18)30611-X.
  • 3. Mohamed AF, Karaiskos I, Plachouras D, Karvanen M, Pontikis K, Jansson B, et al. Application of a loading dose of colistin methanesulfonate in critically ill patients: population pharmacokinetics, protein binding, and prediction of bacterial kill. Antimicrob Agents Chemother. 2012;56(8):4241-4249.
  • 4. Shorr AF. Review of studies of the impact on Gram-negative bacterial resistance on outcomes in the intensive care unit. Crit Care Med. 2009;37(4):1463-1469.
  • 5. Tüzemen NÜ, Efe K, Akalın H, Özakın C. Retrospective evaluation of colistin-resistant isolates in automated system by gradient diffusion method and broth microdilution method. Klimik Derg. 2019; 32(1): 57-61.
  • 6. Magiorakos AP, Srinivasan A, Carey RB, Carmeli Y, Falagas ME, Giske CG, et al. Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: an international expert proposal for interim standard definitions for acquired resistance. Clin Microbiol Infect. 2012;18(3):268-281. doi: 10.1111/j.1469-0691.2011.03570.x.
  • 7. Landersdorfer CB, Nation RL. Colistin: how should it be dosed for the critically ill? Semin Respir Crit Care Med. 2015;36(1):126-135.
  • 8. Rocco M, Montini L, Alessandri E, Venditti M, Laderchi A, De Pascale G, et al. Risk factors for acute kidney injury in critically ill patients receiving high intravenous doses of colistin methanesulfonate and/or other nephrotoxic antibiotics: a retrospective cohort study. Crit Care. 2013;17: R174.
  • 9. Çeti̇n Ç, Türk D, Şenol Ş, Horasan G, Tünger Ö. Colistin efficacy in the treatment of multidrug-resistant and extremelydrug-resistant gram-negative bacterial infections. Turkish Journal of Medical Sciences. 2016; 46(5): 1379-1384.
  • 10. Grégoire N, Mimoz O, Mégarbane B, Comets E, Chatelier D, Lasocki S, et al. New colistin population pharmacokinetic data in critically ill patients suggesting an alternative loading dose rationale. Antimicrob Agents Chemother. 2014;58(12):7324-7330. doi: 10.1128/AAC.03508-14.
  • 11. Nazer LH, Anabtawi N. Optimizing colistin dosing: Is a loading dose necessary? Am J Health Syst Pharm. 2017;74(1):e9-e16. doi: 10.2146/ajhp150876.
  • 12. The Sanford Guide to Antimicrobial Therapy 2012. In: Gilbert DN, Moellering RC, Eliopoulos GM, Chambers HE, Saag MS (eds). 42nd ed.
  • 13. Yemişen M, Özaras R. Kolistin. FLORA. 2011;16(Ek 3):15-26.
  • 14. Tsuji BT, Pogue JM, Zavascki AP, Paul M, Daikos GL, Forrest A, et al. International Consensus Guidelines for the Optimal Use of the Polymyxins: Endorsed by the American College of Clinical Pharmacy (ACCP), European Society of Clinical Microbiology and Infectious Diseases (ESCMID), Infectious Diseases Society of America (IDSA), International Society for Anti-infective Pharmacology (ISAP), Society of Critical Care Medicine (SCCM), and Society of Infectious Diseases Pharmacists (SIDP). Pharmacotherapy. 2019;39(1):10-39. doi: 10.1002/phar.2209.
  • 15. Alp E, Eren E, Elay G, Cevahir F, Esmaoğlu A, Rello J. Efficacy of loading dose of colistin in Acinetobacter baumannii ventilator-associatedpneumonia. Infez Med. 2017;25(4):311-319.
  • 16. Trifi A, Abdellatif S, Daly F, Mahjoub K, Nasri R, et al. Efficacy and Toxicity of High-Dose Colistin in Multidrug-Resistant Gram-Negative Bacilli Infections: A Comparative Study of a Matched Series. Chemotherapy. 2016;61(4):190-6. doi: 10.1159/000442786.
  • 17. Elefritz JL, Bauer KA, Jones C, Mangino JE, Porter K, Murphy CV. Efficacy and Safety of a Colistin Loading Dose, High-Dose Maintenance Regimen in Critically Ill Patients With Multidrug-Resistant Gram-Negative Pneumonia. J Intensive Care Med. 2017;32(8):487-493. doi:10.1177/0885066616646551
