Buscar en
Enfermedades Infecciosas y Microbiología Clínica (English Edition)
Toda la web
Inicio Enfermedades Infecciosas y Microbiología Clínica (English Edition) Current approach to fosfomycin: From bench to bedside
Journal Information
Vol. 37. Issue 1.
Pages 1-3 (January 2019)
Vol. 37. Issue 1.
Pages 1-3 (January 2019)
DOI: 10.1016/j.eimce.2018.10.005
Full text access
Current approach to fosfomycin: From bench to bedside
Uso actual de la fosfomicina: del laboratorio a la práctica clínica
Francisco Javier Candela,
Corresponding author

Corresponding author.
, Rafael Cantónb
a Servicio de Microbiología Clínica, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria San Carlos (IdISSC), Madrid, Spain
b Servicio de Microbiología, Hospital Ramón y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain
Article information
Full Text
Download PDF
Full Text

The need to use effective antimicrobials to treat multidrug-resistant (MDR) infections has driven the pharmaceutical industry to design new molecules, as well as to rediscover molecules which were already known about, such as colistin and fosfomycin. Indeed, use of fosfomycin, which is only approved in some European and Latin American countries, has seen unprecedented growth in the last four years. Fosfomycin, which is only approved by the US Food and Drug Administration as fosfomycin trometamol for the treatment of uncomplicated cystitis, is currently pending approval in intravenous form as disodium salt. In 2013, a randomised, multi-centre, open-label, controlled phase 3 clinical trial to evaluate the efficacy of fosfomycin versus meropenem in the targeted treatment of bacteriaemic urinary tract infection due to extended-spectrum beta-lactamase-producing Escherichia coli (E. coli) (FOREST study) began in Spain.1 In 2017, another multi-centre, randomised, double-blind, phase 2/3 non-inferiority study to evaluate the safety and efficacy of intravenous fosfomycin versus piperacillin-tazobactam in the treatment of adult hospitalised patients with complicated urinary tract infections (ZEUS study) began in the United States.2

Fosfomycin was discovered in Spain by an integrated research team from the now defunct Compañía Española de Penicilina y Antibióticos [Spanish Company of Penicillin and Antibiotics] (CEPA) from an isolate of Streptomyces fradiae collected in 1966 in Jávea (Alicante). As a phosphoenolpyruvate (PEP) analogue, it irreversibly inhibits the cytosolic enzyme MurA (N-acetylglucosamine enolpyruvyl-transferase), which plays a key role in the formation of N-acetylmuramic acid found in the peptidoglycan layer of the cell wall. It also reduces the formation of penicillin-binding proteins (PBP).3 Fosfomycin is water soluble, has a low molecular mass (138) and binds negligibly to proteins, which is why it has excellent tissue diffusion properties.4,5 It also penetrates and diffuses in biofilms in experimental models at concentrations equal to or higher than ciprofloxacin or co-trimoxazole.6 The pharmacokinetic-pharmacodynamic efficacy parameter to take into account to achieve the therapeutic target with fosfomycin is the ratio between the area under the curve at 24h and the MIC. It also shows postantibiotic effect at lower concentrations.7 Some of the resistance mechanisms reported include reduced intracellular transport of the antibiotic (mutations in transporter genes and AMPc glpT or uhpT regulators), change of target caused by murA expression mutations or abnormalities and, finally, the direct inactivation of the antibiotic by metalloenzymes (FosA, FosB and FosX) or by kinases (FormA and FormB).3

The lack of consistency between the CLSI (≥64mg/l) and EUCAST (≥32mg/l) breakpoints, the fact that some microorganisms have a naturally higher MIC (Klebsiella spp., Enterobacter spp., Serratia spp., Pseudomonas aeruginosa) due to the expression of chromosomal genes homologous to FosA and FosB that interact with fosfomycin, and the varying effective concentrations of the drug for Gram-positive and Gram-negative bacteria explains why the dosage recommendations for the treatment of MDR infections range from 8 to 12g/day when Gram-positive microorganisms are involved, and from 16 to 24g/day when treating Gram-negative bacteria.8,9 It has recently been established that E. coli colonies that grow in the inhibition halos of diffusion tests, and whose presence is not related to clinical failure, are mutants with loss of GlpT and UhpT transporter expression.10 Given that the selection frequency of mutants with higher fosfomycin MIC values than those obtained with a wild strain depends on the concentration of fosfomycin present in the medium (5.5×105CFU/ml with concentrations 5 times the MIC and >1.2×109CFU/ml with concentrations 256 times the MIC), the use of high doses of the drug, particularly if prescribed in monotherapy, would avoid this selection window.11 Furthermore, most of these mutants, particularly those selected with a lower fosfomycin concentration, would not be stable in successive passages, impacting on the high MIC values.12 Finally, a recent meta-analysis13 found just 3.4% onset of resistance (95% CI, 1.8%–5.1%) during treatment with fosfomycin in monotherapy, which would presumably be lower or non-existent with combination therapy.

