Fosfomycin#Resistance

Fosfomycin is used to treat bladder infections as well as urinary tract infections (UTIs), where it is usually given as a single dose by mouth.{{cite journal | vauthors = Patel SS, Balfour JA, Bryson HM | title = Fosfomycin tromethamine. A review of its antibacterial activity, pharmacokinetic properties and therapeutic efficacy as a single-dose oral treatment for acute uncomplicated lower urinary tract infections | journal = Drugs | volume = 53 | issue = 4 | pages = 637–656 | date = April 1997 | pmid = 9098664 | doi = 10.2165/00003495-199753040-00007 | s2cid = 46972404 }}

Oral fosfomycin is not recommended for children under 12 years old.{{cite web |url=https://www.drugs.com/uk/monuril-sachets-3g-leaflet.html |title=MONURIL SACHETS 3G |access-date=26 May 2014 |archive-date=28 May 2014 |archive-url=https://web.archive.org/web/20140528005757/http://www.drugs.com/uk/monuril-sachets-3g-leaflet.html |url-status=live }}

Additional uses have been proposed.{{cite journal | vauthors = Falagas ME, Giannopoulou KP, Kokolakis GN, Rafailidis PI | title = Fosfomycin: use beyond urinary tract and gastrointestinal infections | journal = Clinical Infectious Diseases | volume = 46 | issue = 7 | pages = 1069–1077 | date = April 2008 | pmid = 18444827 | doi = 10.1086/527442 | doi-access = free }} The global problem of advancing antimicrobial resistance has led to a renewed interest in its use more recently.{{cite journal | vauthors = Falagas ME, Grammatikos AP, Michalopoulos A | title = Potential of old-generation antibiotics to address current need for new antibiotics | journal = Expert Review of Anti-Infective Therapy | volume = 6 | issue = 5 | pages = 593–600 | date = October 2008 | pmid = 18847400 | doi = 10.1586/14787210.6.5.593 | s2cid = 13158593 }}

Fosfomycin can be used as an efficacious treatment for both UTIs and complicated UTIs including acute pyelonephritis. The standard regimen for complicated UTIs is an oral 3 g dose administered once every 48 or 72 hours for a total of 3 doses or a 6 g dose every 8 hours for 7–14 days when fosfomycin is given in IV form.{{cite journal | vauthors = Zhanel GG, Zhanel MA, Karlowsky JA | title = Oral and Intravenous Fosfomycin for the Treatment of Complicated Urinary Tract Infections | journal = The Canadian Journal of Infectious Diseases & Medical Microbiology | volume = 2020 | pages = 8513405 | date = 28 March 2020 | pmid = 32300381 | pmc = 7142339 | doi = 10.1155/2020/8513405 | publisher = Hindawi Limited | doi-access = free }}

Intravenous fosfomycin is being increasingly used for treating infections caused by multidrug-resistant bacteria, mostly as a partner drug in order to avoid the occurrence of resistances and to take advantage of its synergistic activity with several other antimicrobials. In real-life settings, intravenous fosfomycin is most commonly used to treat pneumonia (34%), bloodstream infections (22%), and urinary tract infections (21%). In the majority of cases, it is administered in combination with a beta-lactam antibiotic, and in approximately half of the cases, it is employed as empirical therapy.{{cite journal | vauthors = Meschiari M, Faltoni M, Kaleci S, Tassoni G, Orlando G, Franceschini E, Burastero G, Bedini A, Serio L, Biagioni E, Melegari G, Venturelli C, Sarti M, Bertellini E, Girardis M, Mussini C | title = Intravenous fosfomycin in combination regimens as a treatment option for difficult-to-treat infections due to multi-drug-resistant Gram-negative organisms: A real-life experience | journal = International Journal of Antimicrobial Agents | volume = 63 | issue = 5 | pages = 107134 | date = May 2024 | pmid = 38453094 | doi = 10.1016/j.ijantimicag.2024.107134 | hdl = 11380/1334689 | hdl-access = free }}{{Cite journal | vauthors = Zerbato V, Sanson G, Fusaro L, Gerussi V, Sincovich S, Dellai F, Del Fabro G, Geremia N, Maurel C, Giacomazzi D,m Biasinutto C, Di Girolamo FG, Scrivo G, Costantino V, Di Santolo M |date=2025-04-14 |title=Intravenous Fosfomycin for Difficult-to-Treat Infections: A Real-Life Multicentric Study in Italy |journal=Antibiotics |language=en |volume=14 |issue=4 |pages=401 |doi=10.3390/antibiotics14040401 |doi-access=free |issn=2079-6382|pmc=12024000 }} Daily adult dose usually ranges from 12 to 24 grams.{{cite journal | vauthors = Antonello RM, Principe L, Maraolo AE, Viaggi V, Pol R, Fabbiani M, Montagnani F, Lovecchio A, Luzzati R, Di Bella S | title = Fosfomycin as Partner Drug for Systemic Infection Management. A Systematic Review of Its Synergistic Properties from In Vitro and In Vivo Studies | journal = Antibiotics | volume = 9 | issue = 8 | pages = 500 | date = August 2020 | pmid = 32785114 | pmc = 7460049 | doi = 10.3390/antibiotics9080500 | doi-access = free }} When administered in continuous infusion, a loading dose of fosfomycin 8 g followed by a daily dose of 16 g or 24 g. Continuous infusion is suggested in patients with normal renal function.{{cite journal | vauthors = Antonello RM, Di Bella S, Maraolo AE, Luzzati R | title = Fosfomycin in continuous or prolonged infusion for systemic bacterial infections: a systematic review of its dosing regimen proposal from in vitro, in vivo and clinical studies | journal = European Journal of Clinical Microbiology & Infectious Diseases | volume = 40 | issue = 6 | pages = 1117–1126 | date = June 2021 | pmid = 33604721 | pmc = 8139892 | doi = 10.1007/s10096-021-04181-x }}

