New Therapeutic Options for Treatment of Multi-drug Resistant Gram-negative Microorganisms

Year 2020, Volume: 73 Issue: 2, 96 - 101, 31.08.2020

Müge Ayhan

Abstract

Recently, antibiotic resistance in gram-negative microorganisms has been increased. While multi-drug resistant and extensively-drug resistant
gram-negative strains are the most common cause of healthcare-associated infections, and they are related with high morbidity and mortality. This
increase in antimicrobial resistance results in frequently inappropriate use of antibiotics. Effective antibiotic options are decreasing, in proportion
to this, new antibiotic development is less than the resistance. However, datas related with on some newly developed and developing antibiotics,
which are included in the old antimicrobial classes, are increasing. In this review, it is aimed to present new antibiotic options that are being used
and are being developed for the treatment of infections which are caused by antibiotic resistant gram-negative microorganisms are presented.
Double carbapenem therapy has been studied and evaluated as a treatment option for carbapenemase producing Enterobacteriaceae. Ceftazidime
-avibactam, meropenem - vaborbactam and ceftolozan - tazobactam, which are new beta-lactam beta-lactamase inhibitors, will soon appear to be
included in daily clinical practice. In addition, imipenem/cilastatin - relebactam, eravacycline, plasomycin and cefiderocol are new antibiotics that
are still being studied for efficacy and safety. Although, with all these new treatment options, we get stronger against infections that are caused
by drug resistant gram-negatives, the best way to combat drug resistant microorganisms is to prevent the resistance and spread of resistant clones
the rational use of antibiotics.

Keywords

Gram-negative , Antibiotic Resistance , Carbapenemases , Multi-drug Resistance

Ethical Statement

Hakem Değerlendirmesi: Editörler kurulunun dışından olan kişiler tarafından değerlendirilmiştir. Finansal Destek: Yazarlar tarafından finansal destek almadıkları bildirilmiştir

Supporting Institution

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Project Number

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Thanks

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Çoklu İlaca Dirençli Gram-negatif Mikroorganizmalarla Gelişen Enfeksiyonlarda Yeni Tedavi Seçenekleri

Abstract

Günümüzde gram-negatif mikroorganizmalarda direnç giderek artmaktadır. Çoklu ilaca dirençli ve yaygın ilaca dirençli suşlar ile gelişen enfeksiyonlar
hastalarda sağlık bakımı ilişkili enfeksiyonların en sık nedeni iken, yüksek mortalite ve morbidite ile ilişkilidir. Dirençteki bu artış antibiyotiklerin
artmış ve kimi zaman uygunsuz kullanımıyla sonuçlanmaktadır. Etkin antibiyotik seçenekleri azalmakta, buna oranla yeni geliştirilen antibiyotik
sayısı direnç karşısında daha az izlenmektedir. Ancak yine de eski sınıflara dahil edilen yeni geliştirilen ve geliştirilmekte olan bazı antibiyotikler ile
ilgili veriler artmaktadır. Bu derlemede, antibiyotik dirençli gram-negatiflerle gelişen enfeksiyonların tedavisi için geliştirilen, kullanılmakta olan
ve geliştirilmekte olan yeni antibiyotik seçenekleri sunulmuştur. İkili karbapenem tedavisi, karbapenemaz üreten enterikler için bir seçenek olarak
değerlendirilmiş ve çalışılmıştır. Yeni beta laktam - beta laktamaz inhibitörleri olan seftazidim - avibaktam, meropenem- vaborbaktam ve seftolozan
- tazobaktam da yakında günlük klinik pratikte yerini alacak gibi görünmektedir. Buna ek olarak, imipenem/silastatin - relebaktam, eravasiklin,
plazomisin ve sefiderokol de etkinlik ve güvenilirlik açısından çalışmaları sürmekte olan yeni antibiyotiklerdir. Tüm bu yeni tedavi seçenekleri
ile elimiz dirençli gram-negatiflerle gelişen enfeksiyonlara karşı güçlenmekte olsa da asıl olan direncin ve yayılımının önlenmesi, bunun için de
antibiyotiklerin akılcı bir şekilde kullanılmasıdır.

