Fosfomycin for Injection: Still Effective, Still in Demand
03.02.2019
Fosfomycin for Injection: Still Effective, Still in Demand
Fosfomycin for Injection: Still Effective, Still in Demand
(Review of Medical Literature)
Today, we are witnessing a renaissance of fosfomycin—an antimicrobial agent with unique pharmacodynamics and pharmacokinetics that has been known for over 50 years.
Fosfomycin acts by inhibiting UDP-N-acetylglucosamine enolpyruvyl transferase (MurA), an enzyme catalyzing the first step in bacterial cell wall synthesis. Thanks to this mechanism, fosfomycin exhibits bactericidal activity against both Gram-positive and Gram-negative aerobic bacteria, including strains expressing multiple resistance factors, particularly beta-lactamases.
Fosfomycin for injection was recently added to the WHO Model List of Essential Medicines, which serves as a guide for national and institutional essential medicines lists (source).
Many healthcare systems consider fosfomycin a treatment option for bacterial infections unresponsive to first- and second-line antibiotics, often due to antimicrobial resistance, biofilm formation, or intolerance to standard drugs. Owing to its unique ability to potentiate the effects of other antimicrobials, fosfomycin is increasingly used in combination therapies for severe systemic infections caused by MRSA, MRSE, multidrug-resistant Enterobacteriaceae, and extensively drug-resistant P. aeruginosa. Recent studies also support its synergistic use with other antibiotics. For example, synergy has been demonstrated between fosfomycin and colistin against carbapenem-resistant A. baumannii (CRAB) [1], and between fosfomycin and daptomycin against MRSA in an in vivo endocarditis model [2]—findings of significant clinical relevance.
Use of Fosfomycin in Treating Infections Caused by Carbapenem-Resistant Klebsiella pneumoniae
A 2017 retrospective study evaluated the efficacy and safety of fosfomycin-based combination therapies for sepsis caused by K. pneumoniae. Outcomes included survival/mortality rates, ICU stay, and duration of mechanical ventilation. Patients receiving fosfomycin in combination therapy showed significantly higher survival rates, with reduced mortality and shorter ventilation time [3].
Fosfomycin Optimizes Gram-Positive Infection Management
Fosfomycin improves outcomes in infections caused by Gram-positive cocci. A retrospective analysis of different combination regimens found 81% efficacy in treating Gram-positive infections, with the best results achieved using fosfomycin plus daptomycin. Fosfomycin was well tolerated—only one out of 75 patients discontinued treatment due to adverse effects [4].
Fosfomycin in Bacterial Endocarditis Treatment
Its efficacy in MRSA-induced endocarditis was recently confirmed in a randomized clinical trial [5]. This study followed a multicenter investigation of fosfomycin plus imipenem (1 g IV every 6 hours) in patients unresponsive to vancomycin, daptomycin, or combination regimens. Clinical remission was achieved in 69% of cases, with 94% of patients tolerating the combination well. Blood cultures turned negative within 72 hours in most cases [6].
Fosfomycin in Cystic Fibrosis-Associated Pulmonary Infections
Antibiotic resistance among Gram-negative pathogens is a major concern in cystic fibrosis care. When multidrug-resistant P. aeruginosa is isolated and beta-lactam intolerance exists, treatment options become limited. One retrospective study evaluated the efficacy and safety of fosfomycin combined with anti-pseudomonal agents in treating lower respiratory tract infections in adult CF patients. The addition of injectable fosfomycin led to significantly faster resolution of infection and inflammation, as confirmed by improved pulmonary function and reduced CRP levels. Moreover, it helped prevent nephrotoxicity typically associated with anti-pseudomonal antibiotics. Renal function remained stable in most patients, with acute kidney injury occurring in only 4%. Potassium/magnesium supplementation was needed in 18% of cases. The most common adverse effect—nausea (48%)—was manageable and did not require discontinuation [7].
New Dosing Recommendations for Treating Multidrug-Resistant Infections
Taking into account fosfomycin’s pharmacokinetic/pharmacodynamic profile and broad therapeutic window, experts recommend adult dosing of 12–24 g/day IV, depending on infection severity. These recommendations are supported by clinical experience, ensuring high efficacy with low toxicity, including in combination therapy settings [8]. Optimal pediatric dosing is still under investigation, with ongoing trials such as Neofosfo evaluating fosfomycin-based regimens in neonatal sepsis.
