Öz
Giriş: Eski bir antibiyotik olan fosfomisin, dirençli enfeksiyonlarda intravenöz formülasyonunun (fosfomisin sodyum) kullanılmasıyla tekrar ön plana çıkmıştır. Bu çalışmanın amacı Enterobacterales kan dolaşımı izolatlarında karbapenem direncini belirlemek ve karbapenem dirençli Enterobacterales (KDE) suşlarında karbapenem türleri ve fosfomisin direnç genlerinin sıklığını araştırmaktır.
Gereç ve Yöntem: Enterobacterales kan dolaşımı izolatları, 2017-2019 yılları arasında 18 yaş ve üzeri karaciğer nakli hastalarında değerlendirildi. Bu izolatlardan herhangi bir karbapenem antibiyotiğe dirençli olanlar tespit edilerek çalışmaya alındı. Karbapenem duyarlılığı E-test, fosfomisin duyarlılığı agar dilüsyon yöntemleri ile test edildi ve European Committee on Antimicrobial Susceptibility Testing kriterlerine göre değerlendirildi. OXA-48, NDM, KPC, VIM, IMP tipi karbapenemazlar ile fosA, fosA3, fosC2 dirençli genlerin sıklığı polimeraz zincir reaksiyonu (PZR) yöntemi kullanılarak araştırıldı.
Bulgular: Enterobacterales kan dolaşımı enfeksiyonlarından toplam 115 izolat incelenerek herhangi bir karbapenem antibiyotiğe dirençli olan 34 (%29,3) izolat tespit edildi. Bu 34 izolatın %61,8’i karbapenemaz üretti ve OXA-48 en yaygın karbapenemaz tipiydi. İzolatların %41,2’si Escherichia coli ve %58,8’i Klebsiella pneumoniae idi. Izolatlarda fosfomisin direnç oranı %73,5 idi. FosA geni %5,9 olarak bulundu. Ancak hiçbir izolatta fosA3 ve fosC2 genleri yoktu. Karbapenem dirençli Enterobacterales izolatlarında fosA+OXA-48 ve fosA+NDM genleri tespit edildi.
Sonuç: Türkiye’de karaciğer nakli yapılan hastaların kan kültürü izolatlarında fosfomisin direnç genlerinin araştırıldığı ilk çalışmadır. Yüksek fosfomisin direncine rağmen sadece iki tane pozitif direnç geni saptanması, diğer direnç mekanizmalarına bağlı olarak fosfomisin direnci olabileceğini ortaya koymaktadır.
Anahtar Kelimeler: Bakteriyemi, Enterobacteriaceae, fosA, fosA3, fosC2, fosfomisin direnci, karaciğer transplantasyonu
Kaynakça
Romero FA, Razonable RR. Infections in liver transplant recipients. World J Hepatol. 2011;3:83–92.
Weiner-Lastinger LM, Abner S, Edwards JR, Kallen AJ, Karlsson M, Magill SS, Pollock D, See I, Soe MM, Walters MS, Dudeck MA. Antimicrobial-resistant pathogens associated with adult healthcare-associated infections: Summary of data reported to the National Healthcare Safety Network, 2015-2017. Infect Control Hosp Epidemiol. 2020;41:1-18.
Falagas ME, Vouloumanou EK, Samonis G, Vardakasa KZ. Fosfomycin. Clin Microbiol Rev. 2016;29:321–47.
Yildiz IE, Topcu A, Bahceci I, Arpa M, Tumkaya L, Mercantepe T, Batcik S, Yildiz Y. The protective role of fosfomycin in lung injury due to oxidative stress and inflammation caused by sepsis. Life Sci. 2021;279:119662.
Zurfluh K, Treier A, Schmitt K, Stephan R. Mobile fosfomycin resistance genes in Enterobacteriaceae-An increasing threat. Microbiologyopen. 2020;9:e1135.