Keywords

Gram-negatif , Antibiyotik Direnci , Karbapenemaz , Çoklu İlaç Direnci

Ethical Statement

Hakem Değerlendirmesi: Editörler kurulunun dışından olan kişiler tarafından değerlendirilmiştir. Finansal Destek: Yazarlar tarafından finansal destek almadıkları bildirilmiştir

Supporting Institution

-

Project Number

-

Thanks

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References

• 1. Sheu CC, Chang YT, Lin SY, et al. Infections caused by carbapenem-resistant Enterobacteriaceae: An update on therapeutic options. Front Microbiol. 2019;10:80.
• 2. Willyard C. Drug-resistant bacteria ranked. Nature. 2017;543:15.
• 3. Shrivastava SR, Shrivastava PS, Ramasamy J. World health organization releases global priority list of antibiotic-resistant bacteria to guide research, discovery, and development of new antibiotics. JMS - J Med Soc. 2018;32:76-77.
• 4. Frieden T. Antibiotic resistance threats in the United States. Centers Dis Control Prev. 2013;114.
• 5. Kaye KS, Pogue JM. Infections Caused by Resistant Gram-Negative Bacteria: Epidemiology and Management. Pharmacotherapy. 2015;35:949-962.
• 6. Bulik CC, Nicolau DP. Double-carbapenem therapy for carbapenemaseproducing Klebsiella pneumoniae. Antimicrob Agents Chemother. 2011;55:3002-3004.
• 7. Anderson KF, Lonsway DR, Rasheed JK, et al. Evaluation of methods to identify the Klebsiella pneumoniae carbapenemase in Enterobacteriaceae. J Clin Microbiol. 2007;45:2723-2725.
• 8. Mashni O, Nazer L, Le J. Critical Review of Double-Carbapenem Therapy for the Treatment of Carbapenemase-Producing Klebsiella pneumoniae. Ann Pharmacother. 2019;53:70-81.
• 9. Souli M, Karaiskos I, Masgala A, et al. Double-carbapenem combination as salvage therapy for untreatable infections by KPC-2-producing Klebsiella pneumoniae. Eur J Clin Microbiol Infect Dis. 2017;36:1305-1315.
• 10. De Pascale G, Martucci G, Montini L, et al. Double carbapenem as a rescue strategy for the treatment of severe carbapenemase-producing Klebsiella pneumoniae infections: A two-center, matched case-control study. Crit Care. 2017;21:1-10.
• 11. Oliva A, Scorzolini L, Castaldi D, et al. Double-carbapenem regimen, alone or in combination with colistin, in the treatment of infections caused by carbapenem-resistant Klebsiella pneumoniae (CR-Kp). J Infect. 2017;74:103-106.
• 12. Rodriguez-Baño J, Gutiérrez-Gutiérrez B, Machuca I, Pascual A. Treatment of Infections Caused by Extended-Spectrum-Beta-. Clin Microbiol Rev [Internet]. 2018;31:1-42. Available from: http://cmr.asm.org/content/31/1/ e00087-17.full.pdf
• 13. Bassetti M, Graziano E, Berruti M, et al. The role of fosfomycin for multidrugresistant gram-negative infections. Curr Opin Infect Dis. 2019;32:617-625.
• 14. Doi Y. Treatment Options for Carbapenem-resistant Gram-negative Bacterial Infections. Clin Infect Dis. 2019;69:S565-575.
• 15. Yu W, Shen P, Bao Z, et al. In vitro antibacterial activity of fosfomycin combined with other antimicrobials against KPC-producing Klebsiella pneumoniae. Int J Antimicrob Agents [Internet]. 2017;50:237-241. Available from: http://dx.doi.org/10.1016/j.ijantimicag.2017.03.011
• 16. Evren E, Azap ÖK, Çolakoğlu Ş, et al. In vitro activity of fosfomycin in combination with imipenem, meropenem, colistin and tigecycline against OXA 48-positive Klebsiella pneumoniae strains. Diagn Microbiol Infect Dis. 2013;76:335-338.