Fosfomycin demonstrated strong antibiofilm activity in both in vitro and in vivo studies, including prosthetic material infections. It maintains antibiofilm activity against both Gram-positive (including MRSA) and Gram-negative bacteria.{{cite journal | vauthors = Di Bella S, Mearelli F, Gatti M | title = The importance of antibiofilm antibiotics in hardware-associated infections | journal = Clinical Infectious Diseases | date = February 2025 | pmid = 39935305 | doi = 10.1093/cid/ciaf064 }}

The fosfomycin molecule has an epoxide or oxirane ring, which is highly strained and thus very reactive.{{citation needed|date=February 2023}}

Fosfomycin has broad antibacterial activity against both Gram-positive and Gram-negative pathogens, with useful activity against E. faecalis, E. coli, and various Gram-negatives such as Citrobacter and Proteus. Given a greater activity in a low-pH milieu, and predominant excretion in active form into the urine, fosfomycin has found use for the prophylaxis and treatment of UTIs caused by these uropathogens. Of note, activity against S. saprophyticus, Klebsiella, and Enterobacter is variable and should be confirmed by minimum inhibitory concentration testing.

Activity against extended-spectrum β-lactamase-producing pathogens, notably ESBL-producing E. coli, is good to excellent, because the drug is not affected by cross-resistance issues.

Existing clinical data support use in uncomplicated UTIs, caused by susceptible organisms. However, susceptibility break-points of 64 mg/L should not be applied for systemic infections.{{citation needed|date=February 2023}}

Development of bacterial resistance under therapy is a frequent occurrence and makes fosfomycin unsuitable for sustained therapy of severe infections. Mutations that inactivate the nonessential glycerophosphate transporter render bacteria resistant to fosfomycin.{{cite journal | vauthors = Navas J, León J, Arroyo M, García Lobo JM | title = Nucleotide sequence and intracellular location of the product of the fosfomycin resistance gene from transposon Tn2921 | journal = Antimicrobial Agents and Chemotherapy | volume = 34 | issue = 10 | pages = 2016–2018 | date = October 1990 | pmid = 1963292 | pmc = 171982 | doi = 10.1128/AAC.34.10.2016 }}{{cite journal | vauthors = Kahan FM, Kahan JS, Cassidy PJ, Kropp H | title = The mechanism of action of fosfomycin (phosphonomycin) | journal = Annals of the New York Academy of Sciences | volume = 235 | pages = 364–386 | date = May 1974 | issue = 1 | pmid = 4605290 | doi = 10.1111/j.1749-6632.1974.tb43277.x | s2cid = 33013586 | bibcode = 1974NYASA.235..364K }}{{cite journal | vauthors = Castañeda-García A, Blázquez J, Rodríguez-Rojas A | title = Molecular Mechanisms and Clinical Impact of Acquired and Intrinsic Fosfomycin Resistance | journal = Antibiotics | volume = 2 | issue = 2 | pages = 217–236 | date = April 2013 | pmid = 27029300 | pmc = 4790336 | doi = 10.3390/antibiotics2020217 | doi-access = free }} Still, fosfomycin can be used to treat MRSA bacteremia.{{cite journal |vauthors=Omori K, Kitagawa H, Takada M, Maeda R, Nomura T, Kubo Y, Shigemoto N, Ohge H |title=Fosfomycin as salvage therapy for persistent methicillin-resistant Staphylococcus aureus bacteremia: A case series and review of the literature |journal=J Infect Chemother |volume=30 |issue=4 |pages=352–356 |date=April 2024 |pmid=37922987 |doi=10.1016/j.jiac.2023.10.024}}