  • 18. Karaiskos I, Friberg LE, Pontikis K, Ioannidis K, Tsagkari V, Galani L, et al. Colistin Population Pharmacokinetics after Application of a Loading Dose of 9 MU Colistin Methanesulfonate in Critically Ill Patients. Antimicrob Agents Chemother. 2015;59(12):7240-7248. doi: 10.1128/AAC.00554-15.
  • 19. Vicari G, Bauer SR, Neuner EA, Lam, SW. Association between colistin dose and microbiologic outcomes in patients with multi-drug resistant gram-negative bacteremia. Clin Infect Dis. 2013;56(3):398–404.
  • 20. Cai Y, Chai D, Wang R, Liang B, Bai N. Colistin resistance of Acinetobacter baumannii: clinical reports, mechanisms and antimicrobial strategies. J Antimicrob Chemother. 2012 Jul;67(7):1607-1615. doi: 10.1093/jac/dks084.
  • 21. Akalın H. Kolistin, ANKEM dergisi. 2007;21(Ek 2):26-68.
  • 22. Nation RL, Li J, Cars O, Couet W, Dudley MN, Kaye KS, et al. Framework for optimisation of the clinical use of colistin and polymyxin B: the Prato polymyxin consensus. Lancet Infect Dis. 2015 Feb;15(2):225-234. doi: 10.1016/S1473-3099(14)70850-3.
  • 23. Abdelsalam MFA, Abdalla MS, El-Abhar HSE. Prospective, comparative clinical study between high-dose colistin monotherapy and colistin-meropenem combination therapy for treatment of hospital-acquired pneumonia and ventilator-associated pneumonia caused by multidrug-resistant Klebsiella pneumoniae. J Glob Antimicrob Resist. 2018;15:127-135. doi: 10.1016/j.jgar.2018.07.003.
  • 24. Rocco M, Montini L, Alessandri E, Venditti M, Laderchi A, De Pascale G, et al. Risk factors for acute kidney injury in critically ill patients receiving high intravenous doses of colistin methanesulfonate and/or other nephrotoxic antibiotics: a retrospective cohort study. Crit Care. 2013;17(4):R174. doi: 10.1186/cc12853.
  • 25. Doshi NM, Mount KL, Murphy CV. Nephrotoxicity associated with intravenous colistin in critically ill patients. Pharmacotherapy. 2011;31(12):1257-1264. doi: 10.1592/phco.31.12.1257.
  • 26. Pogue JM, Lee J, Marchaim D, Yee V, Zhao JJ, Chopra T, et al. Incidence of and risk factors for colistin-associated nephrotoxicity in a large academic health system. Clin Infect Dis. 2011;53(9):879-884. doi: 10.1093/cid/cir611.
  • 27. Katip W, Uitrakul S, Oberdorfer P. Clinical outcomes and nephrotoxicity of colistin loading dose for treatment of extensively drug-resistant Acinetobacter baumannii in cancer patients. Infect Drug Resist. 2017;10:293-298. doi: 10.2147/IDR.S144314.
  • 28. Bellos I, Pergialiotis V, Frountzas M, Kontzoglou K, Daskalakis G, PerreaDN. Efficacy and safety of colistin loading dose: a meta-analysis. J Antimicrob Chemother. 2020;75(7):1689-1698. doi: 10.1093/jac/dkaa064.
  • 29. Nigam A, Kumari A, Jain R, Batra S. Colistin neurotoxicity: revisited. BMJ Case Rep. 2015;2015:bcr2015210787. doi: 10.1136/bcr-2015-210787.
  • 30. Myint T, Evans ME, Burgess DR, Greenberg RN. Respiratory Muscle Paralysis Associated With Colistin, Polymyxin B, and Muscle Relaxants Drugs: A Case Report. J Investig Med High Impact Case Rep. 2016;4(1):2324709616638362. doi: 10.1177/2324709616638362.
  • 31. Lindesmith LA, Baines RD, Jr, Bigelow DB, Petty TL. Reversible respiratory paralysis associated with polymyxin therapy. Ann Intern Med. 1968;68:318-27.
  • 32. Velkov T, Dai C, Ciccotosto GD, Cappai R, Hoyer D, Li J. Polymyxins for CNS infections: Pharmacology and neurotoxicity. Pharmacol Ther. 2018;181:85-90. doi: 10.1016/j.pharmthera.2017.07.012.
  • 33. Dai C, Li J, Li J. New insight in colistin induced neurotoxicity with the mitochondrial dysfunction in mice central nervous tissues. Exp Toxicol Pathol. 2013;65(6):941-948. doi: 10.1016/j.etp.2013.01.008.
  • 34. Grégoire N, Aranzana-Climent V, Magréault S, Marchand S, Couet W. Clinical Pharmacokinetics and Pharmacodynamics of Colistin. Clin Pharmacokinet. 2017;56(12):1441-1460. doi: 10.1007/s40262-017-0561-1.

