Fosfomycin: Pharmacological Prerequisites for Effective Antibiotic Therapy
13.05.2016
Fosfomycin: Pharmacological Prerequisites for Effective Antibiotic Therapy
Today, it can be stated that the problem of antibiotic resistance has affected all areas of healthcare. The enormous financial resources spent annually on the treatment and prevention of infections, the lion's share of which is attributed to antimicrobial drugs, often appear to be ineffective expenditures: the increase in antibiotic consumption leads to an avalanche-like rise in microorganism resistance. It seems that the vicious cycle cannot be broken, especially since in recent decades, the number of new antimicrobial agents entering the market has drastically decreased.
Unfortunately, the costs incurred by companies for the development, research, and marketing of innovative antibiotics are not compensated, and one of the reasons for this is acquired resistance of microorganisms, which outpaces the introduction of new drugs into clinical practice.
Therefore, more and more specialists, in search of a solution, turn to well-known (and sometimes already forgotten) antimicrobial agents, which were once considered to be significantly inferior to newer generations of antibiotics in terms of activity spectrum, safety, and therapy compliance. It is not surprising that today we are witnessing a revival of polymyxins, upgrades of "old" cephalosporins with new beta-lactamase inhibitors, and increased attention to the unique antibiotic fosfomycin.
Fosfomycin was isolated and described in 1969. The bactericidal action of the drug is based on its interaction with targets in the microbial cell, which are not affected by other antimicrobial agents: fosfomycin inhibits the enzyme uridine-diphospho-N-acetylglucosamine-3-O-enolpyruvyltransferase (MurA), which directly participates in the synthesis of bacterial cell wall peptidoglycans—uridine-diphospho-N-acetylmuramic acid from uridine-N-acetylglucosamine.
Fosfomycin has a broad spectrum of antimicrobial activity, including, among others, methicillin-resistant strains of Staphylococcus aureus and Staphylococcus epidermidis, enterococci, pneumococci with multidrug resistance, E. coli, including strains producing plasmid-encoded beta-lactamases, resistant to penicillins and cephalosporins, and K. pneumoniae. According to K. Linsenmeyer et al. [1], among uropathogenic beta-lactamase producers, fosfomycin resistance was found in no more than 19% of cases.
The molecule of fosfomycin has a low molecular weight, allowing the antibiotic to penetrate most tissues and fluids of the body. Its high penetration through the blood-brain barrier has been reliably established, creating bactericidal concentrations in cerebrospinal fluid that exceed the MIC against most sensitive pathogens, with no clinically significant binding to cerebrospinal fluid proteins [2]. Due to its low toxicity, fosfomycin has a rather broad "therapeutic window" and can be administered in high daily doses without the risk of adverse reactions [3].
In the early 2000s, it seemed that the search for promising drugs capable of overcoming acquired microbial resistance had exhausted itself. Scientists recognized the global nature of the antibiotic resistance problem, which, in some countries, had reached the level of a national security threat, but the ways to address it remained unclear. None of the innovative antibiotics were considered a breakthrough in this area, and the potential of the drugs approved for clinical use had been exhausted.
Therefore, the positive results obtained in vitro, in vivo, or in clinical trials using the "old" antibiotic fosfomycin, which is not inferior to, and in some cases exceeds, beta-lactams in terms of safety profile, were met with enthusiasm [4].
Research on fosfomycin, initiated in the 2000s, continued into the next decade of the 21st century. The main directions include optimizing therapy for infections caused by gram-negative multidrug-resistant pathogens and searching for ways to improve treatment efficacy for diseases caused by methicillin-resistant and vancomycin-resistant cocci. Just last year, data emerged showing that fosfomycin is an excellent alternative choice for treating urinary tract infections and prostatitis caused by gram-negative bacteria with multiple resistances [5, 16, 17].
The pronounced synergistic and additive effects of fosfomycin, especially in combinations with antibiotics whose antimicrobial activity is also associated with disruption of bacterial cell structural unit synthesis, are of great practical importance. Recently, research results were presented demonstrating the effectiveness of combinations of fosfomycin + meropenem and fosfomycin + ceftriaxone in eradicating methicillin-resistant Staphylococcus aureus, which also have intermediate sensitivity to glycopeptides, in experimental endocarditis. Importantly, when using these antibiotic combinations, a significantly higher percentage of sterile vegetations on heart valves was achieved compared to the use of vancomycin, both in standard and high-dose regimens [6].
According to a study published in 2016, combining fosfomycin with polymyxin B, tobramycin, or ciprofloxacin showed pronounced antimicrobial synergy against Pseudomonas aeruginosa [7].