Fosfomycin for Injection May Soon Be FDA-Approved
Despite its long history of global use, fosfomycin for injection has not been available in the U.S. Due to rising resistance, especially among urinary tract pathogens, the drug is now under intensive evaluation. The ZEUS trial showed that fosfomycin (6 g IV every 8 hours) outperformed piperacillin-tazobactam (4.5 g every 8 hours) in treating complicated UTIs, including acute pyelonephritis—61% vs. 42% success rates. The standard course lasted 7 days (14 days in bacteremia). Fosfomycin was well tolerated, with only mild, reversible lab or GI abnormalities. Crucially, it was effective against multidrug-resistant Enterobacteriaceae [9].
Fosfomycin’s Importance in Developing Countries
In countries where access to modern beta-lactams and novel beta-lactamase inhibitors is limited, fosfomycin has become a lifesaving agent for treating difficult infections caused by carbapenem-resistant Enterobacteriaceae. Indian clinical experience has shown encouraging outcomes, supporting its use in monotherapy (especially for UTIs) and as part of combination regimens for infections at other sites [10].
References:
1. Leelasupasri S, Santimaleeworagun W, Jitwasinkul T. Antimicrobial Susceptibility among Colistin, Sulbactam, and Fosfomycin and a Synergism Study of Colistin in Combination with Sulbactam or Fosfomycin against Clinical Isolates of Carbapenem-Resistant Acinetobacter baumannii. J Pathog. 2018 Jan 18;2018:3893492.
2. García-de-la-Mària C, Gasch O, García-Gonzalez J, et al. The Combination of Daptomycin and Fosfomycin Has Synergistic, Potent, and Rapid Bactericidal Activity against Methicillin-Resistant Staphylococcus aureus in a Rabbit Model of Experimental Endocarditis. Antimicrob Agents Chemother. 2018 May 25;62(6). pii: e02633-17.
3. Liao Y, Hu GH, Xu YF, Che JP, Luo M, Zhang HM, Peng B, Yao XD, Zheng JH, Liu M. Retrospective analysis of fosfomycin combinational therapy for sepsis caused by carbapenem-resistant Klebsiella pneumoniae. Exp Ther Med. 2017 Mar;13(3):1003-1010.
4. Coronado-Álvarez NM, Parra D, Parra-Ruiz J. Clinical efficacy of fosfomycin combinations against a variety of gram-positive cocci. Enferm Infecc Microbiol Clin. 2019 Jan;37(1):4-10.
5. Pericàs JM, Moreno A, Almela M, et al. Efficacy and safety of fosfomycin plus imipenem versus vancomycin for complicated bacteraemia and endocarditis due to methicillin-resistant Staphylococcus aureus: a randomized clinical trial. Clin Microbiol Infect. 2018 Jun;24(6):673-676.
6. del Río A, Gasch O, Moreno A, Peña C, Cuquet J, Soy D, Mestres CA, Suárez C, Pare JC, Tubau F, Garcia de la Mària C, Marco F, Carratalà J, Gatell JM, Gudiol F, Miró JM; FOSIMI Investigators. 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. 2014 Oct 15;59(8):1105-12.
7. Spoletini G, Kennedy M, Flint L, et al. Intravenous fosfomycin for pulmonary exacerbation of cystic fibrosis: Real life experience of a large adult CF centre. Pulm Pharmacol Ther. 2018 Jun;50:82-87.
8. Dimopoulos G, Koulenti D, Parker SL Roberts JA, Arvaniti K, Poulakou G. Intravenous fosfomycin for the treatment of multidrug resistant pathogens: what is the evidence on dosing regimens? Expert Rev Anti Infect Ther. 2019 Jan 22. [Epub ahead of print]
9. Shorr AF, Pogue JM, Mohr JF. Intravenous fosfomycin for the treatment of hospitalized patients with serious infections. Expert Rev Anti Infect Ther. 2017 Oct;15(10):935-945. doi: 10.1080/14787210.2017.1379897. Epub 2017 Sep 22.
10. Saiprasad PV, Krishnaprasad K. Exploring the hidden potential of fosfomycin for the fight against severe Gram-negative infections. Indian J Med Microbiol. 2016 Oct-Dec;34(4):416-420.
