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The Impact of Fosfomycin on Gram Negative Infections: A Comprehensive Review

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Abstract

Multidrug-resistant or extended drug resistance has created havoc when it comes to patient treatment, as options are limited because of the spread of pathogens that are extensively or multidrug-resistant (MDR or XDR) and the absence of novel antibiotics that are effective against these pathogens. Physicians have therefore started using more established antibiotics such as polymyxins, tetracyclines, and aminoglycosides. Fosfomycin has just come to light as a result of the emergence of resistance to these medications since it continues to be effective against MDR and XDR bacteria that are both gram-positive and gram-negative. Fosfomycin, a bactericidal analogue of phosphoenolpyruvate that was formerly utilised as an oral medication for uncomplicated urinary tract infections, has recently attracted the interest of clinicians around the world. It may generally be a suitable therapy option for patients with highly resistant pathogenic infections, according to the advanced resistance shown by gram-negative bacteria. This review article aims to comprehensively evaluate the impact of fosfomycin on gram negative infections, highlighting its mechanism of action, pharmacokinetics, clinical efficacy, and resistance patterns.

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References:

  1. Hendlin D, Stapley EO, Jackson M, Wallick H, Miller AK, Wolf FJ, Miller TW, Chaiet L, Kahan FM, Foltz EL, Woodruff HB, Mata JM, Hernandez S, Mochales S (1969) Phosphonomycin, a new antibiotic produced by strains of streptomyces. Science 166:122–123. https://doi.org/10.1126/science.166.3901.122

    Article  CAS  PubMed  Google Scholar 

  2. Falagas ME, Giannopoulou KP, Kokolakis GN, Rafailidis PI (2008) Fosfomycin: use beyond urinary tract and gastrointestinal infections. Clin Infect Dis 46:1069–1077. https://doi.org/10.1086/527442

    Article  PubMed  Google Scholar 

  3. Paladin Labs (2007) Monurol package insert. Paladin Labs, Quebec

    Google Scholar 

  4. Popovic M, Steinort D, Pillai S, Joukhadar C (2010) Fosfomycin: an old, new friend? Eur J Clin Microbiol Infect Dis 29:127–142

    Article  CAS  PubMed  Google Scholar 

  5. Kahan FM, Kahan JS, Cassidy PJ, Kropp H (1974) The mechanism of action of Fosfomycin (Phosphonomycin). Ann NY Acad Sci 235:364–386

    Article  CAS  PubMed  Google Scholar 

  6. Brown ED, Vivas EI, Walsh CT, Kolter R (1995) MurA (MurZ), the enzyme that catalyzes the first committed step in peptidoglycan biosynthesis, is essential in Escherichia coli. J Bacteriol 177:4194–4197

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Utsui Y, Ohya S, Magaribuchi T, Tajima M, Yokota T (1986) Antibacterial activity of cefmetazole alone and in combination with fosfomycin against methicillin- and cephem-resistant Staphylococcus aureus. Antimicrob Agents Chemother 30:917–922

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Parker S, Lipman J, Koulenti D, Dimopoulos G, Roberts JA (2013) What is the relevance of fosfomycin pharmacokinetics in the treatment of serious infections in critically ill patients? A systematic review. Int J Antimicrob Agents 42:289–293. https://doi.org/10.1016/j.ijantimicag.2013.05.018

    Article  CAS  PubMed  Google Scholar 

  9. Dijkmans AC, Zacarías NVO, Burggraaf J, Mouton JW, Wilms EB, van Nieuwkoop C et al (2017) Fosfomycin: pharmacological, clinical and future perspectives. Antibiotics (Basel) 6:E24. https://doi.org/10.3390/antibiotics6040024

    Article  CAS  Google Scholar 

  10. Kirby WM (1977) Pharmacokinetics of fosfomycin. Chemotherapy 23:141–151

    Article  PubMed  Google Scholar 

  11. Samonis G, Vardakas KZ, Tansarli GS, Dimopoulou D, Papadimitriou G, Kofteridis DP et al (2016) Fosfomycin. Clin Microbiol Rev 29:321–347. https://doi.org/10.1128/CMR.00068-15

    Article  PubMed  PubMed Central  Google Scholar 

  12. Joukhadar C, Klein N, Dittrich P, Zeitlinger M, Geppert A, Skhirtladze K et al (2003) Target site penetration of fosfomycin in critically ill patients. J Antimicrob Chemother 51:1247–1252

    Article  CAS  PubMed  Google Scholar 

  13. Udy AA, Roberts JA, De Waele JJ, Paterson DL, Lipman J (2012) What’s behind the failure of emerging antibiotics in the critically ill? Understanding the impact of altered pharmacokinetics and augmented renal clearance. Int J Antimicrob Agents 39:455–457. https://doi.org/10.1016/j.ijantimicag.2012.02.010

    Article  CAS  PubMed  Google Scholar 

  14. Parker SL, Frantzeskaki F, Wallis SC, Diakaki C, Giamarellou H, Koulenti D et al (2015) Population pharmacokinetics of fosfomycin in critically ill patients. Antimicrob Agents Chemother 59:6471–6476. https://doi.org/10.1128/AAC.01321-15

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Michalopoulos AS, Livaditis IG, Gougoutas V (2011) The revival of fosfomycin. Int J Infect Dis 15:e732–e739. https://doi.org/10.1016/j.ijid.2011.07.007

    Article  CAS  PubMed  Google Scholar 

  16. Karaiskos I, Giamarellou H (2014) Multidrug-resistant and extensively drug-resistant gram-negative pathogens: current and emerging therapeutic approaches. Expert Opin Pharmacother 15:1351–1370. https://doi.org/10.1517/14656566.2014.914172

