Tugba SARI, Şükran KÖSE, Hüseyin TURGUT, Müge ÖZGÜLER, Sinem AKKAYA IŞIK, Ayşe ÖZKAN ACAR

İntravenöz Fosfomisin Kombinasyonlarının Klinik Değeri

ÖZET Amaç Multi-Drug Resistance (MDR) ve Extensively Drug Resistant (XDR) patojenlerin artması ve yeni antibiyotiklerin geliştirilmesindeki zorluklar nedeniyle, bazı kombinasyonlar denenmektedir. Fosfomisin, fosfonik asit derive UDP-N-asetil glukozamin (MurA) inhibitörüdür. Fosfomisin bakteriyel hücre duvarı sentezini ilk aşamada inhibe eder. Gram negatif ve gram pozitif MDR ve XDR bakterilere etkilidir. Üriner sistem ve respiratuar sistem epiteline invazyonu engeller. Gereç ve yöntemler: Dört farklı merkezden intravenöz fosfomisin kullanılan toplam 77 hasta çalışmaya alındı. Bulgular: Hastaların 41’i (%53.2) kadın, 36’sı (%46.8) erkekti. Yaş ortalamaları 60.5 idi. Hastaların 46’sında (%59.7) tedaviden 72 saat sonra klinik yanıt alınmışken, tedavi sonunda 45 (%58.4) bulundu. Mikrobiyal eradikasyon oranı ilk 72 saatte 40 (%51.9) hastada ulaşılmışken, 39 (%50.6) hastada tedavi sonunda ulaşılmıştır. Tedaviden yetmiş iki saat sonraki ve tedavi sonu klinik yanıt oranları birbirleri ile benzer bulunmuştur. Sonuç: Sonuç olarak, MDR ve XDR patojenlerin tedavisinde düşük yan etki profili ve ilaç etkileşimi olmaması nedeniyle, kombinasyon tedavisinde bir alternatif olabilir.

Anahtar Kelimeler:

Fosfomisin, Çoklu İlaç Dirençli patojenler, Genişlemiş İlaç Dirençli patojenler, gram pozitif, gram negatif

Clinical Value Of Intravenous Fosfomycin Combinations

Aims:Due to the increasing number of Multi-Drug Resistance (MDR) and Extensively Drug Resistant (XDR) pathogens and the difficulties in developing new antibiotics, some combinations are being tried. Fosfomycin is a phosphonic acid derivative UDP-N-acetyl glucosamine (MurA) inhibitor. Fosfomycin inhibits bacteria cell wall synthesis in its first step. It acts against both gram-positive and gram-negative Multi-Drug Resistance (MDR) and Extensive Drug-Resistant (XDR) bacteria. It prevents bacterial invasion into the urinary system and respiratory tract epithelİum. It was aimed to evaluate the clinical and microbiological response rates of intravenous fosfomycin treatment in gram-negative MDR and XDR bacterial infections in this study. Methods: Total 77 patients from four different centers where used intravenous fosfomycin treatment were involved to the study. It was evaluated clinical and microbiological response in 72 hours after the beginning of treatment and at the end of treatment. Clinical and microbiological response have been evaluated in the study population. Results: While 41 of the patients were female (53.2%), 36 were male (46.8%), it is found that their mean age was 60.5. Clinical response rates 72 hours after the initiation of treatment and at the end of treatment were 46 (59.7%) and 45 (58.4%), respectively. Microbiological eradication rate was achieved in 40 (51.9%) patients in the first 72 hours and in 39 (50.6%) patients at the end of the treatment. Clinical response and microbiological eradication rates after seventy two hours and at the end of treatment were found to be similar with together. Conclusions: As a result, fosfomycin may be an alternative in combination therapy due to its low side effect profile and lack of drug interaction in the treatment of MDR and XDR pathogens.

Keywords:

Fosfomycin, Multi Drug Resistance pathogens, Extensively Drug Resistant pathogens, gram-positive, gram-negative.,