(Review of Medical Literature)
Today, we are witnessing a renaissance of fosfomycin—an antimicrobial agent with unique pharmacodynamics and pharmacokinetics that has been known for over 50 years.
Fosfomycin acts by inhibiting UDP-N-acetylglucosamine enolpyruvyl transferase (MurA), an enzyme catalyzing the first step in bacterial cell wall synthesis. Thanks to this mechanism, fosfomycin exhibits bactericidal activity against both Gram-positive and Gram-negative aerobic bacteria, including strains expressing multiple resistance factors, particularly beta-lactamases.
Fosfomycin for injection was recently added to the WHO Model List of Essential Medicines, which serves as a guide for national and institutional essential medicines lists (source).
Many healthcare systems consider fosfomycin a treatment option for bacterial infections unresponsive to first- and second-line antibiotics, often due to antimicrobial resistance, biofilm formation, or intolerance to standard drugs. Owing to its unique ability to potentiate the effects of other antimicrobials, fosfomycin is increasingly used in combination therapies for severe systemic infections caused by MRSA, MRSE, multidrug-resistant Enterobacteriaceae, and extensively drug-resistant P. aeruginosa. Recent studies also support its synergistic use with other antibiotics. For example, synergy has been demonstrated between fosfomycin and colistin against carbapenem-resistant A. baumannii (CRAB) [1], and between fosfomycin and daptomycin against MRSA in an in vivo endocarditis model [2]—findings of significant clinical relevance.
Use of Fosfomycin in Treating Infections Caused by Carbapenem-Resistant Klebsiella pneumoniae
A 2017 retrospective study evaluated the efficacy and safety of fosfomycin-based combination therapies for sepsis caused by K. pneumoniae. Outcomes included survival/mortality rates, ICU stay, and duration of mechanical ventilation. Patients receiving fosfomycin in combination therapy showed significantly higher survival rates, with reduced mortality and shorter ventilation time [3].
Fosfomycin Optimizes Gram-Positive Infection Management
Fosfomycin improves outcomes in infections caused by Gram-positive cocci. A retrospective analysis of different combination regimens found 81% efficacy in treating Gram-positive infections, with the best results achieved using fosfomycin plus daptomycin. Fosfomycin was well tolerated—only one out of 75 patients discontinued treatment due to adverse effects [4].
Fosfomycin in Bacterial Endocarditis Treatment
Its efficacy in MRSA-induced endocarditis was recently confirmed in a randomized clinical trial [5]. This study followed a multicenter investigation of fosfomycin plus imipenem (1 g IV every 6 hours) in patients unresponsive to vancomycin, daptomycin, or combination regimens. Clinical remission was achieved in 69% of cases, with 94% of patients tolerating the combination well. Blood cultures turned negative within 72 hours in most cases [6].
Fosfomycin in Cystic Fibrosis-Associated Pulmonary Infections
Antibiotic resistance among Gram-negative pathogens is a major concern in cystic fibrosis care. When multidrug-resistant P. aeruginosa is isolated and beta-lactam intolerance exists, treatment options become limited. One retrospective study evaluated the efficacy and safety of fosfomycin combined with anti-pseudomonal agents in treating lower respiratory tract infections in adult CF patients. The addition of injectable fosfomycin led to significantly faster resolution of infection and inflammation, as confirmed by improved pulmonary function and reduced CRP levels. Moreover, it helped prevent nephrotoxicity typically associated with anti-pseudomonal antibiotics. Renal function remained stable in most patients, with acute kidney injury occurring in only 4%. Potassium/magnesium supplementation was needed in 18% of cases. The most common adverse effect—nausea (48%)—was manageable and did not require discontinuation [7].
New Dosing Recommendations for Treating Multidrug-Resistant Infections
Taking into account fosfomycin’s pharmacokinetic/pharmacodynamic profile and broad therapeutic window, experts recommend adult dosing of 12–24 g/day IV, depending on infection severity. These recommendations are supported by clinical experience, ensuring high efficacy with low toxicity, including in combination therapy settings [8]. Optimal pediatric dosing is still under investigation, with ongoing trials such as Neofosfo evaluating fosfomycin-based regimens in neonatal sepsis.