Çoklu İlaca Dirençli Gram-negatif Bakteriyel Enfeksiyonların Tedavisinde Yükleme Dozlu veya Yüklemesiz Kolistin Tedavisinin Etkinliğinin Değerlendirilmesi

Yıl 2022, Cilt 12, Sayı 2, 312 - 318, 15.03.2022
https://doi.org/10.16899/jcm.1058903

Öz

Amaç: Kolistin (Col), çok ilaca dirençli gram-negatif (MDRGN) bakteriyel enfeksiyonların tedavisinde kullanılan bir ajandır. Bu ilaç hızlı klinik yanıt ve terapötik kan seviyeleri sağlamak için son yıllarda yükleme dozu ile uygulanmaktadır. Çalışmamızda MDRGN bakteriyel enfeksiyonlarının tedavisinde Col tedavisinin yükleme dozunun etkinliği ile mortalite, tedavi sırasındaki mikrobiyolojik klirens, nefrotoksisite ve nörotoksisite yan etkileri arasında bir ilişki olup olmadığını değerlendirmeyi amaçladık. Gereç yöntem: Kontrol grubu içeren bu retrospektif çalışmada 6 yıllık veriler analiz edildi. Toplamda yükleme dozu (LD) olan veya olmayan Col tedavisi alan 323 hasta çalışmaya dahil edildi. Hastalar iki gruba ayrıldı; I: Col-LD rejimi almayanlar (2011-2014'te hastaneye yatırılanlar), II: Col-LD rejimi uygulananlar (2015-2017'de hastaneye yatırılanlar). Hastaların yaş, cinsiyet, mikrobiyolojik kültürler, laboratuvar sonuçları, yan etkiler ve mortalite gibi demografik özellikleri değerlendirildi. Bulgular: Col-LD rejimi ile nefrotoksisite arasında istatistiksel olarak anlamlı bir ilişki bulundu. Ancak Col-LD rejimi olmadan mikrobiyolojik klirens arasında istatistiksel olarak anlamlı bir ilişki olmadığı belirlendi. Col-LD rejimi ile nefrotoksisitenin azaldığı bulundu. Nörotoksisite, Col-LD rejiminde daha sık (%3.7) gözlendi. İlk ve son C-reaktif protein (CRP) ve prokalsitonin (PCT) seviyeleri Col-LD rejiminde istatistiksel olarak anlamlı derecede düşüktü. Sonuç: Col-LD rejiminin nefrotoksisite, nörotoksisite ve tedavi sonucu üzerinde istatistiksel olarak anlamlı bir etkiye sahip olduğu, ancak mikrobiyolojik klirens üzerinde hiçbir etkisinin olmadığı bulundu. Ayrıca Col-LD rejimi ile CRP ve PCT değerlerinin düşürülmesinde etkili olmuştur.