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. VanScoy BD, McCauley J, Ellis-Grosse EJ, Okusanya OO, Bhavnani SM, Forrest A et al (2015) Exploration of the pharmacokinetic-pharmacodynamic relationships for fosfomycin efficacy using an in vitro infection model. Antimicrob Agents Chemother 59:7170–7177. https://doi.org/10.1128/AAC.04955-14

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Grabein B, Graninger W, Rodríguez Baño J, Dinh A, Liesenfeld DB (2017) Intravenous fosfomycin-back to the future systematic review and meta-analysis of the clinical literature. Clin Microbiol Infect 23:363–372. https://doi.org/10.1016/j.cmi.2016.12.005

    Article  CAS  PubMed  Google Scholar 

  19. The European Committee on Antimicrobial Susceptibility Testing. Breakpoint tables for interpretation of MICs and zone diameters. Version 8.0, 2018. http://www.eucast.org.

  20. Walsh CC, McIntosh MP, Peleg AY, Kirkpatrick CM, Bergen PJ (2015) In vitro pharmacodynamics of fosfomycin against clinical isolates of Pseudomonas aeruginosa. J Antimicrob Chemother 70:3042–3050. https://doi.org/10.1093/jac/dkv221[PubMed][CrossRef][GoogleScholar]

    Article  CAS  PubMed  Google Scholar 

  21. Roussos N, Karageorgopoulos DE, Samonis G, Falagas ME (2009) Clinical significance of the pharmacokinetic and pharmacodynamic characteristics of fosfomycin for the treatment of patients with systemic infections. Int J Antimicrob Agents 34:506–515. https://doi.org/10.1016/j.ijantimicag.2009.08.013

    Article  CAS  PubMed  Google Scholar 

  22. Lepak AJ, Zhao M, VanScoy B, Taylor DS, Ellis-Grosse E, Ambrose PG et al (2017) In vivo pharmacokinetics and pharmacodynamics of ZTI-01 (Fosfomycin for Injection) in the neutropenic murine thigh infection model against Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa. Antimicrob Agents Chemother. https://doi.org/10.1128/AAC.00476-17

    Article  PubMed  PubMed Central  Google Scholar 

  23. Asuphon O, Montakantikul P, Houngsaitong J, Kiratisin P, Sonthisombat P (2016) Optimizing intravenous fosfomycin dosing in combination with carbapenems for treatment of Pseudomonas aeruginosa infections in critically ill patients based on pharmacokinetic/pharmacodynamic (PK/PD) simulation. Int J Infect Dis 50:23–29. https://doi.org/10.1016/j.ijid.2016.06.017

    Article  CAS  PubMed  Google Scholar 

  24. Spanish agency for medicines and health products. http://www.ern.es/wp-content/uploads/2013/01/FT-Fosfocina-IV-IM.pdf. Accessed 29 Jan 2019

  25. Coronado-Alvarez MN, Parra D, Parra-Ruiz J (2019) Clinical efficacy of fosfomycin combinations against a variety of gram-positive cocci. Enferm Infecc Microbiol Clin 37:4–10. https://doi.org/10.1016/j.eimc.2018.05.009[PubMed][CrossRef][GoogleScholar]

    Article  Google Scholar 

  26. Del Rio A, Gasch O, Moreno A et al (2014) Efficacy and safety of fosfomycin plus imipenem as rescue therapy for complicated bacteremia and endocarditis due to methicillin-resistant Staphylococcus aureus: a multicenter clinical trial. Clin Infect Dis 59:1105–1112. https://doi.org/10.1093/cid/ciu580[PubMed][CrossRef][GoogleScholar]

    Article  PubMed  Google Scholar 

  27. Cañamares-Orbis I, Silva JT, López-Medrano F, Aguado JM (2015) Is high-dose intravenous fosfomycin safe for the treatment of patients prone to heart failure? Enferm Infecc Microbiol Clin 33:294. https://doi.org/10.1016/j.eimc.2014.07.005[PubMed][CrossRef][GoogleScholar]

    Article  PubMed  Google Scholar 

  28. Candel FJ, Matesanz M, Martín-Sánchez FJ, González Del Castillo JM (2016) Monitoring of high-dose fosfomycin guided by NT-proBNP. Int J Cardiol 209:131–132. https://doi.org/10.1016/j.ijcard.2016.02.037[PubMed][CrossRef][GoogleScholar]

    Article  PubMed  Google Scholar 

  29. Falagas ME, Vouloumanou EK, Samonis G, Vardakas KZ (2016) Fosfomycin. Clin Microbiol Rev 29:321–347. https://doi.org/10.1128/CMR.00068-15

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Goto M, Sugiyama M, Nakajima S, Yamashina H (1981) Fosfomycin kinetics after intravenous and oral administration to human volunteers. Antimicrob Agents Chemother 20:393–397

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Kastoris AC, Rafailidis PI, Vouloumanou EK, GkegkesMatthew ID, Falagas E (2010) Synergy of fosfomycin with other antibiotics for gram positive and gram-negative bacteria. Eur J Clin Pharmacol 66:359–368. https://doi.org/10.1007/s00228-010-0794-5

    Article  CAS  PubMed  Google Scholar 

  32. Samonis G, Maraki S, Karageorgopoulos DE, Vouloumanou EK, Falagas ME (2012) Synergy of fosfomycin with carbapenems, colistin, netilmicin, and tigecycline against multidrug-resistant Klebsiella pneumoniae, Escherichia coli, and Pseudomonas aeruginosa clinical isolates. Eur J Clin Microbiol Infect Dis 31:695–701. https://doi.org/10.1007/s10096-011-1360-5

