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Clinical Microbiology Reviews Apr 2016The treatment of bacterial infections suffers from two major problems: spread of multidrug-resistant (MDR) or extensively drug-resistant (XDR) pathogens and lack of... (Review)
Review
The treatment of bacterial infections suffers from two major problems: spread of multidrug-resistant (MDR) or extensively drug-resistant (XDR) pathogens and lack of development of new antibiotics active against such MDR and XDR bacteria. As a result, physicians have turned to older antibiotics, such as polymyxins, tetracyclines, and aminoglycosides. Lately, due to development of resistance to these agents, fosfomycin has gained attention, as it has remained active against both Gram-positive and Gram-negative MDR and XDR bacteria. New data of higher quality have become available, and several issues were clarified further. In this review, we summarize the available fosfomycin data regarding pharmacokinetic and pharmacodynamic properties, the in vitro activity against susceptible and antibiotic-resistant bacteria, mechanisms of resistance and development of resistance during treatment, synergy and antagonism with other antibiotics, clinical effectiveness, and adverse events. Issues that need to be studied further are also discussed.
Topics: Anti-Bacterial Agents; Drug Antagonism; Drug Resistance, Multiple, Bacterial; Drug Synergism; Fosfomycin; Gram-Negative Bacteria; Gram-Positive Bacteria; Microbial Sensitivity Tests
PubMed: 26960938
DOI: 10.1128/CMR.00068-15 -
JAMA May 2018The use of nitrofurantoin and fosfomycin has increased since guidelines began recommending them as first-line therapy for lower urinary tract infection (UTI). (Comparative Study)
Comparative Study Randomized Controlled Trial
IMPORTANCE
The use of nitrofurantoin and fosfomycin has increased since guidelines began recommending them as first-line therapy for lower urinary tract infection (UTI).
OBJECTIVE
To compare the clinical and microbiologic efficacy of nitrofurantoin and fosfomycin in women with uncomplicated cystitis.
DESIGN, SETTING, AND PARTICIPANTS
Multinational, open-label, analyst-blinded, randomized clinical trial including 513 nonpregnant women aged 18 years and older with symptoms of lower UTI (dysuria, urgency, frequency, or suprapubic tenderness), a positive urine dipstick result (with detection of nitrites or leukocyte esterase), and no known colonization or previous infection with uropathogens resistant to the study antibiotics. Recruitment took place from October 2013 through April 2017 at hospital units and outpatient clinics in Geneva, Switzerland; Lodz, Poland; and Petah-Tiqva, Israel.
INTERVENTIONS
Participants were randomized in a 1:1 ratio to oral nitrofurantoin, 100 mg 3 times a day for 5 days (n = 255), or a single 3-g dose of oral fosfomycin (n = 258). They returned 14 and 28 days after therapy completion for clinical evaluation and urine culture collection.
MAIN OUTCOMES AND MEASURES
The primary outcome was clinical response in the 28 days following therapy completion, defined as clinical resolution (complete resolution of symptoms and signs of UTI without prior failure), failure (need for additional or change in antibiotic treatment due to UTI or discontinuation due to lack of efficacy), or indeterminate (persistence of symptoms without objective evidence of infection). Secondary outcomes included bacteriologic response and incidence of adverse events.
RESULTS
Among 513 patients who were randomized (median age, 44 years [interquartile range, 31-64]), 475 (93%) completed the trial and 377 (73%) had a confirmed positive baseline culture. Clinical resolution through day 28 was achieved in 171 of 244 patients (70%) receiving nitrofurantoin vs 139 of 241 patients (58%) receiving fosfomycin (difference, 12% [95% CI, 4%-21%]; P = .004). Microbiologic resolution occurred in 129 of 175 (74%) vs 103 of 163 (63%), respectively (difference, 11% [95% CI, 1%-20%]; P = .04). Adverse events were few and primarily gastrointestinal; the most common were nausea and diarrhea (7/248 [3%] and 3/248 [1%] in the nitrofurantoin group vs 5/247 [2%] and 5/247 [1%] in the fosfomycin group, respectively).
CONCLUSIONS AND RELEVANCE
Among women with uncomplicated UTI, 5-day nitrofurantoin, compared with single-dose fosfomycin, resulted in a significantly greater likelihood of clinical and microbiologic resolution at 28 days after therapy completion.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT01966653.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-Infective Agents, Urinary; Drug Administration Schedule; Drug Resistance, Bacterial; Female; Fosfomycin; Humans; Middle Aged; Nitrofurantoin; Treatment Outcome; Urinary Tract Infections; Urine; Young Adult
PubMed: 29710295
DOI: 10.1001/jama.2018.3627 -
Clinical Infectious Diseases : An... May 2021We aimed to determine whether daptomycin plus fosfomycin provides higher treatment success than daptomycin alone for methicillin-resistant Staphylococcus aureus (MRSA)... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
We aimed to determine whether daptomycin plus fosfomycin provides higher treatment success than daptomycin alone for methicillin-resistant Staphylococcus aureus (MRSA) bacteremia and endocarditis.