Kaynakça

  • 1. Aydın M, Azak E, Bilgin H, Menekse S, Asan A, Mert HTE, et al. Changes in antimicrobial resistance and outcomes of health careassociated infections. Eur J Clin Microbiol Infect Dis. 2021. doi: 10.1007/s10096-020-04140-y.
  • 2. LaPlante K, Cusumano J, Tillotson G. Colistin for the treatment of multidrug-resistant infections. Lancet Infect Dis. 2018;18(11):1174-1175. doi: 10.1016/S1473-3099(18)30611-X.
  • 3. Mohamed AF, Karaiskos I, Plachouras D, Karvanen M, Pontikis K, Jansson B, et al. Application of a loading dose of colistin methanesulfonate in critically ill patients: population pharmacokinetics, protein binding, and prediction of bacterial kill. Antimicrob Agents Chemother. 2012;56(8):4241-4249.
  • 4. Shorr AF. Review of studies of the impact on Gram-negative bacterial resistance on outcomes in the intensive care unit. Crit Care Med. 2009;37(4):1463-1469.
  • 5. Tüzemen NÜ, Efe K, Akalın H, Özakın C. Retrospective evaluation of colistin-resistant isolates in automated system by gradient diffusion method and broth microdilution method. Klimik Derg. 2019; 32(1): 57-61.
  • 6. Magiorakos AP, Srinivasan A, Carey RB, Carmeli Y, Falagas ME, Giske CG, et al. Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: an international expert proposal for interim standard definitions for acquired resistance. Clin Microbiol Infect. 2012;18(3):268-281. doi: 10.1111/j.1469-0691.2011.03570.x.
  • 7. Landersdorfer CB, Nation RL. Colistin: how should it be dosed for the critically ill? Semin Respir Crit Care Med. 2015;36(1):126-135.
  • 8. Rocco M, Montini L, Alessandri E, Venditti M, Laderchi A, De Pascale G, et al. Risk factors for acute kidney injury in critically ill patients receiving high intravenous doses of colistin methanesulfonate and/or other nephrotoxic antibiotics: a retrospective cohort study. Crit Care. 2013;17: R174.
  • 9. Çeti̇n Ç, Türk D, Şenol Ş, Horasan G, Tünger Ö. Colistin efficacy in the treatment of multidrug-resistant and extremelydrug-resistant gram-negative bacterial infections. Turkish Journal of Medical Sciences. 2016; 46(5): 1379-1384.
  • 10. Grégoire N, Mimoz O, Mégarbane B, Comets E, Chatelier D, Lasocki S, et al. New colistin population pharmacokinetic data in critically ill patients suggesting an alternative loading dose rationale. Antimicrob Agents Chemother. 2014;58(12):7324-7330. doi: 10.1128/AAC.03508-14.
  • 11. Nazer LH, Anabtawi N. Optimizing colistin dosing: Is a loading dose necessary? Am J Health Syst Pharm. 2017;74(1):e9-e16. doi: 10.2146/ajhp150876.
  • 12. The Sanford Guide to Antimicrobial Therapy 2012. In: Gilbert DN, Moellering RC, Eliopoulos GM, Chambers HE, Saag MS (eds). 42nd ed.
  • 13. Yemişen M, Özaras R. Kolistin. FLORA. 2011;16(Ek 3):15-26.