    Article  CAS  PubMed  Google Scholar 

  33. Grossato A, Sartori R, Fontana R (1991) Effect of non-b-lactam antibiotics on penicillin-binding protein synthesis of enterococcus hirae ATCC 9790. J Antimicrob Chemother 27:263–271

    Article  CAS  PubMed  Google Scholar 

  34. Totsuka K, Uchiyama T, Shimizu K, Kanno Y, Takata T, Yoshida T (1997) In vitro combined effects of fosfomycin and b-lactam antibiotics against penicillin-resistant Streptococcus pneumoniae. J Infect Chemother 3:49–54. https://doi.org/10.1007/BF02489184

    Article  CAS  Google Scholar 

  35. Yamada S, Hyo Y, Ohmori S, Ohuchi M (2007) Role of ciprofloxacin in its synergistic effect with fosfomycin on drug-resistant strains of Pseudomonas aeruginosa. Chemotherapy 53:202–209. https://doi.org/10.1159/000098419

    Article  CAS  PubMed  Google Scholar 

  36. Okazaki M, Suzuki K, Asano N et al (2002) Effectiveness of fosfomycin combined with other antimicrobial agents against multidrug-resistant Pseudomonas aeruginosa isolates using the efficacy time index assay. J Infect Chemother 8:37–42. https://doi.org/10.1007/s101560200004

    Article  CAS  PubMed  Google Scholar 

  37. Tessier F, Quentin C (1997) In vitro activity of fosfomycin combined with ceftazidime, imipenem, amikacin, and ciprofloxacin against Pseudomonas aeruginosa. Eur J Clin Microbiol Infect Dis 16:159–162

    Article  CAS  PubMed  Google Scholar 

  38. Martinez-Martinez L, Rodriguez G, Pascual A, Suárez AI, Perea EJ (1996) In vitro activity of antimicrobial agent combinations against multiresistant Acinetobacter baumannii. J Antimicrob Chemother 38:1107–1108. https://doi.org/10.1093/jac/38.6.1107

    Article  CAS  PubMed  Google Scholar 

  39. Santimaleeworagun W, Wongpoowarak P, Chayakul P, Pattharachayakul S, Tansakul P, Garey KW (2011) In vitro activity of colistin or sulbactam in combination with fosfomycin or imipenem against clinical isolates of carbapenem-resistant Acinetobacter baumannii producing OXA-23 carbapenemases. Southeast Asian J Trop Med Public Health 42:890–900

    CAS  PubMed  Google Scholar 

  40. Inouye S, Watanabe T, Tsuruoka T, Kitasato I (1989) An increase in the antimicrobial activity in vitro of fosfomycin under anaerobic conditions. J Antimicrob Chemother 24:657–666. https://doi.org/10.1093/jac/24.5.657

    Article  CAS  PubMed  Google Scholar 

  41. Yanagida C, Ito K, Komiya I, Horie T (2004) Protective effect of fosfomycin on gentamicin-induced lipid peroxidation of rat renal tissue. Chem Biol Interact 148:139–147. https://doi.org/10.1016/j.cbi.2004.05.005

    Article  CAS  PubMed  Google Scholar 

  42. Nakamura T, Kokuryo T, Hashimoto Y, Inui KI (1999) Effects of fosfomycin and imipenem-cilastatin on the nephrotoxicity of vancomycin and cisplatin in rats. J Pharm Pharmacol 51:227–232

    Article  CAS  PubMed  Google Scholar 

  43. Infectopharm Arzneimittel und Consilium GmbH (2015) Fomicyt Package Insert. Infectopharm, Heppenheim

    Google Scholar 

  44. Florent A, Chichmanian RM, Cua E, Pulcini C (2011) Adverse events associated with intravenous fosfomycin. Int J Antimicrob Agents 37:82–83. https://doi.org/10.1016/j.ijantimicag.2010.09.002

    Article  CAS  PubMed  Google Scholar 

  45. Castaneda-Garcia A, Blazquez J, Rodriguez-Rojas A (2013) Molecular mechanisms and clinical impact of acquired and intrinsic fosfomycin resistance. Antibiotics 2:217–236

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Tsuruoka T, Yamada Y (1975) Charactertization of spontaneous fosfomycin (phosphonomycin)-resistant cells of Escherichia coli B in vitro. J Antibiot 28:906–911

    Article  CAS  Google Scholar 

  47. Kadner RJ, Winkler HH (1973) Isolation and characterization of mutations affecting the transport of hexose phosphates in Escherichia coli. J Bacteriol 113:895–900

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Kim DH, Lees WJ, Kempsell KE, Lane WS, Duncan K, Walsh CT (1996) Characterization of a Cys115 to Asp substitution in the Escherichia coli cell wall biosynthetic enzyme UDP-GlcNAc enolpyruvyl transferase (MurA) that confers resistance to inactivation by the antibiotic fosfomycin. Biochemistry 35:4923–4928

    Article  CAS  PubMed  Google Scholar 

  49. Horii T, Kimura T, Sato K, Shibayama K, Ohta M (1999) Emergence of fosfomycin-resistant isolates of Shiga-like toxin-producing Escherichia coli O26. Antimicrob. Agents Chemother 43:789–793

    Article  CAS  Google Scholar 

  50. Rigsby RE, Fillgrove KL, Beihoffer LA, Armstrong RN (2005) Fosfomycin resistance proteins: a nexus of glutathione transferases and epoxide hydrolases in a metalloenzyme superfamily. Methods Enzymol 401:367–379