Prescribing fosfomycin together with at least another active drug reduces the risk of developing bacterial resistance. Fosfomycin acts synergistically with many other antibiotics, including aminoglycosides, carbapenems, cephalosporins, daptomycin and oritavancin.{{cite journal | vauthors = Lagatolla C, Mehat JW, La Ragione RM, Luzzati R, Di Bella S | title = In Vitro and In Vivo Studies of Oritavancin and Fosfomycin Synergism against Vancomycin-Resistant Enterococcus faecium | journal = Antibiotics | volume = 11 | issue = 10 | pages = 1334 | date = September 2022 | pmid = 36289992 | pmc = 9598191 | doi = 10.3390/antibiotics11101334 | doi-access = free }}

Enzymes conferring resistance to fosfomycin have also been identified and are encoded both chromosomally and on plasmids.{{cite book | vauthors = Rigsby RE, Fillgrove KL, Beihoffer LA, Armstrong RN | chapter = Fosfomycin resistance proteins: a nexus of glutathione transferases and epoxide hydrolases in a metalloenzyme superfamily | volume = 401 | pages = [https://archive.org/details/gluthionetransfe00sies/page/367 367–379] | year = 2005 | pmid = 16399398 | doi = 10.1016/S0076-6879(05)01023-2 | isbn = 9780121828066 | series = Methods in Enzymology | title = {{sic|nolink=y|reason=error in source|Gluthione}} Transferases and Gamma-Glutamyl Transpeptidases | chapter-url = https://archive.org/details/gluthionetransfe00sies/page/367 }}

Three related fosfomycin resistance enzymes (named FosA, FosB, and FosX) are members of the glyoxalase superfamily. These enzymes function by nucleophilic attack on carbon 1 of fosfomycin, which opens the epoxide ring and renders the drug ineffective.{{citation needed|date=February 2023}}

The enzymes differ by the identity of the nucleophile used in the reaction: glutathione for FosA, bacillithiol for FosB,{{cite journal | vauthors = Sharma SV, Jothivasan VK, Newton GL, Upton H, Wakabayashi JI, Kane MG, Roberts AA, Rawat M, La Clair JJ, Hamilton CJ | title = Chemical and Chemoenzymatic syntheses of bacillithiol: a unique low-molecular-weight thiol amongst low G + C Gram-positive bacteria | journal = Angewandte Chemie | volume = 50 | issue = 31 | pages = 7101–7104 | date = July 2011 | pmid = 21751306 | doi = 10.1002/anie.201100196 }}{{cite journal | vauthors = Roberts AA, Sharma SV, Strankman AW, Duran SR, Rawat M, Hamilton CJ | title = Mechanistic studies of FosB: a divalent-metal-dependent bacillithiol-S-transferase that mediates fosfomycin resistance in Staphylococcus aureus | journal = The Biochemical Journal | volume = 451 | issue = 1 | pages = 69–79 | date = April 2013 | pmid = 23256780 | pmc = 3960972 | doi = 10.1042/BJ20121541 }} and water for FosX.

In general, FosA and FosX enzymes are produced by Gram-negative bacteria, whereas FosB is produced by Gram-positive bacteria.

FosC uses ATP and adds a phosphate group to fosfomycin, thus altering its properties and making the drug ineffective.{{cite journal | vauthors = García P, Arca P, Evaristo Suárez J | title = Product of fosC, a gene from Pseudomonas syringae, mediates fosfomycin resistance by using ATP as cosubstrate | journal = Antimicrobial Agents and Chemotherapy | volume = 39 | issue = 7 | pages = 1569–1573 | date = July 1995 | pmid = 7492106 | pmc = 162783 | doi = 10.1128/aac.39.7.1569 }}

The drug is well tolerated and has a low incidence of harmful side effects.