Fosfomycin has at least an additive effect, or even a synergistic effect in combination with almost all the antimicrobials tested thanks to its high diffusion and unique mechanism of action. In this edition of the journal, Coronado-Alvarez et al.14 present an interesting study that highlights the synergistic activity in vitro of fosfomycin at suprainhibitory concentrations (above the MIC) in combination with other antimicrobials (daptomycin, vancomycin, imipenem or linezolid) against strains of methicillin-susceptible Staphylococcus aureus (MSSA) and methicillin-resistant S. aureus (MRSA). Previous studies had demonstrated an additive effect of fosfomycin at subinhibitory concentrations (below the MIC). Coronado-Alvarez et al.14 also show the clinical correlation of their observations in vitro in patients administered fosfomycin in combination to treat bacteraemia caused by MRSA and MSSA, as well as by Enterococcus faecium. The most active combinations in vitro were those containing daptomycin or imipenem, while those with vancomycin or linezolid were less effective. The clinical results also revealed greater efficacy with daptomycin (93% therapeutic success) when compared with vancomycin (47% therapeutic success). In all cases, sterilisation of blood cultures was observed 48h after initiating combination therapy with fosfomycin. Although a variety of regimens were used, no significant differences were observed when the combination therapy was administered at baseline versus 72h after the onset of bacteraemia.

The results published by Coronado-Alvarez et al.14 corroborate those already published by other authors with combinations of fosfomycin with daptomycin15 or with imipenem.16 The current guidelines on the treatment of persistent infection, or infection complicated by MRSA, issued by the Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica [Spanish Society of Infectious Diseases and Clinical Microbiology], recommend the combination of fosfomycin and daptomycin.17 This recommendation is expected to be further reinforced when the results of an ongoing trial comparing the combined activity of fosfomycin and daptomycin versus daptomycin in monotherapy for the treatment of MRSA infection are published.18

Furthermore, the combination of fosfomycin with other antimicrobials has also demonstrated synergy in vitro against multidrug-resistant Gram-negative microorganisms,19 and there is published clinical evidence of its use at high doses and in combination with other agents in the treatment of carbapenemase-producing enterobacteriaceae20–22 and extensively-drug resistant Pseudomonas spp.23

Fosfomycin is considered to be a relatively safe and well-tolerated antimicrobial. Nevertheless, cases of intolerance caused by sodium overload have been reported in exceptional cases. One gram of fosfomycin sodium contains 0.33g (14.4meq) of sodium,24 which means that treatment with 12–24g of fosfomycin provides the extracellular compartment with 4–8g of sodium. Cases of heart failure have been reported in patients being treated with fosfomycin, including patients with a normal ejection fraction, requiring the drug to be withdrawn.14,16,25 Monitoring sodium overload in patients treated with high doses of fosfomycin (16–24g/day) could be complicated in comorbid patients with water retention (cirrhosis, heart or kidney failure) as the neurohormonal expression of soluble factors (norepinephrine, vasopressin, atrial natriuretic peptides, etc.) could trigger an episode of volume overload in the extracellular compartment.26 In standard practice, the stability of fosfomycin at room temperature has led to its use in continuous infusion, particularly to treat MDR infections, striving for relatively low doses (12–16g/day) that guarantee plasma trough concentrations above 32mg/l, thereby reducing the total salt overload that would require the administration of fractionated doses. This could be particularly beneficial for patients suffering from the water retention conditions referred to above.

In conclusion, although this molecule is not new, its positioning has yet to be fully defined. The more we find out about fosfomycin, the more potential benefits it seems to reveal. Given its safety and activity, the most attractive therapeutic model is probably that proposed by Coronado-Alvarez et al.,14 featuring the synergistic combination with other antimicrobials to treat complicated MDR infections.