    Article  CAS  PubMed  Google Scholar 

  51. Kobayashi S, Kuzuyama T, Seto H (2000) Characterization of the fomA and fomB gene products from Streptomyces wedmorensis, which confer fosfomycin resistance on Escherichia coli. Antimicrob Agents Chemother 44:647–650

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Kuzuyama T, Kobayashi S, O’Hara K, Hidaka T, Seto H (1996) Fosfomycin monophosphate and fosfomycin diphosphate, two inactivated fosfomycin derivatives formed by gene products of fomA and fomB from a fosfomycin producing organism Streptomyces wedmorensis. J Antibiot 49:502–504

    Article  CAS  Google Scholar 

  53. Bernat BA, Laughlin LT, Armstrong RN (1997) Fosfomycin resistance protein (FosA) is a manganese metalloglutathione transferase related to glyoxalase I and the extradiol dioxygenases. Biochemistry 36:3050–3055

    Article  CAS  PubMed  Google Scholar 

  54. Bernat BA, Laughlin LT, Armstrong RN (1999) Elucidation of a monovalent cation dependence and characterization of the divalent cation binding site of the fosfomycin resistance protein (FosA). Biochemistry 38:7462–7469

    Article  CAS  PubMed  Google Scholar 

  55. Beharry Z, Palzkill T (2005) Functional analysis of active site residues of the fosfomycin resistance enzyme FosA from Pseudomonas aeruginosa. J Biol Chem 280:17786–17791

    Article  CAS  PubMed  Google Scholar 

  56. Arca P, Reguerra G, Hardisson C (1997) Plasmid-encoded fosfomycin resistance in bacteria isolated from the urinary tract in a multicentre survey. J Antimicrob Chemother 40:393–399

    Article  CAS  PubMed  Google Scholar 

  57. Wright GD (2005) Bacterial resistance to antibiotics: enzymatic degradation and modification. Adv Drug Deliv Rev 57:1451–1470

    Article  CAS  PubMed  Google Scholar 

  58. Lu W, Zhou S, Ma X, Xu N, Liu D, Zhang K, Zheng Y, Wu S (2023) fosA11, a novel chromosomal-encoded fosfomycin resistance gene identified in Providencia rettgeri. Microbiol Spectr. https://doi.org/10.1128/spectrum.02542-23

    Article  PubMed  PubMed Central  Google Scholar 

  59. Etienne J, Gerbaud G, Fleurette J, Courvalin P (1991) Characterization of staphylococcal plasmids hybridizing with the fosfomycin resistance gene fos B. FEMS Microbiol Lett 84:119–122

    Article  CAS  Google Scholar 

  60. Cao M, Bernat BA, Wang Z, Armstrong RN, Helmann JD (2001) FosB, a cysteinedependent fosfomycin resistance protein under the control of σW, an extracytoplasmic-function σ factor in Bacillus subtilis. J Bacteriol 183:2380–2383

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Garcia P, Arca P, Suarez JE (1995) Product of fosC, a gene from Pseudomonas syringae, mediates fosfomycin resistance by using ATP as cosubstrate. Antimicrob Agents Chemother 39:1569–1573

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Shimizu M, Shigenobu F, Miyakozawa I et al (2000) Novel fosfomycin resistance of Pseudomonas aeruginosa clinical isolates recovered in Japan in 1996. Antimicrob Agents Chemother 44:2007–2008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Fillgrove KL, Pakhoma S, Newcomer ME, Armstrong RN (2003) Mechanistic diversity of fosfomycin resistance in pathogenic microorganisms. J Am Chem Soc 125:15730–15731

    Article  CAS  PubMed  Google Scholar 

  64. Fillgrove KL, Pakhoma S, Schaab MR, Newcomer ME, Armstrong RN (2007) Structure and mechanism of the genomically encoded fosfomycin resistance protein, FosX, from Listeria monocytogenes. Biochemistry 46:8110–8120

    Article  CAS  PubMed  Google Scholar 

  65. Chen Y, Ji S, Sun L, Wang H, Zhu F, Chen M, Zhuang H, Wang Z, Jiang S, Yu Y, Chen Y (2022) The novel fosfomycin resistance gene fosY is present on a genomic island in CC1 methicillin-resistant Staphylococcus aureus. Emerging Microbes Infect 11:1166–1173. https://doi.org/10.1080/22221751.2022.2058421

    Article  CAS  Google Scholar 

  66. Barry AL, Brown SD (1995) Antibacterial spectrum of fosfomycin trometamol. J Antimicrob Chemother 35:228–230. https://doi.org/10.1093/jac/35.1.228

    Article  CAS  PubMed  Google Scholar 

  67. Patel SS, Balfour JA, Bryson HM (1997) Fosfomycin tromethamine. A review of its antibacterial activity, pharmacokinetic properties and therapeutic effificacy as a single-dose oral treatment for acute uncomplicated lower urinary tract infections. Drugs 53:637–656

    Article  CAS  PubMed  Google Scholar 

  68. Fukuyama M, Furuhata K, Oonaka K, Hara T, Sunakawa K (2000) Antibacterial activity of fosfomycin against the causative bacteria isolated from bacterial enteritis. Jpn J Antibiot 53:522–531

    CAS  PubMed  Google Scholar 

  69. Samonis G, Maraki S, Rafailidis PI, Kapaskelis A, Kastoris AC, Falagas ME (2010) Antimicrobial susceptibility of gram-negative nonurinary bacteria to fosfomycin and other antimicrobials. Future Microbiol 5:961–970. https://doi.org/10.2217/fmb.10.47