Fosfomycin for Injection May Soon Be FDA-Approved
Despite its long history of global use, fosfomycin for injection has not been available in the U.S. Due to rising resistance, especially among urinary tract pathogens, the drug is now under intensive evaluation. The ZEUS trial showed that fosfomycin (6 g IV every 8 hours) outperformed piperacillin-tazobactam (4.5 g every 8 hours) in treating complicated UTIs, including acute pyelonephritis—61% vs. 42% success rates. The standard course lasted 7 days (14 days in bacteremia). Fosfomycin was well tolerated, with only mild, reversible lab or GI abnormalities. Crucially, it was effective against multidrug-resistant Enterobacteriaceae [9].
Fosfomycin’s Importance in Developing Countries
In countries where access to modern beta-lactams and novel beta-lactamase inhibitors is limited, fosfomycin has become a lifesaving agent for treating difficult infections caused by carbapenem-resistant Enterobacteriaceae. Indian clinical experience has shown encouraging outcomes, supporting its use in monotherapy (especially for UTIs) and as part of combination regimens for infections at other sites [10].
References:
1. Leelasupasri S, Santimaleeworagun W, Jitwasinkul T. Antimicrobial Susceptibility among Colistin, Sulbactam, and Fosfomycin and a Synergism Study of Colistin in Combination with Sulbactam or Fosfomycin against Clinical Isolates of Carbapenem-Resistant Acinetobacter baumannii. J Pathog. 2018 Jan 18;2018:3893492.
2. García-de-la-Mària C, Gasch O, García-Gonzalez J, et al. The Combination of Daptomycin and Fosfomycin Has Synergistic, Potent, and Rapid Bactericidal Activity against Methicillin-Resistant Staphylococcus aureus in a Rabbit Model of Experimental Endocarditis. Antimicrob Agents Chemother. 2018 May 25;62(6). pii: e02633-17.
3. Liao Y, Hu GH, Xu YF, Che JP, Luo M, Zhang HM, Peng B, Yao XD, Zheng JH, Liu M. Retrospective analysis of fosfomycin combinational therapy for sepsis caused by carbapenem-resistant Klebsiella pneumoniae. Exp Ther Med. 2017 Mar;13(3):1003-1010.
4. Coronado-Álvarez NM, Parra D, Parra-Ruiz J. Clinical efficacy of fosfomycin combinations against a variety of gram-positive cocci. Enferm Infecc Microbiol Clin. 2019 Jan;37(1):4-10.
5. Pericàs JM, Moreno A, Almela M, et al. Efficacy and safety of fosfomycin plus imipenem versus vancomycin for complicated bacteraemia and endocarditis due to methicillin-resistant Staphylococcus aureus: a randomized clinical trial. Clin Microbiol Infect. 2018 Jun;24(6):673-676.
6. del Río A, Gasch O, Moreno A, Peña C, Cuquet J, Soy D, Mestres CA, Suárez C, Pare JC, Tubau F, Garcia de la Mària C, Marco F, Carratalà J, Gatell JM, Gudiol F, Miró JM; FOSIMI Investigators. 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. 2014 Oct 15;59(8):1105-12.
7. Spoletini G, Kennedy M, Flint L, et al. Intravenous fosfomycin for pulmonary exacerbation of cystic fibrosis: Real life experience of a large adult CF centre. Pulm Pharmacol Ther. 2018 Jun;50:82-87.
8. Dimopoulos G, Koulenti D, Parker SL Roberts JA, Arvaniti K, Poulakou G. Intravenous fosfomycin for the treatment of multidrug resistant pathogens: what is the evidence on dosing regimens? Expert Rev Anti Infect Ther. 2019 Jan 22. [Epub ahead of print]
9. Shorr AF, Pogue JM, Mohr JF. Intravenous fosfomycin for the treatment of hospitalized patients with serious infections. Expert Rev Anti Infect Ther. 2017 Oct;15(10):935-945. doi: 10.1080/14787210.2017.1379897. Epub 2017 Sep 22.
10. Saiprasad PV, Krishnaprasad K. Exploring the hidden potential of fosfomycin for the fight against severe Gram-negative infections. Indian J Med Microbiol. 2016 Oct-Dec;34(4):416-420.