METHODS
A randomized (1:1) phase 3 superiority, open-label, and parallel group clinical trial of adult inpatients with MRSA bacteremia was conducted at 18 Spanish hospitals. Patients were randomly assigned to receive either 10 mg/kg of daptomycin intravenously daily plus 2 g of fosfomycin intravenously every 6 hours, or 10 mg/kg of daptomycin intravenously daily. Primary endpoint was treatment success 6 weeks after the end of therapy.
RESULTS
Of 167 patients randomized, 155 completed the trial and were assessed for the primary endpoint. Treatment success at 6 weeks after the end of therapy was achieved in 40 of 74 patients who received daptomycin plus fosfomycin and in 34 of 81 patients who were given daptomycin alone (54.1% vs 42.0%; relative risk, 1.29 [95% confidence interval, .93-1.8]; P = .135). At 6 weeks, daptomycin plus fosfomycin was associated with lower microbiologic failure (0 vs 9 patients; P = .003) and lower complicated bacteremia (16.2% vs 32.1%; P = .022). Adverse events leading to treatment discontinuation occurred in 13 of 74 patients (17.6%) receiving daptomycin plus fosfomycin, and in 4 of 81 patients (4.9%) receiving daptomycin alone (P = .018).
CONCLUSIONS
Daptomycin plus fosfomycin provided 12% higher rate of treatment success than daptomycin alone, but this difference did not reach statistical significance. This antibiotic combination prevented microbiological failure and complicated bacteremia, but it was more often associated with adverse events.
CLINICAL TRIALS REGISTRATION
NCT01898338.
Topics: Adult; Anti-Bacterial Agents; Bacteremia; Daptomycin; Endocarditis; Fosfomycin; Humans; Methicillin-Resistant Staphylococcus aureus; Staphylococcal Infections; Treatment Outcome
PubMed: 32725216
DOI: 10.1093/cid/ciaa1081 -
Cold Spring Harbor Perspectives in... Feb 2017Fosfomycin, a natural product antibiotic, has been in use for >20 years in Spain, Germany, France, Japan, Brazil, and South Africa for urinary tract infections (UTIs)... (Review)
Review
Fosfomycin, a natural product antibiotic, has been in use for >20 years in Spain, Germany, France, Japan, Brazil, and South Africa for urinary tract infections (UTIs) and other indications and was registered in the United States for the oral treatment of uncomplicated UTIs because of Enterococcus faecalis and Escherichia coli in 1996. It has a broad spectrum, is bactericidal, has very low toxicity, and acts as a time-dependent inhibitor of the MurA enzyme, which catalyzes the first committed step of peptidoglycan synthesis. Whereas resistance to fosfomycin arises rapidly in vitro through loss of active transport mechanisms, resistance is rarely seen during therapy of UTIs, seemingly because of the low fitness of the resistant organisms. Recently, interest has grown in the use of fosfomycin against multidrug-resistant (MDR) pathogens in other indications, prompting the advent of development in the United States of a parenteral formulation for use, initially, in complicated UTIs. Whereas resistance has not been problematic in the uncomplicated UTI setting, it remains to be seen whether resistance remains at bay with expansion to other indications.
Topics: Administration, Oral; Anti-Bacterial Agents; Drug Resistance, Multiple, Bacterial; Fosfomycin; Humans; Microbial Sensitivity Tests; Urinary Tract Infections
PubMed: 28062557
DOI: 10.1101/cshperspect.a025262 -
Revista Espanola de Quimioterapia :... May 2019Due to the increase in antimicrobial resistance, strategies such as antimicrobial stewardship programs (ASP) have been developed to improve the clinical results,... (Review)
Review
Due to the increase in antimicrobial resistance, strategies such as antimicrobial stewardship programs (ASP) have been developed to improve the clinical results, decrease the adverse effects and the development of resistances and ensure cost-effective therapies. Fosfomycin has a unique mechanism of action against Gram-positive and Gram-negative bacteria. Cross-resistance is uncommon; however, fosfomycin should be used in combination in severe infections to avoid selecting resistant mutations. Fosfomycin's oral formulation facilitates sequential treatment, has low toxicity and high tissue penetration, even in the central nervous system and bone. Fosfomycin is active against resistant Gram-positive bacteria such as methicillin-resistant Staphylococcus aureus (MRSA), vancomycin- resistant enterococci and penicillin-resistant Streptococcus pneumoniae, as well as against resistant Gram-negative bacteria such as extended-spectrum beta-lactamase-producing and carbapenemase-producing enterobacteria. Fosfomycin is therefore useful for cases of persistent bacteremia, skin and soft tissue infections, as a glycopeptide-sparing and carbapenem-sparing drug for healthcare-associated infections and for polymicrobial infections. Published studies have demonstrated the synergy between fosfomycin and beta-lactams, daptomycin and glycopeptides against MSSA and MRSA; with linezolid in biofilm-associated infections and with aminoglycosides and colistin against Gram-negative bacteria, providing a nephroprotective effect.