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1. Septimus EJ. Antimicrobial Resistance: An Antimicrobial/Diagnostic Stewardship and Infection Prevention Approach. Med Clin North Am. 2018;102(5):819-29.
2. Falagas ME, Vouloumanou EK, Samonis G, Vardakas KZ. Fosfomycin. Clin Microbiol Rev. 2016;29(2):321-47.
3. Silver LL. Fosfomycin: Mechanism and Resistance. Cold Spring Harb Perspect Med. 2017;7(2).
4. Reffert JL, Smith WJ. Fosfomycin for the treatment of resistant gram-negative bacterial infections. Insights from the Society of Infectious Diseases Pharmacists. Pharmacotherapy. 2014;34(8):845-57.
5. Grabein B, Graninger W, Rodríguez Baño J, Dinh A, Liesenfeld DB. Intravenous fosfomycin-back to the future. Systematic review and meta-analysis of the clinical literature. Clin Microbiol Infect Off Publ Eur Soc Clin Microbiol Infect Dis. 2017;23(6):363-72.
6. Putensen C, Ellger B, Sakka SG, Weyland A, Schmidt K, Zoller M, vd. Current clinical use of intravenous fosfomycin in ICU patients in two European countries. Infection. 2019;47(5):827-36.
7. Rodríguez-Avial C, Rodríguez-Avial I, Hernández E, Picazo JJ. (Increasing prevalence of fosfomycin resistance in extended-spectrum-beta-lactamase-producing Escherichia coli urinary isolates (2005-2009-2011)). Rev Espanola Quimioter Publicacion Of Soc Espanola Quimioter. 2013;26(1):43-6.
8. de Cueto M, López L, Hernández JR, Morillo C, Pascual A. In vitro activity of fosfomycin against extended-spectrum-beta-lactamase-producing Escherichia coli and Klebsiella pneumoniae: comparison of susceptibility testing procedures. Antimicrob Agents Chemother. 2006;50(1):368-70.
9. Jiang Y, Shen P, Wei Z, Liu L, He F, Shi K, et al. 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(1):66-70.
10. Castanheira M, Rhomberg PR, Flamm RK, Jones RN. Effect of the β-Lactamase Inhibitor Vaborbactam Combined with Meropenem against Serine Carbapenemase-Producing Enterobacteriaceae. Antimicrob Agents Chemother. 2016;60(9):5454-8.
11. Dinh A, Salomon J, Bru JP, Bernard L. Fosfomycin: efficacy against infections caused by multidrug-resistant bacteria. Scand J Infect Dis. 2012;44(3):182-9.
12. Singkham-In U, Chatsuwan T. In vitro activities of carbapenems in combination with amikacin, colistin, or fosfomycin against carbapenem-resistant Acinetobacter baumannii clinical isolates. Diagn Microbiol Infect Dis. 2018;91(2):169-74.
13. Papst L, Beović B, Pulcini C, Durante-Mangoni E, Rodríguez-Baño J, Kaye KS, et al. Antibiotic treatment of infections caused by carbapenem-resistant Gram-negative bacilli: an international ESCMID cross-sectional survey among infectious diseases specialists practicing in large hospitals. Clin Microbiol Infect Off Publ Eur Soc Clin Microbiol Infect Dis. 2018;24(10):1070-6.
14. Kaye KS, Rice LB, Dane AL, Stus V, Sagan O, Fedosiuk E, et al. Fosfomycin for Injection (ZTI-01) Versus Piperacillin-tazobactam for the Treatment of Complicated Urinary Tract Infection Including Acute Pyelonephritis: ZEUS, A Phase 2/3 Randomized Trial. Clin Infect Dis Off Publ Infect Dis Soc Am. 2019;69(12):2045-56.
15. Evren E, Azap ÖK, Çolakoğlu Ş, Arslan H. 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(3):335-8.
16. Berçot B, Poirel L, Dortet L, Nordmann P. In vitro evaluation of antibiotic synergy for NDM-1-producing Enterobacteriaceae. J Antimicrob Chemother. 2011;66(10):2295-7.
17. Wang J, He J-T, Bai Y, Wang R, Cai Y. Synergistic Activity of Colistin/Fosfomycin Combination against Carbapenemase-Producing Klebsiella pneumoniae in an In Vitro Pharmacokinetic/Pharmacodynamic Model. BioMed Res Int. 2018;2018:5720417.
18. Sirijatuphat R, Thamlikitkul V. Preliminary study of colistin versus colistin plus fosfomycin for treatment of carbapenem-resistant Acinetobacter baumannii infections. Antimicrob Agents Chemother. 2014;58(9):5598-601.
19. Grabein B, Graninger W, Rodríguez Baño J, Dinh A, Liesenfeld DB. Intravenous fosfomycin-back to the future. Systematic review and meta-analysis of the clinical literature. Clin Microbiol Infect Off Publ Eur Soc Clin Microbiol Infect Dis. 2017;23(6):363-72.
20. Jung SY, Lee SH, Lee SY, Yang S, Noh H, Chung EK, et al. Antimicrobials for the treatment of drug-resistant Acinetobacter baumannii pneumonia in critically ill patients: a systemic review and Bayesian network meta-analysis. Crit Care Lond Engl. 2017;21(1):319.
21. Liao Y, Hu G-H, Xu Y-F, Che J-P, Luo M, Zhang H-M, et al. Retrospective analysis of fosfomycin combinational therapy for sepsis caused by carbapenem-resistant Klebsiella pneumoniae. Exp Ther Med. 2017;13(3):1003-10.
22. del Río A, García-de-la-Mària C, Entenza JM, Gasch O, Armero Y, Soy D, et al. Fosfomycin plus β-Lactams as Synergistic Bactericidal Combinations for Experimental Endocarditis Due to Methicillin-Resistant and Glycopeptide-Intermediate Staphylococcus aureus. Antimicrob Agents Chemother. 2016;60(1):478-86.
23. Tang H-J, Chen C-C, Zhang C-C, Su B-A, Li C-M, Weng T-C, et al. In vitro efficacy of fosfomycin-based combinations against clinical vancomycin-resistant Enterococcus isolates. Diagn Microbiol Infect Dis. 2013;77(3):254-7.
24. Tang H-J, Chen C-C, Cheng K-C, Toh H-S, Su B-A, Chiang S-R, et al. In vitro efficacy of fosfomycin-containing regimens against methicillin-resistant Staphylococcus aureus in biofilms. J Antimicrob Chemother. 2012;67(4):944-50.
25. Shorr AF, Pogue JM, Mohr JF. Intravenous fosfomycin for the treatment of hospitalized patients with serious infections. Expert Rev Anti Infect Ther. 2017;15(10):935-45.