    Article  CAS  PubMed  Google Scholar 

  70. Barahona-Garrido J, Quinonez NF, Cerda-Contreras E, Maria Sarti H, Tellez-Avila FI (2013) Fosfomycin-containing second-line treatment for Helicobacter pylori infection. Am J Gastroenterol 108:858–859. https://doi.org/10.1038/ajg.2013.48

    Article  CAS  PubMed  Google Scholar 

  71. Hirzel C, Guilarte YN, Hirzberger L, Furrer H, Marschall J, Endimiani A (2015) In vitro susceptibility of Aerococcus urinae isolates to antibiotics used for uncomplicated urinary tract infection. J Infect 71:395–397. https://doi.org/10.1016/j.jinf.2015.04.020

    Article  PubMed  Google Scholar 

  72. Hauser C, Hirzberger L, Unemo M, Furrer H, Endimiani A (2015) In vitro activity of fosfomycin alone and in combination with ceftriaxone or azithromycin against clinical Neisseria gonorrhoeae isolates. Antimicrob Agents Chemother 59:1605–1611. https://doi.org/10.1128/AAC.04536-14

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Lepe JA, Torres MJ, Smani Y, Parra-Millan R, Pachon J, VazquezBarba I, Aznar J (2014) In vitro and intracellular activities of fosfomycin against clinical strains of Listeria monocytogenes. Int J Antimicrob Agents 43:135–139. https://doi.org/10.1016/j.ijantimicag.2013.10.018

    Article  CAS  PubMed  Google Scholar 

  74. Altes Gutierrez A, Rodriguez NA (1977) In vitro sensitivity of anaerobic bacteria to fosfomycin. Chemotherapy 23:S51–S57

    Article  Google Scholar 

  75. Piriz S, Cuenca R, Valle J, Vadillo S (1992) Susceptibilities of anaerobic bacteria isolated from animals with ovine foot rot to 28 antimicrobial agents. Antimicrob Agents Chemother 36:198–201. https://doi.org/10.1128/AAC.36.1.198

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. De Smet KA, Kempsell KE, Gallagher A, Duncan K, Young DB (1999) Alteration of a single amino acid residue reverses fosfomycin resistance of recombinant MurA from Mycobacterium tuberculosis. Microbiology 145:3177–3184. https://doi.org/10.1099/00221287-145-11-3177

    Article  PubMed  Google Scholar 

  77. Stock I, Wiedemann B (1998) Identifification and natural antibiotic susceptibility of Morganella morganii. Diagn Microbiol Infect Dis 30:153–165. https://doi.org/10.1016/S0732-8893(97)00243-5

    Article  CAS  PubMed  Google Scholar 

  78. Vardakas KZ, Legakis NJ, Triarides N, Falagas ME (2016) Susceptibility of contemporary isolates to fosfomycin: a systematic review of the literature. Int J Antimicrob Agents 47:269–285. https://doi.org/10.1016/j.ijantimicag.2016.02.001

    Article  CAS  PubMed  Google Scholar 

  79. Sastry S, Clarke LG, Alrowais H, Querry AM, Shutt KA, Doi Y (2015) Clinical appraisal of fosfomycin in the era of antimicrobial resistance. Antimicrob Agents Chemother 59:7355–7361. https://doi.org/10.1128/AAC.01071-15

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Rodríguez-Avial C, Rodríguez-Avial I, Hernández E, Picazo JJ (2013) Increasing prevalence of fosfomycin resistance in extended-spectrum-beta-lactamase-producing Escherichia coli urinary isolates (2005–2009-2011). Rev Esp Quimioter 26:43–46 (PMID: 23546462)

    PubMed  Google Scholar 

  81. Shaikh S, Fatima J, Shakil S, Rizvi SMD, Kamal MA (2015) Antibiotic resistance and extended spectrum beta-lactamases: types, epidemiology and treatment. Saudi J Biol Sci 22:90–101. https://doi.org/10.1016/j.sjbs.2014.08.002

    Article  CAS  PubMed  Google Scholar 

  82. De Cueto M, López L, Hernández JR, Morillo C, Pascual A (2006) In vitro activity of fosfomycin against extended-spectrum-beta-lactamase-producing Escherichia coli and Klebsiella pneumoniae: comparison of susceptibility testing procedures. Antimicrob Agents Chemother 50:368–370. https://doi.org/10.1128/AAC.50.1.368-370.2006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Jiang Y, Shen P, Wei Z, Liu L, He F, Shi K et al (2015) 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 45:66–70. https://doi.org/10.1016/j.ijantimicag.2014.08.010

    Article  CAS  PubMed  Google Scholar 

  84. Castanheira M, Griffin MA, Deshpande LM, Mendes RE, Jones RN, Flamm RK (2016) Detection of mcr-1 among Escherichia coli clinical isolates collected worldwide as part of the SENTRY antimicrobial surveillance program in 2014 and 2015. Antimicrob Agents Chemother 60:5623–5624. https://doi.org/10.1128/AAC.01267-16.PMID:27401568;PMCID:PMC4997847

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Rodríguez-Baño J, Cisneros JM, Cobos-Trigueros N, Fresco G, Navarro-San Francisco C, Gudiol C et al (2015) Executive summary of the diagnosis and antimicrobial treatment of invasive infections due to multidrug-resistant Enterobacteriaceae. Guidelines of the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC). Enferm Infecc Microbiol Clin 33:338–341. https://doi.org/10.1016/j.eimc.2014.11.015

    Article  PubMed  Google Scholar 

  86. Shaikh S, Fatima J, Shakil S, Danish Rizvi SM, Kamal MA (2015) Prevalence of multidrug resistant and extended spectrum beta-lactamase producing Pseudomonas aeruginosa in a tertiary care hospital. Saudi J Biol Sci 22:62–64. https://doi.org/10.1016/j.sjbs.2014.06.001