Topics: Animals; Anti-Bacterial Agents; Antimicrobial Stewardship; Bacterial Infections; Drug Resistance, Multiple, Bacterial; Fosfomycin; Gram-Negative Bacterial Infections; Gram-Positive Bacterial Infections; Humans
PubMed: 31131594
DOI: No ID Found -
Revista Espanola de Quimioterapia :... May 2019Fosfomycin, a low molecular weight and hydrophilic drug with negligible protein binding, is eliminated almost exclusively by glomerular filtration, whose clearance is... (Review)
Review
Fosfomycin, a low molecular weight and hydrophilic drug with negligible protein binding, is eliminated almost exclusively by glomerular filtration, whose clearance is subject to patient renal function. The volume of distribution approximates to the extracellular body water (about 0.3 L/Kg) in healthy volunteers, but it is increased in critically ill patients with bacterial infections. Fosfomycin presents a high ability to distribute into many tissues, including inflamed tissues and abscess fluids. Based on PK/PD analysis and Monte Carlo simulations, we have evaluated different fosfomycin dosing regimen to optimize the treatment of septic patients due to Enterobacterales and Pseudomonas aeruginosa. As PK/PD targets, we selected %T>MIC > 70% for all pathogens, and AUC24/MIC > 24 and AUC24/MIC > 15 for net stasis of Enterobacterales and P. aeruginosa, respectively. Pharmacokinetic parameters in critically ill patients were obtained from the literature. Several dosing regimens were studied in patients with normal renal function: fosfomycin 2-8 g given every 6-12 hours, infused over 30 minutes- 24 hours. At the susceptibility EUCAST breakpoint for Enterobacterales and Staphylococcus spp. (MIC ≤ 32 mg/L), fosfomycin 4 g/8h or higher infused over 30 minutes achieved a probability of target attainment (PTA) > 90%, based in both %T>MIC and AUC24/MIC. For MIC of 64 mg/L, fosfomycin 6 g/6h in 30-minute infusion and 8 g/ 8h in 30-minute and 6 hours infusions also achieved PTA values higher than 90%. No fosfomycin monotherapy regimen was able to achieve PK/PD targets related to antimicrobial efficacy for P. aeruginosa with MICs of 256-512 mg/L.
Topics: Animals; Anti-Bacterial Agents; Bacterial Infections; Fosfomycin; Humans
PubMed: 31131588
DOI: No ID Found -
International Journal of Infectious... Nov 2011Fosfomycin, originally named phosphonomycin, was discovered in Spain in 1969. There are three forms of fosfomycin: fosfomycin tromethamine (a soluble salt) and... (Review)
Review
Fosfomycin, originally named phosphonomycin, was discovered in Spain in 1969. There are three forms of fosfomycin: fosfomycin tromethamine (a soluble salt) and fosfomycin calcium for oral use, and fosfomycin disodium for intravenous use. Fosfomycin is a bactericidal antibiotic that interferes with cell wall synthesis in both Gram-positive and Gram-negative bacteria by inhibiting the initial step involving phosphoenolpyruvate synthetase. It has a broad spectrum of activity against a wide range of Gram-positive and Gram-negative bacteria. It is highly active against Gram-positive pathogens such as Staphylococcus aureus and Enterococcus, and against Gram-negative bacteria such as Pseudomonas aeruginosa and Klebsiella pneumoniae. Its unique mechanism of action may provide a synergistic effect to other classes of antibiotics including beta-lactams, aminoglycosides, and fluoroquinolones. Oral fosfomycin is mainly used in the treatment of urinary tract infections, particularly those caused by Escherichia coli and Enterococcus faecalis. Intravenous fosfomycin has been administered in combination with other antibiotics for the treatment of nosocomial infections due to multidrug-resistant (MDR) Gram-positive and Gram-negative bacteria. Fosfomycin has good distribution into tissues, achieving clinically relevant concentrations in serum, kidneys, bladder wall, prostate, lungs, inflamed tissues, bone, cerebrospinal fluid, abscess fluid, and heart valves. Fosfomycin is well tolerated, with a low incidence of adverse events. Further randomized controlled trials are needed in order to evaluate the efficacy of intravenous fosfomycin for the management of nosocomial infections due to MDR pathogens.