Despite its name (ending in -omycin) Fosfomycin is not a macrolide, but a member of a novel class of phosphonic antibiotics. Fosfomycin is bactericidal and inhibits bacterial cell wall biogenesis by inactivating the enzyme UDP-N-acetylglucosamine-3-enolpyruvyltransferase, also known as MurA.{{cite journal | vauthors = Brown ED, Vivas EI, Walsh CT, Kolter R | title = MurA (MurZ), the enzyme that catalyzes the first committed step in peptidoglycan biosynthesis, is essential in Escherichia coli | journal = Journal of Bacteriology | volume = 177 | issue = 14 | pages = 4194–4197 | date = July 1995 | pmid = 7608103 | pmc = 177162 | doi = 10.1128/jb.177.14.4194-4197.1995 }} This enzyme catalyzes the committed step in peptidoglycan biosynthesis, namely the ligation of phosphoenolpyruvate (PEP) to the 3'-hydroxyl group of UDP-N-acetylglucosamine. This pyruvate moiety provides the linker that bridges the glycan and peptide portion of peptidoglycan. Fosfomycin is a PEP analog that inhibits MurA by alkylating an active site cysteine residue (Cys 115 in the Escherichia coli enzyme).{{cite journal | vauthors = Zhu JY, Yang Y, Han H, Betzi S, Olesen SH, Marsilio F, Schönbrunn E | title = Functional consequence of covalent reaction of phosphoenolpyruvate with UDP-N-acetylglucosamine 1-carboxyvinyltransferase (MurA) | journal = The Journal of Biological Chemistry | volume = 287 | issue = 16 | pages = 12657–12667 | date = April 2012 | pmid = 22378791 | pmc = 3339971 | doi = 10.1074/jbc.M112.342725 | doi-access = free }}{{cite journal | vauthors = Krekel F, Samland AK, Macheroux P, Amrhein N, Evans JN | title = Determination of the pKa value of C115 in MurA (UDP-N-acetylglucosamine enolpyruvyltransferase) from Enterobacter cloacae | journal = Biochemistry | volume = 39 | issue = 41 | pages = 12671–12677 | date = October 2000 | pmid = 11027147 | doi = 10.1021/bi001310x }}

Fosfomycin enters the bacterial cell through the glycerophosphate transporter.{{cite journal | vauthors = Santoro A, Cappello AR, Madeo M, Martello E, Iacopetta D, Dolce V | title = Interaction of fosfomycin with the glycerol 3-phosphate transporter of Escherichia coli | journal = Biochimica et Biophysica Acta (BBA) - General Subjects | volume = 1810 | issue = 12 | pages = 1323–1329 | date = December 2011 | pmid = 21791237 | doi = 10.1016/j.bbagen.2011.07.006 }}

Fosfomycin (originally known as phosphonomycin) was discovered in a joint effort of Merck and Co. and Spain's Compañía Española de Penicilina y Antibióticos (CEPA). It was first isolated by screening broth cultures of Streptomyces fradiae isolated from soil samples for the ability to cause formation of spheroplasts by growing bacteria. The discovery was described in a series of papers published in 1969.{{cite book | vauthors = Silver LL | chapter = Rational Approaches to Antibacterial Discovery: Pre-Genomic Directed and Phenotypic Screening | veditors = Dougherty T, Pucci MJ |title= Antibiotic Discovery and Development |publisher=Springer |date=2011 |pages=46 |isbn=978-1-4614-1400-1|doi=10.1007/978-1-4614-1400-1_2}} CEPA began producing fosfomycin on an industrial scale in 1971 at its Aranjuez facility.{{cite web | work = Encros | url = http://www.ercros.es/eng/internas.asp?arxiu=qh_aranjuezh |title = About us: Our history | archive-url = https://web.archive.org/web/20110914142734/http://www.ercros.es/eng/internas.asp?arxiu=qh_aranjuezh | archive-date= 14 September 2011 }}

The complete fosfomycin biosynthetic gene cluster from Streptomyces fradiae has been cloned and sequenced and the heterologous production of fosfomycin in S. lividans has been achieved by Ryan Woodyer of the Huimin Zhao and Wilfred van der Donk research groups.{{cite journal | vauthors = Woodyer RD, Shao Z, Thomas PM, Kelleher NL, Blodgett JA, Metcalf WW, van der Donk WA, Zhao H | title = Heterologous production of fosfomycin and identification of the minimal biosynthetic gene cluster | journal = Chemistry & Biology | volume = 13 | issue = 11 | pages = 1171–1182 | date = November 2006 | pmid = 17113999 | doi = 10.1016/j.chembiol.2006.09.007 | doi-access = free }}

Large scale production of fosfomycin is achieved by making an epoxide of cis-propenylphosphonic acid to yield racemic mixture fosfomycin.{{cite journal | vauthors = Marocco CP, Davis EV, Finnell JE, Nguyen PH, Mateer SC, Ghiviriga I, Padgett CW, Feske BD | title=Asymmetric synthesis of (−)-fosfomycin and its trans-(1S,2S)-diastereomer using a biocatalytic reduction as the key step | journal=Tetrahedron: Asymmetry | publisher=Elsevier BV | volume=22 | issue=18–19 | year=2011 | issn=0957-4166 | doi=10.1016/j.tetasy.2011.10.009 | pages=1784–1789}}

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