Falagas ME, Athanasaki F, Voulgaris GL, Triarides NA, Vardakas KZ. Resistance to fosfomycin: Mechanisms, Frequency and Clinical Consequences. Int J Antimicrob Agents. 2019;53:22-8.
Carbapenem Resistant Enterobacterales Technical Information. https://www.cdc.gov/hai/organisms/cre/technical-info.html. 25 July 2021
Singhal N, Kumar M, Kanaujia PK, Virdi JS. MALDI-TOF mass spectrometry: an emerging technology for microbial identification and diagnosis. Front Microbiol. 2015;6:791.
The European Committee on Antimicrobial Susceptibility Testing. Breakpoint tables for interpretation of MICs and zone diameters. Version 12.0, 2022. Available from: http://www.eucast.org
Marroki A, Bousmaha-Marroki L. Antibiotic Resistance Diagnostic Methods for Pathogenic Bacteria. Elsevier. 2022;4:320-34.
Hudzicki J. Kirby-Bauer disk diffusion susceptibility test protocol. American Society for Microbiology. 2009;15:55-63.
Sato N, Kawamura K, Nakane K, Wachino J, Arakawa Y. First detection of fosfomycin resistance gene fosA3 in CTX-M-producing Escherichia coli isolates from healthy individuals in Japan. Microb Drug Resist. 2013;19:477-82.
Poirel L, Walsh TR, Cuvillier V, Nordmann P. Multiplex PCR for detection of acquired carbapenemase genes. Diagn Microbiol Infect Dis. 2011;70:119-23.
Hou J, Huang X, Deng Y, He L, Yang T, Zeng Z, Chen Z, Liu JH. Dissemination of the fosfomycin resistance gene fosA3 with CTX-M β-lactamase genes and rmtB carried on IncFII plasmids among Escherichia coli isolates from pets in China. Antimicrob Agents Chemother. 2012;56:2135-8.
Grundmann HJ, Towner KJ, Dijkshoorn L, Gerner-Smidt P, Maher M, Seifert H, Vaneechoutte M. Multicenter study using standardized protocols and reagents for evaluation of reproducibility of PCR-based fingerprinting of Acinetobacter spp. J Clin Microbiol. 1997;35:3071-7.
Singh N, Haidar G, Limaye AP. Infections in solid-organ transplant recipients. In: Bennet JE, Dolin R, Blaser MJ, edıtors. Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases, 9th ed. Canada, Elsevier. 2020. p.3672–97.
van Duin D, Arias CA, Komarow L, Chen L, Hanson BM, Weston G, Cober E, Garner OB, Jacob JT, Satlin MJ, Fries BC, Garcia-Diaz J, Doi Y, Dhar S, Kaye KS, Earley M, Hujer AM, Hujer KM, Domitrovic TN, Shropshire WC, Dinh A, Manca C, Luterbach CL, Wang M, Paterson DL, Banerjee R, Patel R, Evans S, Hill C, Arias R, Chambers HF, Fowler VG Jr, Kreiswirth BN, Bonomo RA; Multi-Drug Resistant Organism Network Investigators. Molecular and clinical epidemiology of carbapenem-resistant Enterobacterales in the USA (CRACKLE-2): a prospective cohort study. Lancet Infect Dis. 2020;20(6):731-41. Erratum in: Lancet Infect Dis. 2020.
Bodro M, Sabé N, Tubau F, Lladó L, Baliellas C, Roca J, Cruzado JM, Carratalà J. Risk factors and outcomes of bacteremia caused by drug-resistant ESKAPE pathogens in solid-organ transplant recipients. Transplantation. 2013;96:843-9.
Jafarpour Z, Pouladfar G, Malek Hosseini SA, Firoozifar M, Jafari P. Bacterial infections in the early period after liver transplantation in adults: A prospective single-center cohort study. Microbiol Immunol. 2020;64:407–15.