    Article  CAS  PubMed  Google Scholar 

  87. Bassetti M, Vena A, Croxatto A, Righi E, Guery B (2018) How to manage Pseudomonas aeruginosa infections. Drugs in Context 7:212527. https://doi.org/10.7573/dic.212527.PMID:29872449;PMCID:PMC5978525

    Article  PubMed  PubMed Central  Google Scholar 

  88. Vidal E, Cervera C, Cordero E, Armiñanzas C, Carratalá J, Cisneros JM et al (2015) Management of urinary tract infection in solid organ transplant recipients: consensus statement of the Group for the Study of Infection in Transplant Recipients (GESITRA) of the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC) and the Spanish Network for Research in Infectious Diseases (REIPI). Enferm Infecc Microbiol Clin 33:679.e1-679.e21. https://doi.org/10.1016/j.eimc.2015.03.024. (PMID: 25976754)

    Article  PubMed  Google Scholar 

  89. De Cueto M, Aliaga L, Alós J-I, Canut A, Los-Arcos I, Martínez JA et al (2017) Executive summary of the diagnosis and treatment of urinary tract infection: guidelines of the Spanish Society of Clinical Microbiology and Infectious Diseases (SEIMC). Enferm Infecc Microbiol Clin 35:314–320. https://doi.org/10.1016/j.eimc.2016.11.005. (PMID: 28017477)

    Article  PubMed  Google Scholar 

  90. Neuner EA, Sekeres J, Hall GS, van Duin D (2012) Experience with fosfomycin for treatment of urinary tract infections due to multidrug-resistant organisms. Antimicrob Agents Chemother 56:5744–5748. https://doi.org/10.1128/AAC.00402-12.PMID:22926565;PMCID:PMC3486602

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Giancola SE, Mahoney MV, Hogan MD, Raux BR, McCoy C, Hirsch EB (2017) Assessment of fosfomycin for complicated or multidrug-resistant urinary tract infections: patient characteristics and outcomes. Chemotherapy 62:100–104. https://doi.org/10.1159/000449422

    Article  CAS  PubMed  Google Scholar 

  92. Rizvi M, Malhotra S, Agarwal J, Siddiqui AH, Poojary A, Thakuria B, Darling I, Sami H, Gupta A, Jitendranath A, Mohan B, Banashankari GS, Khan F, Kalita B, Jain M, Singh N, Gur R, Mohapatra S, Farooq S, … Livermore DM (nd). Antimicrobial susceptibility profile of community-acquired uropathogenic Escherichia coli across India: a multicentric study promoting diagnostic stewardship in the management of UTI. https://ssrn.com/abstract=4598960.

  93. Rosso-Fernández C, Sojo-Dorado J, Barriga A et al (2015) Fosfomycin versus meropenem in bacteraemic urinary tract infections caused by extended-spectrum β-lactamase-producing Escherichia coli (FOREST): study protocol for an investigator-driven randomised controlled trial. BMJ Open 5:e007363. https://doi.org/10.1136/bmjopen-2014-007363

    Article  PubMed  PubMed Central  Google Scholar 

  94. Matzi V, Lindenmann J, Porubsky C, Kugler SA, Maier A, Dittrich P et al (2010) Extracellular concentrations of fosfomycin in lung tissue of septic patients. J Antimicrob Chemother 65:995–998. https://doi.org/10.1093/jac/dkq070

    Article  CAS  PubMed  Google Scholar 

  95. Pontikis K, Karaiskos I, Bastani S, Dimopoulos G, Kalogirou M, Katsiari M et al (2014) Outcomes of critically ill intensive care unit patients treated with fosfomycin for infections due to pandrug-resistant and extensively drug-resistant carbapenemase-producing Gram-negative bacteria. Int J Antimicrob Agents 43:52–59. https://doi.org/10.1016/j.ijantimicag.2013.09.010

    Article  CAS  PubMed  Google Scholar 

  96. Mirakhur A, Gallagher MJ, Ledson MJ, Hart CA, Walshaw MJ (2003) Fosfomycin therapy for multiresistant Pseudomonas aeruginosa in cystic fibrosis. J Cyst Fibros 2:19–24. https://doi.org/10.1016/S1569-1993(02)00143-1

    Article  CAS  PubMed  Google Scholar 

  97. Wilke M, Grube R (2013) Update on management options in the treatment of nosocomial and ventilator assisted pneumonia: review of actual guidelines and economic aspects of therapy. Infect Drug Resist 7:1–7. https://doi.org/10.2147/IDR.S25985

    Article  PubMed  PubMed Central  Google Scholar 

  98. Murillo O, Grau I, Lora-Tamayo J, Gomez-Junyent J, Ribera A, Tubau F et al (2015) The changing epidemiology of bacteraemic osteoarticular infections in the early 21st century. Clin Microbiol Infect 21:254.e1–8. https://doi.org/10.1016/j.cmi.2014.09.007.