  • 14. Tsuji BT, Pogue JM, Zavascki AP, Paul M, Daikos GL, Forrest A, et al. International Consensus Guidelines for the Optimal Use of the Polymyxins: Endorsed by the American College of Clinical Pharmacy (ACCP), European Society of Clinical Microbiology and Infectious Diseases (ESCMID), Infectious Diseases Society of America (IDSA), International Society for Anti-infective Pharmacology (ISAP), Society of Critical Care Medicine (SCCM), and Society of Infectious Diseases Pharmacists (SIDP). Pharmacotherapy. 2019;39(1):10-39. doi: 10.1002/phar.2209.
  • 15. Alp E, Eren E, Elay G, Cevahir F, Esmaoğlu A, Rello J. Efficacy of loading dose of colistin in Acinetobacter baumannii ventilator-associatedpneumonia. Infez Med. 2017;25(4):311-319.
  • 16. Trifi A, Abdellatif S, Daly F, Mahjoub K, Nasri R, et al. Efficacy and Toxicity of High-Dose Colistin in Multidrug-Resistant Gram-Negative Bacilli Infections: A Comparative Study of a Matched Series. Chemotherapy. 2016;61(4):190-6. doi: 10.1159/000442786.
  • 17. Elefritz JL, Bauer KA, Jones C, Mangino JE, Porter K, Murphy CV. Efficacy and Safety of a Colistin Loading Dose, High-Dose Maintenance Regimen in Critically Ill Patients With Multidrug-Resistant Gram-Negative Pneumonia. J Intensive Care Med. 2017;32(8):487-493. doi:10.1177/0885066616646551
  • 18. Karaiskos I, Friberg LE, Pontikis K, Ioannidis K, Tsagkari V, Galani L, et al. Colistin Population Pharmacokinetics after Application of a Loading Dose of 9 MU Colistin Methanesulfonate in Critically Ill Patients. Antimicrob Agents Chemother. 2015;59(12):7240-7248. doi: 10.1128/AAC.00554-15.
  • 19. Vicari G, Bauer SR, Neuner EA, Lam, SW. Association between colistin dose and microbiologic outcomes in patients with multi-drug resistant gram-negative bacteremia. Clin Infect Dis. 2013;56(3):398–404.
  • 20. Cai Y, Chai D, Wang R, Liang B, Bai N. Colistin resistance of Acinetobacter baumannii: clinical reports, mechanisms and antimicrobial strategies. J Antimicrob Chemother. 2012 Jul;67(7):1607-1615. doi: 10.1093/jac/dks084.
  • 21. Akalın H. Kolistin, ANKEM dergisi. 2007;21(Ek 2):26-68.
  • 22. Nation RL, Li J, Cars O, Couet W, Dudley MN, Kaye KS, et al. Framework for optimisation of the clinical use of colistin and polymyxin B: the Prato polymyxin consensus. Lancet Infect Dis. 2015 Feb;15(2):225-234. doi: 10.1016/S1473-3099(14)70850-3.
  • 23. Abdelsalam MFA, Abdalla MS, El-Abhar HSE. Prospective, comparative clinical study between high-dose colistin monotherapy and colistin-meropenem combination therapy for treatment of hospital-acquired pneumonia and ventilator-associated pneumonia caused by multidrug-resistant Klebsiella pneumoniae. J Glob Antimicrob Resist. 2018;15:127-135. doi: 10.1016/j.jgar.2018.07.003.
  • 24. Rocco M, Montini L, Alessandri E, Venditti M, Laderchi A, De Pascale G, et al. Risk factors for acute kidney injury in critically ill patients receiving high intravenous doses of colistin methanesulfonate and/or other nephrotoxic antibiotics: a retrospective cohort study. Crit Care. 2013;17(4):R174. doi: 10.1186/cc12853.