These results confirm the feasibility of using combinations of anti-pseudomonal antimicrobial agents with fosfomycin (both for systemic antibiotic therapy and inhalation therapy) for treating infections such as nosocomial pneumonia, including pneumonia in patients on mechanical ventilation, and pulmonary infections in cystic fibrosis patients [8].
With the emergence of Acinetobacter baumannii producing carbapenemases, choosing a drug for treating infections caused by this pathogen presents a significant problem. Moreover, since Acinetobacter baumannii carbapenemase producers have a higher rate of polymyxin resistance, finding alternative antibiotics is essentially an unsolvable task. However, as shown by the results of an in-vitro study conducted by T.C. Menegucci et al. [9], combining fosfomycin with meropenem and/or polymyxin B can significantly optimize pharmacodynamic parameters, including reducing the MIC of the antibiotics in the combinations, thereby achieving the necessary bactericidal effect against polymyxin B-resistant Acinetobacter baumannii strains. The authors emphasize that the pharmacodynamic parameters obtained are not the result of extremely high drug doses (the parameters were modeled using medium therapeutic doses), but rather the synergistic effect of fosfomycin with carbapenem or polymyxin.
When using fosfomycin for the treatment of various bacterial infections, the drug not only exhibits strong bactericidal activity but also potentiates antimicrobial action through its immunomodulatory effect, primarily by stimulating phagocytosis. Additionally, it is capable of penetrating biofilms formed by bacteria around foreign bodies, such as those on catheters and implants [10]. In a recent study, the results presented by F. Shen et al. [11] showed that fosfomycin activated phagocytosis of Staphylococcus aureus by macrophages and neutrophils and provided complete intracellular lysis of bacterial cells.
An undeniable advantage of fosfomycin is the absence of clinically significant pharmacological interactions with other drugs, including those leading to mutual physical-chemical inactivation. These interactions should be considered when prescribing, for example, combined therapy with beta-lactams and aminoglycosides, especially in patients with renal insufficiency, as drug accumulation in biological fluids, including blood plasma, may lead to inactivation of antibiotics in vivo [4, 14].
Thus, today, there are all the prerequisites to consider fosfomycin as an effective and safe alternative antibiotic for treating infections of various localizations caused by pathogens resistant to routinely used antimicrobial drugs. The use of combinations of fosfomycin with other antimicrobial agents will optimize the clinical response to treatment and reduce the doses and duration of the therapy.
References used:
Unfortunately, the costs incurred by companies for the development, research, and marketing of innovative antibiotics are not compensated, and one of the reasons for this is acquired resistance of microorganisms, which outpaces the introduction of new drugs into clinical practice.
Therefore, more and more specialists, in search of a solution, turn to well-known (and sometimes already forgotten) antimicrobial agents, which were once considered to be significantly inferior to newer generations of antibiotics in terms of activity spectrum, safety, and therapy compliance. It is not surprising that today we are witnessing a revival of polymyxins, upgrades of "old" cephalosporins with new beta-lactamase inhibitors, and increased attention to the unique antibiotic fosfomycin.
Fosfomycin was isolated and described in 1969. The bactericidal action of the drug is based on its interaction with targets in the microbial cell, which are not affected by other antimicrobial agents: fosfomycin inhibits the enzyme uridine-diphospho-N-acetylglucosamine-3-O-enolpyruvyltransferase (MurA), which directly participates in the synthesis of bacterial cell wall peptidoglycans—uridine-diphospho-N-acetylmuramic acid from uridine-N-acetylglucosamine.
Fosfomycin has a broad spectrum of antimicrobial activity, including, among others, methicillin-resistant strains of Staphylococcus aureus and Staphylococcus epidermidis, enterococci, pneumococci with multidrug resistance, E. coli, including strains producing plasmid-encoded beta-lactamases, resistant to penicillins and cephalosporins, and K. pneumoniae. According to K. Linsenmeyer et al. [1], among uropathogenic beta-lactamase producers, fosfomycin resistance was found in no more than 19% of cases.
The molecule of fosfomycin has a low molecular weight, allowing the antibiotic to penetrate most tissues and fluids of the body. Its high penetration through the blood-brain barrier has been reliably established, creating bactericidal concentrations in cerebrospinal fluid that exceed the MIC against most sensitive pathogens, with no clinically significant binding to cerebrospinal fluid proteins [2]. Due to its low toxicity, fosfomycin has a rather broad "therapeutic window" and can be administered in high daily doses without the risk of adverse reactions [3].