Cinar G, Kalkan İA, Azap A, Kirimker OE, Balci D, Keskin O, Yuraydin C, Ormeci N, Dokmeci A. Carbapenemase-Producing Bacterial Infections in Patients With Liver Transplant. Transplant Proc. 2019;51:2461-5.
Zhang Y, Wang Q, Yin Y, Chen H, Jin L, Gu B, Xie L, Yang C, Ma X, Li H, Li W, Zhang X, Liao K, Man S, Wang S, Wen H, Li B, Guo Z, Tian J, Pei F, Liu L, Zhang L, Zou C, Hu T, Cai J, Yang H, Huang J, Jia X, Huang W, Cao B, Wang H. Epidemiology of Carbapenem-Resistant Enterobacteriaceae Infections: Report from the China CRE Network. Antimicrob Agents Chemother. 2018;62:e01882-17.
Erturk Sengel B, Altinkanat Gelmez G, Soyletir G, Korten V. In vitro synergistic activity of fosfomycin in combination with meropenem, amikacin and colistin against OXA-48 and/or NDM-producing Klebsiella pneumoniae. J Chemother. 2020;32:237-43.
Barber GR. Unique Antibacterial Agents. In: Bennet JE, Dolin R, Blaser MJ, edıtors. Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases, 9th ed. Canada, Elsevier. 2020.p.449–60.
Machuca I, Gutiérrez-Gutiérrez B, Gracia-Ahufinger I, Rivera Espinar F, Cano Á, Guzmán-Puche J, Pérez-Nadales E, Natera C, Rodríguez M, León R, Castón JJ, Rodríguez-López F, Rodríguez-Baño J, Torre-Cisneros J. Mortality Associated with Bacteremia Due to Colistin-Resistant Klebsiella pneumoniae with High-Level Meropenem Resistance: Importance of Combination Therapy without Colistin and Carbapenems. Antimicrob Agents Chemother. 2017;61:e00406-17.
Simkins J, Fan J, Camargo JF, Aragon L, Frederick C. Intravenous Fosfomycin Treatment for Carbapenem-Resistant Klebsiella pneumoniae in the United States. Ann Pharmacother. 2015;49:1177-8. Erratum in: Ann Pharmacother. 2015;49:1362.
Mills JP, Wilck MB, Weikert BC, Porrett PM, Timko D, Alby K, Bonomo RA, Blumberg EA. Successful treatment of a disseminated infection with extensively drug-resistant Klebsiella pneumoniae in a liver transplant recipient with a fosfomycin-based multidrug regimen. Transpl Infect Dis. 2016;18:777-81.
Tseng SP, Wang SF, Ma L, Wang TY, Yang TY, Siu LK, Chuang YC, Lee PS, Wang JT, Wu TL, Lin JC, Lu PL. The plasmid-mediated fosfomycin resistance determinants and synergy of fosfomycin and meropenem in carbapenem-resistant Klebsiella pneumoniae isolates in Taiwan. J Microbiol Immunol Infect. 2017;50:653-61.
Jiang Y, Shen P, Wei Z, Liu L, He F, Shi K, Wang Y, Wang H, Yu Y. Dissemination of a clone carrying a fosA3-harbouring plasmid mediates high fosfomycin resistance rate of KPC-producing Klebsiella pneumoniae in China. Int J Antimicrob Agents. 2015;45:66-70.
Zarakolu P, Eser ÖK, Otlu B, Gürpınar Ö, Özakın C, Akalın H, Köksal İ, Ünal S. In-vitro activity of fosfomycin against Escherichiacoli and Klebsiella pneumoniae bloodstream isolates and frequency of OXA-48, NDM, KPC, VIM, IMP types of carbapenemases in the carbapenem-resistant groups. J Chemother. 2022;34:235-40.
Demirci-Duarte S, Unalan-Altintop T, Gulay Z, Sari Kaygisiz AN, Cakar A, Gur D. In vitro susceptibility of OXA-48, NDM, VIM and IMP enzyme- producing Klebsiella spp. and Escherichia coli to fosfomycin. J Infect Dev Ctries. 2020;14:394-7.