Conflicts of interest

FJC and RC have participated in training activities sponsored by Laboratorios ERN.

C. Rosso-Fernández, J. Sojo-Dorado, A. Barriga, L. Lavín-Alconero, Z. Palacios, I. López-Hernández, et al.
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 (2015), pp. e007363
K.S. Kaye, L.B. Rice, A. Dane, V. Stus, O. Sagan, E. Fedosiuk, et al.
Intravenous fosfomycin (ZTI-01) for the treatment of complicated urinary tract infections (cUTI) including acute pyelonephritis (AP): results from a multi-center, randomized double-blind phase 2/3 study in hospitalized adults (ZEUS).
Open Forum Infectious Diseases, 4 (2017), pp. S528
A.C. Dijkmans, N.V.O. Zacarías, J. Burggraaf, J.W. Mouton, E.B. Wilms, C. van Nieuwkoop, et al.
Fosfomycin: pharmacological, clinical and future perspectives.
Antibiotics, 6 (2017), pp. 24
V. Matzi, J. Lindenmann, C. Porubsky, S.A. Kugler, A. Maier, P. Dittrich, et al.
Extracellular concentrations of fosfomycin in lung tissue of septic patients.
J Antimicrob Chemother, 65 (2010), pp. 995-998
M. Gobernado.
Rev Esp Quimiot, 16 (2003), pp. 15-40
J.M. Rodríguez-Martínez, S. Ballesta, A. Pascual.
Activity and penetration of fosfomycin, ciprofloxacin, amoxicillin/clavulanic acid and co-trimoxazole in Escherichia coli and Pseudomonas aeruginosa biofilms.
Int J Antimicrob Agents, 30 (2007), pp. 366-368
A.J. Lepak, M. Zhao, B. VanScoy, D.S. Taylor, E. Ellis-Grosse, P.G. Ambrose, et al.
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.
Antimicrobial Agents Chemother, 61 (2017),
M. De Cueto, L. López, J.R. Hernández, C. Morillo, A. Pascual.
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 (2006), pp. 368-370
J. Rodríguez-Baño, J.M. Cisneros, N. Cobos-Trigueros, G. Fresco, C. Navarro-San Francisco, C. Gudiol, et al.
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 (2015), pp. 338-341
A.E. Lucas, R. Ito, M.M. Mustapha, C.L. McElheny, R.T. Mettus, S.L. Bowler, et al.
Frequency and mechanisms of spontaneous fosfomycin non-susceptibility observed upon disk diffusion testing of Escherichia coli.
J Clin Microbiol, 56 (2017),
B.D. Van Scoy, J. McCauley, E.J. Ellis-Grosse, O.O. Okusanya, S.M. Bhavnani, A. Forrest, et al.
Exploration of the pharmacokinetic-pharmacodynamic relationships for fosfomycin efficacy using an in vitro infection model.
Antimicrob Agents Chemother, 59 (2015), pp. 7170-7177
M. Ballestero-Téllez, F. Docobo-Pérez, I. Portillo-Calderón, J.M. Rodríguez-Martínez, L. Racero, M.S. Ramos-Guelfo, et al.
Molecular insights into fosfomycin resistance in Escherichia coli.
J Antimicrob Chemother, 72 (2017), pp. 1303-1309
B. Grabein, W. Graninger, J. Rodríguez Baño.
Intravenous fosfomycin-back to the future systematic review and meta-analysis of the clinical literature.
Clin Microbiol Infect, 23 (2017), pp. 363-372
M.N. Coronado-Alvarez, D. Parra, J. Parra-Ruiz.
Clinical efficacy of fosfomycin combinations against a variety of gram-positive cocci.
Enferm Infecc Microbiol Clin, (2018),
J.M. Miró, J.M. Entenza, A. del Río, M. Velasco, X. Castañeda, C. Garcia de la Mària, et al.
High-dose daptomycin plus fosfomycin is safe and effective in treating methicillin-susceptible and methicillin-resistant Staphylococcus aureus endocarditis.
Antimicrob Agents Chemother, 56 (2012), pp. 4511-4515
A. Del Río, O. Gasch, A. Moreno, C. Peña, J. Cuquet, D. Soy, et al.
Efficacy and safety of fosfomycin plus imipenem as rescue therapy for complicated bacteriemia and endocarditis due to methicillin-resistant Staphylococcus aureus: a multicenter clinical trial.
Clin Infect Dis, 59 (2014), pp. 1105-1112
F. Gudiol, J.M. Aguado, B. Almirante, E. Bouza, E. Cercenado, M.A. Domínguez, et al.
Diagnosis and treatment of bacteriemia and endocarditis due to Staphylococcus aureus. A clinical guideline from the Spanish Society of Clinical Microbiology and Infectious Diseases (SEIMC).
Enferm Infecc Microbiol Clin, 33 (2015), pp. 625.e1-625.e23
E. Shaw, J.M. Miró, M. Puig-Asensio, C. Pigrau, F. Barcenilla, J. Murillas, et al.
Daptomycin plus fosfomycin versus daptomycin monotherapy in treating MRSA: protocol of a multicentre, randomised, phase III trial.
BMJ Open, 5 (2015), pp. e006723
M.E. Falagas, E.K. Vouloumanou, G. Samonis, K.Z. Vardakas.
Clin Microbiol Rev, 29 (2016), pp. 321-347
M. Bassetti, M. Peghin, D. Pecori.
The management of multidrug-resistant Enterobacteriaceae.
Curr Opin Infect Dis, 29 (2016), pp. 583-594
A. Michalopoulos, S. Virtzili, P. Rafailidis, G. Chalevelakis, M. Damala, M.E. Falagas.
Intravenous fosfomycin for the treatment of nosocomial infections caused by carbapenem-resistant Klebsiella pneumoniae in critically ill patients: a prospective evaluation.
Clin Microbiol Infect, 16 (2010), pp. 184-186
K. Pontikis, I. Karaiskos, S. Bastani, G. Dimopoulos, M. Kalogirou, M. Katsiari, et al.
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.
Intern J Antimicrob Agents, 43 (2014), pp. 52-59
O. Asuphon, P. Montakantikul, J. Houngsaitong, P. Kiratisin, P. Sonthisombat.
Optimizing intravenous fosfomycin dosing in combination with carbapenémicos for treatment of Pseudomonas aeruginosa infections in critically ill patients based on pharmacokinetic/pharmacodynamic (PK/PD) simulation.
Intern J Infect Dis, 50 (2016), pp. 23-29
Spanish Agency for Medicines and Health Products. Available from: [accessed 09.09.18].
I. Cañamares-Orbis, J.T. Silva, F. López-Medrano, J.M. Aguado.
Is high-dose intravenous fosfomycin safe for the treatment of patients prone to heart failure?.
Enferm Infecc Microbiol Clin, 33 (2015), pp. 294
F.J. Candel, M. Matesanz, F.J. Martín-Sánchez, J.M. González del Castillo.
Monitoring of high-dose fosfomycin guided by NT-proBNP.
Int J Cardiol, 209 (2016), pp. 131-132