• 17. Zhao M, Bulman ZP, Lenhard JR, et al. Pharmacodynamics of colistin and fosfomycin: A “treasure trove” combination combats KPC-producing Klebsiella pneumoniae. J Antimicrob Chemother. 2017;72:1985-1990.
• 18. Michalopoulos A, Virtzili S, Rafailidis P, et al. Intravenous fosfomycin for the treatment of nosocomial infections caused by carbapenem-resistant Klebsiella pneumoniae in critically ill patients: A prospective evaluation. Clin Microbiol Infect [Internet]. 2010;16:184-186. Available from: http:// dx.doi.org/10.1111/j.1469-0691.2009.02921.x
• 19. Pontikis K, Karaiskos I, Bastani S, et al. Outcomes of critically ill intensive care unit patients treated with fosfomycin for infections due to pandrugresistant and extensively drug-resistant carbapenemase-producing Gramnegative bacteria. Int J Antimicrob Agents [Internet]. 2014;43:52-59. Available from: http://dx.doi.org/10.1016/j.ijantimicag.2013.09.010
• 20. Liao Y, Hu GH, Xu YF, et al. Retrospective analysis of fosfomycin combinational therapy for sepsis caused by carbapenem-resistant Klebsiella pneumoniae. Exp Ther Med. 2017;13:1003-1010.
• 21. Merdjan H, Rangaraju M, Tarral A. Safety and Pharmacokinetics of Single and Multiple Ascending Doses of Avibactam Alone and in Combination with Ceftazidime in Healthy Male Volunteers: Results of Two Randomized, Placebo-Controlled Studies. Clin Drug Investig. 2015;35:307-317.
• 22. Wagenlehner FM, Sobel JD, Newell P, et al. Ceftazidime-avibactam Versus Doripenem for the Treatment of Complicated Urinary Tract Infections, Including Acute Pyelonephritis: RECAPTURE, a Phase 3 Randomized Trial Program. Clin Infect Dis. 2016;63:754-762.
• 23. Mazuski JE, Gasink LB, Armstrong J, et al. Efficacy and safety of ceftazidimeavibactam plus metronidazole versus meropenem in the treatment of complicated intra-abdominal infection: Results from a randomized, controlled, double-blind, phase 3 program. Clin Infect Dis. 2016;62:1380- 1389.
• 24. Shields RK, Potoski BA, Haidar G, et al. Clinical Outcomes, Drug Toxicity, and Emergence of Ceftazidime-Avibactam Resistance Among Patients Treated for Carbapenem-Resistant Enterobacteriaceae Infections. Clin Infect Dis. 2016;63:1615-1618.
• 25. Shields RK, Chen L, Cheng S, et al. crossm Emergence of Ceftazidime- Avibactam Mutations during Treatment of. Antimicrob Agents Chemother. 2017;61:1-11.
• 26. Livermore DM, Mushtaq S. Activity of biapenem (RPX2003) combined with the boronate β-lactamase inhibitor RPX7009 against carbapenem-resistant Enterobacteriaceae. J Antimicrob Chemother. 2013;68:1825-1831.
• 27. Kaye KS, Bhowmick T, Metallidis S, et al. Effect of meropenem-vaborbactam vs piperacillin-Tazobactam on clinical cure or improvement and microbial eradication in complicated urinary tract infection the TANGO I randomized clinical trial. JAMA - J Am Med Assoc. 2018;319:788-799.
• 28. Wunderink RG, Giamarellos-Bourboulis EJ, Rahav G, et al. Effect and Safety of Meropenem–Vaborbactam versus Best-Available Therapy in Patients with Carbapenem-Resistant Enterobacteriaceae Infections: The TANGO II Randomized Clinical Trial. Infect Dis Ther [Internet]. 2018;7:439-455. Available from: https://doi.org/10.1007/s40121-018-0214-1
• 29. Karaiskos I, Lagou S, Pontikis K, et al. The “Old” and the “New” antibiotics for MDR Gram-negative pathogens: For whom, when, and how. Front Public Heal. 2019;7:1-25.
• 30. Theuretzbacher U. Global antimicrobial resistance in Gram-negative pathogens and clinical need. Curr Opin Microbiol. 2017;39:106-112.