    Article  CAS  PubMed  Google Scholar 

  99. Sirot J, Lopitaux R, Dumont C, Rampon S, Cluzel R (1983) Diffusion of fosfomycin into bone tissue in man. Pathol Biol (Paris) 31:522–524

    CAS  PubMed  Google Scholar 

  100. Meissner A, Haag R, Rahmanzadeh R (1989) Adjuvant fosfomycin medication in chronic osteomyelitis. Infection 17:146–151

    Article  CAS  PubMed  Google Scholar 

  101. Corvec S, Furustrand Tafin U, Betrisey B, Borens O, Trampuz A (2013) Activities of fosfomycin, tigecycline, colistin, and gentamicin against extended-spectrum-β-lactamase-producing Escherichia coli in a foreign-body infection model. Antimicrob Agents Chemother 57:1421–1427. https://doi.org/10.1128/AAC.01718-12

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Liu C, Bayer A, Cosgrove SE, Daum RS, Fridkin SK, Gorwitz RJ et al (2011) Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children. Clin Infect Dis 52:e18e5. https://doi.org/10.1093/cid/ciq146

    Article  Google Scholar 

  103. Habib G, Lancelotti P, Antunes MJ (2015) ESC guidelines for the management of infective endocarditis: the task force for the management of infective endocarditis of the European Society of Cardiology (ESC): endorsed by European Association for Cardio-thoracic Surgery (EACTS), the European Association of Nuclear Medicine (EANM). Eur Heart J 36:3075–3128. https://doi.org/10.1093/eurheartj/ehv319[PubMed][CrossRef][GoogleScholar]

    Article  PubMed  Google Scholar 

  104. Gasch O, Camoez M, Domínguez MA, Padilla B, Pintado V, Almirante B et al (2014) Emergence of resistance to daptomycin in a cohort of patients with methicillin-resistant Staphylococcus aureus persistent bacteraemia treated with daptomycin. J Antimicrob Chemother 69:568–571. https://doi.org/10.1093/jac/dkt396.[PubMed][CrossRef][GoogleScholar]

    Article  CAS  PubMed  Google Scholar 

  105. Farina C et al (2011) In vitro Activity Effects of Twelve Antibiotics Alone and in Association against Twenty-Seven Enterococcus faecalis Strains Isolated from Italian Patients with infective endocarditis: high in vitro synergistic effect of the association ceftriaxone-fosfomycin. Chemotherapy 57:426–433. https://doi.org/10.1159/000330458.[PubMed][CrossRef][GoogleScholar]

    Article  CAS  PubMed  Google Scholar 

  106. Benachinmardi KK, Ravikumar R, Indiradevi B (2017) Role of biofilm in cerebrospinal fluid shunt infections: a study at tertiary neurocare center from South India. J Neurosci Rural Pract 8:335–341. https://doi.org/10.4103/jnrp.jnrp_22_17.PMID:;PMCID:[PMCfreearticle][PubMed][CrossRef][GoogleScholar]

    Article  PubMed  PubMed Central  Google Scholar 

  107. Pfausler B, Spiss H, Dittrich P, Zeitlinger M, Schmutzhard E, Joukhadar C (2004) Concentrations of fosfomycin in the cerebrospinal fluid of neurointensive care patients with ventriculostomy-associated ventriculitis. J Antimicrob Chemother 53:848–852. https://doi.org/10.1093/jac/dkh158

    Article  CAS  PubMed  Google Scholar 

  108. Tseng Y-C, Kan L-P, Huang L-Y, Yin T, Yang Y-S, Lin J-C et al (2014) Successful treatment of a patient with ventriculoperitoneal shunt-associated meningitis caused by extended-spectrum β-lactamase-producing Klebsiella pneumoniae. Tohoku J Exp Med 233:301–305

    Article  PubMed  Google Scholar 

  109. Tajiri H, Nishi J, Ushijima K, Shimizu T, Ishige T, Shimizu M et al (2015) A role for fosfomycin treatment in children for prevention of haemolytic-uraemic syndrome accompanying Shiga toxin-producing Escherichia coli infection. Int J Antimicrob Agents 46:586–589. https://doi.org/10.1016/j.ijantimicag.2015.08.006.

    Article  CAS  PubMed  Google Scholar 

  110. Tobudic S, Matzneller P, Stoiser B, Wenisch JM, Zeitlinger M, Vychytil A et al (2012) Pharmacokinetics of intraperitoneal and intravenous fosfomycin in automated peritoneal dialysis patients without peritonitis. Antimicrob Agents Chemother 56:3992–3995. https://doi.org/10.1128/AAC.00126-12.PMID:22564843;PMCID:PMC3393440

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Gallardo A, Sáez JM, Enriquez G, Cobacho AR, Torronteras R, Recordan C et al (1977) Surgical suppurating infections and surgical abdominal infections treated with fosfomycin. Chemotherapy 23:392–398. https://doi.org/10.1159/000222080

    Article  PubMed  Google Scholar 

  112. Papst L, Beović B, Pulcini C, Durante-Mangoni E, RodríguezBaño J, Kaye KS et al (2018) ESGAP, ESGBIS, ESGIE and the CRGNB treatment survey study group. 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 24:1070–1076. https://doi.org/10.1016/j.cmi.2018.01.015

    Article  CAS  PubMed  Google Scholar 

  113. Gutiérrez-Gutiérrez B, Salamanca E, de Cueto M, Hsueh PR, Viale P, Paño-Pardo JR et al (2017) REIPI/ESGBIS/INCREMENT Investigators Effect of appropriate combination therapy on mortality of patients with bloodstream infections due to carbapenemase-producing. Enterobacteriaceae (INCREMENT): a retrospective cohort study. Lancet Infect Dis 17:726–734. https://doi.org/10.1016/S1473-3099(17)30228-1

    Article  PubMed  Google Scholar 

  114. Apisarnthanarak A, Mundy LM (2012) Carbapenem-resistant Pseudomonas aeruginosa pneumonia with intermediate minimum inhibitory concentrations to doripenem: combination therapy with high-dose, 4-h infusion of doripenem plus fosfomycin versus intravenous colistin plus fosfomycin. Int J Antimicrob Agents 39:271–272. https://doi.org/10.1016/j.ijantimicag.2011.11.012