Please cite this article as: Candel FJ, Cantón R. Uso actual de la fosfomicina: del laboratorio a la práctica clínica. Enferm Infecc Microbiol Clin. 2019;37:1–3.

Copyright © 2018. Elsevier España, S.L.U. and Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica
Article options
es en pt

¿Es usted profesional sanitario apto para prescribir o dispensar medicamentos?

Are you a health professional able to prescribe or dispense drugs?

Você é um profissional de saúde habilitado a prescrever ou dispensar medicamentos

es en pt
Política de cookies Cookies policy Política de cookies
Utilizamos cookies propias y de terceros para mejorar nuestros servicios y mostrarle publicidad relacionada con sus preferencias mediante el análisis de sus hábitos de navegación. Si continua navegando, consideramos que acepta su uso. Puede cambiar la configuración u obtener más información aquí. To improve our services and products, we use "cookies" (own or third parties authorized) to show advertising related to client preferences through the analyses of navigation customer behavior. Continuing navigation will be considered as acceptance of this use. You can change the settings or obtain more information by clicking here. Utilizamos cookies próprios e de terceiros para melhorar nossos serviços e mostrar publicidade relacionada às suas preferências, analisando seus hábitos de navegação. Se continuar a navegar, consideramos que aceita o seu uso. Você pode alterar a configuração ou obter mais informações aqui.