In the early 2000s, it seemed that the search for promising drugs capable of overcoming acquired microbial resistance had exhausted itself. Scientists recognized the global nature of the antibiotic resistance problem, which, in some countries, had reached the level of a national security threat, but the ways to address it remained unclear. None of the innovative antibiotics were considered a breakthrough in this area, and the potential of the drugs approved for clinical use had been exhausted.
Therefore, the positive results obtained in vitro, in vivo, or in clinical trials using the "old" antibiotic fosfomycin, which is not inferior to, and in some cases exceeds, beta-lactams in terms of safety profile, were met with enthusiasm [4].
Research on fosfomycin, initiated in the 2000s, continued into the next decade of the 21st century. The main directions include optimizing therapy for infections caused by gram-negative multidrug-resistant pathogens and searching for ways to improve treatment efficacy for diseases caused by methicillin-resistant and vancomycin-resistant cocci. Just last year, data emerged showing that fosfomycin is an excellent alternative choice for treating urinary tract infections and prostatitis caused by gram-negative bacteria with multiple resistances [5, 16, 17].
The pronounced synergistic and additive effects of fosfomycin, especially in combinations with antibiotics whose antimicrobial activity is also associated with disruption of bacterial cell structural unit synthesis, are of great practical importance. Recently, research results were presented demonstrating the effectiveness of combinations of fosfomycin + meropenem and fosfomycin + ceftriaxone in eradicating methicillin-resistant Staphylococcus aureus, which also have intermediate sensitivity to glycopeptides, in experimental endocarditis. Importantly, when using these antibiotic combinations, a significantly higher percentage of sterile vegetations on heart valves was achieved compared to the use of vancomycin, both in standard and high-dose regimens [6].
According to a study published in 2016, combining fosfomycin with polymyxin B, tobramycin, or ciprofloxacin showed pronounced antimicrobial synergy against Pseudomonas aeruginosa [7].
These results confirm the feasibility of using combinations of anti-pseudomonal antimicrobial agents with fosfomycin (both for systemic antibiotic therapy and inhalation therapy) for treating infections such as nosocomial pneumonia, including pneumonia in patients on mechanical ventilation, and pulmonary infections in cystic fibrosis patients [8].
With the emergence of Acinetobacter baumannii producing carbapenemases, choosing a drug for treating infections caused by this pathogen presents a significant problem. Moreover, since Acinetobacter baumannii carbapenemase producers have a higher rate of polymyxin resistance, finding alternative antibiotics is essentially an unsolvable task. However, as shown by the results of an in-vitro study conducted by T.C. Menegucci et al. [9], combining fosfomycin with meropenem and/or polymyxin B can significantly optimize pharmacodynamic parameters, including reducing the MIC of the antibiotics in the combinations, thereby achieving the necessary bactericidal effect against polymyxin B-resistant Acinetobacter baumannii strains. The authors emphasize that the pharmacodynamic parameters obtained are not the result of extremely high drug doses (the parameters were modeled using medium therapeutic doses), but rather the synergistic effect of fosfomycin with carbapenem or polymyxin.
When using fosfomycin for the treatment of various bacterial infections, the drug not only exhibits strong bactericidal activity but also potentiates antimicrobial action through its immunomodulatory effect, primarily by stimulating phagocytosis. Additionally, it is capable of penetrating biofilms formed by bacteria around foreign bodies, such as those on catheters and implants [10]. In a recent study, the results presented by F. Shen et al. [11] showed that fosfomycin activated phagocytosis of Staphylococcus aureus by macrophages and neutrophils and provided complete intracellular lysis of bacterial cells.
An undeniable advantage of fosfomycin is the absence of clinically significant pharmacological interactions with other drugs, including those leading to mutual physical-chemical inactivation. These interactions should be considered when prescribing, for example, combined therapy with beta-lactams and aminoglycosides, especially in patients with renal insufficiency, as drug accumulation in biological fluids, including blood plasma, may lead to inactivation of antibiotics in vivo [4, 14].
Thus, today, there are all the prerequisites to consider fosfomycin as an effective and safe alternative antibiotic for treating infections of various localizations caused by pathogens resistant to routinely used antimicrobial drugs. The use of combinations of fosfomycin with other antimicrobial agents will optimize the clinical response to treatment and reduce the doses and duration of the therapy.
References used:
- Linsenmeyer K, Strymish J, Weir S, Berg G, Brecher S, Gupta K. Activity of Fosfomycin against Extended-Spectrum-β-Lactamase-Producing Uropathogens in Patients in the Community and Hospitalized Patients.Antimicrob Agents Chemother. 2015 Nov 23;60(2):1134-6.