    Article  CAS  PubMed  Google Scholar 

  115. Bassetti M, Peghin M, Pecori D (2016) The management of multidrug-resistant Enterobacteriaceae. Curr Opin Infect Dis 29:583–594. https://doi.org/10.1097/QCO.0000000000000314

    Article  CAS  PubMed  Google Scholar 

  116. Silva JT, Fernández-Ruiz M, Aguado JM (2018) Multidrug-resistant Gram negative infection in solid organ transplant recipients: implications for outcome and treatment. Curr Opin Infect Dis 31:499–505. https://doi.org/10.1097/QCO.0000000000000488

    Article  PubMed  Google Scholar 

  117. Kaye KS, Rice LB, Dane A, Stu V, Sagan O, Fedosiuk E et al (2019) Fosfomycin for injection (ZTI-01) vs Piperacillin-Tazobactam (PIP-TAZ) for the treatment of complicated urinary tract infection (cUTI) including acute pyelonephritis (AP): ZEUS, a phase 2/3 randomized trial. Clin Infect Dis. https://doi.org/10.1093/cid/ciz181/5370034

    Article  PubMed  PubMed Central  Google Scholar 

  118. Zurfluh K, Treier A, Schmitt K, Stephan R. (2020) Mobile fosfomycin resistance genes in Enterobacteriaceae—an increasing threat. MicrobiologyOpen. 9(12):e1135. https://doi.org/10.1002/mbo3.1135

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Navas J, Leon J, Arroyo M, Garcia Lobo JM (1990) Nucleotide sequence and intracellular location of the product of the fosfomycin resistance gene from transposon Tn2921. Antimicrob Agents Chemother 34(10):2016–2018. https://doi.org/10.1128/AAC.34.10.2016

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Wachino JI, Yamane K, Suzuki S, Kimura K, Arakawa Y (2010) 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 54(7):3061–3064. https://doi.org/10.1128/AAC.01834-09

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Nakamura, G., Wachino, J. I., Sato, N., Kimura, K., Yamada, K., Jin, W., Shibayama, K., Yagi, T., Kawamura, K., & Arakawa, Y. (2014). Practical agar-based disk potentiation test for detection of fosfomycin-nonsusceptible Escherichia coli clinical isolates producing glutathione S-transferases. J Clin Microbiol 52(9):3175–3179. https://doi.org/10.1128/JCM.01094-14

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Ma Y, Xu X, Guo Q, Wang P, Wang W, Wang M (2015) Characterization of fosA5, a new plasmidmediated fosfomycin resistance gene in Escherichia coli. Lett Appl Microbiol 60(3):259–264. https://doi.org/10.1111/lam.12366

    Article  CAS  PubMed  Google Scholar 

  123. Guo Q, Tomich AD, McElheny CL, Cooper VS, Stoesser N, Wang M, Sluis-Cremer N, Doi Y (2016) Glutathione-S-transferase FosA6 of Klebsiella pneumoniae origin conferring fosfomycin resistance in ESBL-producing Escherichia coli. J Antimicrob Chemother 71:2460–2464

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Poirel L, Vuillemin X, Kieffer N, Mueller L, Descombes MC, Nordmann P (2019) Identification of FosA8, a plasmid-encoded fosfomycin resistance determinant from Escherichia coli, and its origin in Leclercia adecarboxylata. Antimicrob Agents Chemother 63(11):e01403-19. https://doi.org/10.1128/AAC.01403-19

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. ten Doesschate T, Abbott IJ, Willems RJL, Top J, Rogers MRC, Bonten MM, Paganelli FL (2019) In vivo acquisition of fosfomycin resistance in Escherichia coli by fosA transmission from commensal flora. J Antimicrob Chemother 74(12):3630–3632. https://doi.org/10.1093/jac/dkz380

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Huang Y, Lin Q, Zhou Q, Lv L, Wan M, Gao X, Wang C, Liu J-H (2020) Identification of fosA10, a novel plasmid-mediated fosfomycin resistance gene of Klebsiella pneumoniae origin, in Escherichia coli. Infect Drug Resist 13:1273–1279. https://doi.org/10.2147/IDR.S251360

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Lu W, Zhou S, Ma X, Xu N, Liu D, Zhang K, Zheng Y, Wu S (2023) fosA11, a novel chromosomal-encoded fosfomycin resistance gene identified in Providencia rettgeri. Microbiol Spectrum. https://doi.org/10.1128/spectrum.02542-23

    Article  Google Scholar 

  128. Kieffer N, Poirel L, Descombes MC, Nordmann P (2020) Characterization of FosL1, a plasmid-encoded fosfomycin resistance protein identified in Escherichia coli. Antimicrob Agents Chemother 64(4):e02042-19. https://doi.org/10.1128/AAC.02042-19

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

Thanks are extended to Prof. Areena Hoda Siddiqui and Dr. Meenakshi Sharma, who revised this paper. University Manuscript ID (MCN No.) IU/R&D/2024-MCN0002391

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  1. Department of Microbiology, Integral Institute of Medical Sciences Research, Integral University, Lucknow, Uttar Pradesh, India

    Sandeepika Dubey & Areena Hoda Siddiqui

  2. Autonomous State Medical College, Lakhimpur Kheri, Uttar Pradesh, India

    Meenakshi Sharma

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Dubey, S., Siddiqui, A.H. & Sharma, M. The Impact of Fosfomycin on Gram Negative Infections: A Comprehensive Review. Indian J Microbiol (2024). https://doi.org/10.1007/s12088-024-01293-8

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