Deldar Abad Paskeh M, Mehdipour Moghaddam MJ, Salehi Z. Prevalence of plasmid-encoded carbapenemases in multi-drug resistant Escherichia coli from patients with urinary tract infection in northern Iran. Iran J Basic Med Sci. 2020;23:586-93.
Gajdács M, Ábrók M, Lázár A, Jánvári L, Tóth Á, Terhes G, Burián K. Detection of VIM, NDM and OXA-48 producing carbapenem resistant Enterobacterales among clinical isolates in Southern Hungary. Acta Microbiol Immunol Hung. 2020;67:209-215.
Elshimy R, Zedan H, Elmorsy TH, Khattab RA. A Study on Multidrug-Resistant Escherichia coli Clinical Isolates from Different Hospitals in Greater Cairo. Microb Drug Resist. 2021;27:1420-32.
Kashefieh M, Hosainzadegan H, Baghbanijavid S, Ghotaslou R. The Molecular Epidemiology of Resistance to Antibiotics among Klebsiella pneumoniae Isolates in Azerbaijan, Iran. J Trop Med. 2021;2021:9195184.
Xiang DR, Li JJ, Sheng ZK, Yu HY, Deng M, Bi S, Hu FS, Chen W, Xue XW, Zhou ZB, Doi Y, Sheng JF, Li LJ. Complete Sequence of a Novel IncR-F33:A-:B- Plasmid, pKP1034, Harboring fosA3, blaKPC-2, blaCTX-M-65, blaSHV-12, and rmtB from an Epidemic Klebsiella pneumoniae Sequence Type 11 Strain in China. Antimicrob Agents Chemother. 2015;60:1343-8.
Ghanavati R, Ohadi E, Kazemian H, Yazdani F, Torki A, Kalani BS, Irajian G. Evaluation of Fosfomycin Activity Against Extended Spectrum Beta Lactamase (ESBL) Producing Enterobacteriaceae Isolated from Three Centers of Tehran, Iran. Recent Pat Antiinfect Drug Discov. 2018;13:180-6.
Wachino J, Yamane K, Suzuki S, Kimura K, Arakawa Y. Prevalence of fosfomycin resistance among CTX-M-producing Escherichia coli clinical isolates in Japan and identification of novel plasmid-mediated fosfomycin-modifying enzymes. Antimicrob Agents Chemother. 2010;54:3061-4.
Mueller L, Cimen C, Poirel L, Descombes MC, Nordmann P. Prevalence of fosfomycin resistance among ESBL-producing Escherichia coli isolates in the community, Switzerland. Eur J Clin Microbiol Infect Dis. 2019;38:945-9.
Loras C, Mendes AC, Peixe L, Novais Â, Alós JI. Escherichia coli resistant to fosfomycin from urinary tract infections: Detection of the fosA3 gene in Spain. J Glob Antimicrob Resist. 2020;21:414-6.
Yang TY, Lu PL, Tseng SP. Update on fosfomycin-modified genes in Enterobacteriaceae. J Microbiol Immunol Infect. 2019;52:9-21.
Nigiz Ş, Hazırolan G, Köseoglu Eser Ö, Gür D. First Detection of Klebsiella pneumoniae Isolate Co-Harboring Fosfomycin Resistance Gene fosA3 and blactx-m Among Gram Negative Urine Isolates in a Turkish Hospital. Microb Drug Resist. 2022;28:317-21.
Demirci-Duarte S, Unalan-Altintop T, Eser OK, Cakar A, Altun B, Sancak B, Gur D. Prevalence of O25b-ST131 clone and fosfomycin resistance in urinary Escherichia coli isolates and their relation to CTX-M determinant. Diagn Microbiol Infect Dis. 2020;98:115098.