  • 25. Doshi NM, Mount KL, Murphy CV. Nephrotoxicity associated with intravenous colistin in critically ill patients. Pharmacotherapy. 2011;31(12):1257-1264. doi: 10.1592/phco.31.12.1257.
  • 26. Pogue JM, Lee J, Marchaim D, Yee V, Zhao JJ, Chopra T, et al. Incidence of and risk factors for colistin-associated nephrotoxicity in a large academic health system. Clin Infect Dis. 2011;53(9):879-884. doi: 10.1093/cid/cir611.
  • 27. Katip W, Uitrakul S, Oberdorfer P. Clinical outcomes and nephrotoxicity of colistin loading dose for treatment of extensively drug-resistant Acinetobacter baumannii in cancer patients. Infect Drug Resist. 2017;10:293-298. doi: 10.2147/IDR.S144314.
  • 28. Bellos I, Pergialiotis V, Frountzas M, Kontzoglou K, Daskalakis G, PerreaDN. Efficacy and safety of colistin loading dose: a meta-analysis. J Antimicrob Chemother. 2020;75(7):1689-1698. doi: 10.1093/jac/dkaa064.
  • 29. Nigam A, Kumari A, Jain R, Batra S. Colistin neurotoxicity: revisited. BMJ Case Rep. 2015;2015:bcr2015210787. doi: 10.1136/bcr-2015-210787.
  • 30. Myint T, Evans ME, Burgess DR, Greenberg RN. Respiratory Muscle Paralysis Associated With Colistin, Polymyxin B, and Muscle Relaxants Drugs: A Case Report. J Investig Med High Impact Case Rep. 2016;4(1):2324709616638362. doi: 10.1177/2324709616638362.
  • 31. Lindesmith LA, Baines RD, Jr, Bigelow DB, Petty TL. Reversible respiratory paralysis associated with polymyxin therapy. Ann Intern Med. 1968;68:318-27.
  • 32. Velkov T, Dai C, Ciccotosto GD, Cappai R, Hoyer D, Li J. Polymyxins for CNS infections: Pharmacology and neurotoxicity. Pharmacol Ther. 2018;181:85-90. doi: 10.1016/j.pharmthera.2017.07.012.
  • 33. Dai C, Li J, Li J. New insight in colistin induced neurotoxicity with the mitochondrial dysfunction in mice central nervous tissues. Exp Toxicol Pathol. 2013;65(6):941-948. doi: 10.1016/j.etp.2013.01.008.
  • 34. Grégoire N, Aranzana-Climent V, Magréault S, Marchand S, Couet W. Clinical Pharmacokinetics and Pharmacodynamics of Colistin. Clin Pharmacokinet. 2017;56(12):1441-1460. doi: 10.1007/s40262-017-0561-1.

Ayrıntılar

Birincil Dil İngilizce
Konular Sağlık Bilimleri ve Hizmetleri
Bölüm Orjinal Araştırma
Yazarlar

Emine Kübra DİNDAR DEMİRAY (Sorumlu Yazar)
Bitlis Devlet Hastanesi, Enfeksiyon Hastalıkları Ve Klinik Mikrobiyoloji , Bitlis
0000-0001-6459-7182
Türkiye


Sebnem SENOL
Celal Bayar University Hafsa Sultan Hospital, Department of Infectious Diseases and Clinical Microbiology, Manisa, Turkey
0000-0001-7438-7306
Türkiye

Destekleyen Kurum yok
Proje Numarası yok
Erken Görünüm Tarihi 1 Ocak 2022
Yayımlanma Tarihi 15 Mart 2022
Kabul Tarihi 26 Ocak 2022
Yayınlandığı Sayı Yıl 2022, Cilt 12, Sayı 2

Kaynak Göster

AMA Dindar Demiray E. K. , Senol S. Evaluation of the Efficacy of Colistin Therapy with or without Loading Dose in the Treatment of Multi Drug Resistant Gram-negative Bacterial Infections. J Contemp Med. 2022; 12(2): 312-318.