- Matzneller P, Burian A, Zeitlinger M, Sauermann R. Understanding the Activity of Antibiotics in Cerebrospinal Fluid in vitro.Pharmacology. 2016;97(5-6):233-44.
- Sastry S, Doi Y. Fosfomycin: Resurgence of an old companion.J Infect Chemother. 2016 May;22(5):273-80.
- Falagas ME, Vouloumanou EK, Samonis G, Vardakas KZ. Fosfomycin. ClinMicrobiol Rev. 2016 Apr;29(2):321-47. doi: 10.1128/CMR.00068-15.
- Schaeffer EM. Re: Is Fosfomycin a Potential Treatment Alternative for Multidrug-Resistant Gram-Negative Prostatitis?J Urol. 2015 Dec;194(6):1642.
- del Río A, García-de-la-Mària C1, Entenza JM, Gasch O, Armero Y, Soy D, Mestres CA, Pericás JM, Falces C, Ninot S, Almela M, Cervera C, Gatell JM, Moreno A, Moreillon P, Marco F, Miró JM; Hospital Clinic Experimental Endocarditis Study Group. Fosfomycin plus β-Lactams as Synergistic Bactericidal Combinations for Experimental Endocarditis Due to Methicillin-Resistant and Glycopeptide-Intermediate Staphylococcus aureus.Antimicrob Agents Chemother. 2015 Nov 2;60(1):478-86.
- Walsh CC, Landersdorfer CB, McIntosh MP, Peleg AY, Hirsch EB, Kirkpatrick CM, Bergen PJ. Clinically relevant concentrations of fosfomycin combined with polymyxin B, tobramycin or ciprofloxacin enhance bacterial killing of Pseudomonas aeruginosa, but do not suppress the emergence of fosfomycin resistance.J AntimicrobChemother. 2016 Apr 26. [Epub ahead of print]
- Montgomery AB, Vallance S, Abuan T, Tservistas M, Davies A. A randomized double-blind placebo-controlled dose-escalation phase 1 study of aerosolized amikacin and fosfomycin delivered via the PARI investigational eFlow® inline nebulizer system in mechanically ventilated patients. J Aerosol Med Pulm Drug Deliv. 2014 Dec;27(6):441-8.
- Menegucci TC, Albiero J, Migliorini LB, Alves JL, Viana GF, Mazucheli J, Carrara-Marroni FE, Cardoso CL, Tognim MC. Strategies for the treatment of polymyxin B-resistant Acinetobacter baumanniiinfections.Int J Antimicrob Agents. 2016 Apr 5. [Epub ahead of print]
- Shi J, Mao NF, Wang L, Zhang HB, Chen Q, Liu H, Tang X, Jin T, Zhu CT, Li FB, Sun LH, Xu XM, Xu YQ.Efficacy of combined vancomycin and fosfomycin against methicillin-resistant Staphylococcus aureus in biofilms in vivo. PLoS One. 2014 Dec 31;9(12):e113133.
- Shen F, Tang X, Cheng W, Wang Y, Wang C, Shi X, An Y, Zhang Q, Liu M,4, Liu B, Yu L. Fosfomycin enhances phagocyte-mediated killing of Staphylococcus aureus by extracellular traps and reactive oxygen species.Sci Rep. 2016 Jan 18;6:19262.
- DiCicco M, Neethirajan S, Weese JS, Singh A. In vitro synergism of fosfomycin and clarithromycin antimicrobials against methicillin-resistant Staphylococcus pseudintermedius. BMC Microbiol. 2014 May 19;14:129.
- Taneja N, Kaur H. Insights into Newer Antimicrobial Agents Against Gram-negative Bacteria.Microbiol Insights. 2016 Mar 20;9:9-19.
- Sastry S, Doi Y. Fosfomycin: Resurgence of an old companion.JInfectChemother. 2016 May;22(5):273-80.
- Yılmaz N, Ağuş N, Bayram A, Şamlıoğlu P, Şirin MC, Derici YK, Hancı SY. Antimicrobial susceptibilities of Escherichia coli isolates as agents of community-acquired urinary tract infection (2008-2014). Turk J Urol. 2016 Mar;42(1):32-6.
- Sultan A, Rizvi M, Khan F, Sami H, Shukla I, Khan HM. Increasing antimicrobial resistance among uropathogens: Is fosfomycin the answer? UrolAnn. 2015 Jan-Mar;7(1):26-30.
- Sabharwal ER, Sharma R. Fosfomycin: An Alternative Therapy for the Treatment of UTI Amidst Escalating Antimicrobial Resistance. J ClinDiagnRes. 2015 Dec;9(12):DC06-9.