Topics: Anti-Bacterial Agents; Cross Infection; Enterococcus faecalis; Escherichia coli; Fosfomycin; Gram-Negative Bacterial Infections; Gram-Positive Bacterial Infections; Humans; Klebsiella pneumoniae; Pseudomonas aeruginosa; Urinary Tract Infections
PubMed: 21945848
DOI: 10.1016/j.ijid.2011.07.007 -
Revista Espanola de Quimioterapia :... May 2019The discovery of fosfomycin more than 40 years ago was an important milestone in antibiotic therapy. The antibiotic's usefulness, alone or in combination, for treating... (Review)
Review
The discovery of fosfomycin more than 40 years ago was an important milestone in antibiotic therapy. The antibiotic's usefulness, alone or in combination, for treating infections caused by multidrug-resistant microorganisms is clearer than ever. Both the European Medicines Agency and the US Food and Drug Administration have open processes for reviewing the accumulated information on the use of fosfomycin and the information from new clinical trials on this compound. The agencies' objectives are to establish common usage criteria for Europe and authorize the sale of fosfomycin in the US, respectively. Fosfomycin's single mechanism of action results in no cross-resistance with other antibiotics. However, various fosfomycin-resistance mechanisms have been described, the most important of which, from the epidemiological standpoint, is enzymatic inactivation, which is essentially associated with a gene carrying a fosA3-harboring plasmid. Fosfomycin has been found more frequently in Asia in extended-spectrum beta-lactamase-producing and carbapenemase-producing Enterobacterales. Although fosfomycin presents lower intrinsic activity against Pseudomonas aeruginosa compared with that presented against Escherichia coli, fosfomycin's activity has been demonstrated in biofilms, especially in combination with aminoglycosides. The current positioning of fosfomycin in the therapeutic arsenal for the treatment of infections caused by multidrug-resistant microorganisms requires new efforts to deepen our understanding of this compound, including those related to the laboratory methods employed in the antimicrobial susceptibility testing study.
Topics: Animals; Anti-Bacterial Agents; Bacteria; Bacterial Infections; Drug Resistance, Bacterial; Fosfomycin; Humans; Microbial Sensitivity Tests
PubMed: 31131587
DOI: No ID Found -
Antimicrobial Agents and Chemotherapy Feb 2022Multidrug-resistant (MDR) Pseudomonas aeruginosa presents a serious threat to public health due to its widespread resistance to numerous antibiotics. P. aeruginosa... (Review)
Review
Multidrug-resistant (MDR) Pseudomonas aeruginosa presents a serious threat to public health due to its widespread resistance to numerous antibiotics. P. aeruginosa commonly causes nosocomial infections including urinary tract infections (UTI) which have become increasingly difficult to treat. The lack of effective therapeutic agents has renewed interest in fosfomycin, an old drug discovered in the 1960s and approved prior to the rigorous standards now required for drug approval. Fosfomycin has a unique structure and mechanism of action, making it a favorable therapeutic alternative for MDR pathogens that are resistant to other classes of antibiotics. The absence of susceptibility breakpoints for fosfomycin against P. aeruginosa limits its clinical use and interpretation due to extrapolation of breakpoints established for Escherichia coli or without supporting evidence. Furthermore, fosfomycin use and efficacy for treatment of P. aeruginosa are also limited by both inherent and acquired resistance mechanisms. This narrative review provides an update on currently identified mechanisms of resistance to fosfomycin, with a focus on those mediated by P. aeruginosa such as peptidoglycan recycling enzymes, chromosomal Fos enzymes, and transporter mutation. Additional fosfomycin resistance mechanisms exhibited by , including mutations in transporters and associated regulators, plasmid-mediated Fos enzymes, kinases, and modification, are also summarized and contrasted. These data highlight that different fosfomycin resistance mechanisms may be associated with elevated MIC values in P. aeruginosa compared to , emphasizing that extrapolation of E. coli breakpoints to P. aeruginosa should be avoided.
Topics: Anti-Bacterial Agents; Escherichia coli; Fosfomycin; Microbial Sensitivity Tests; Pseudomonas aeruginosa
PubMed: 34807759
DOI: 10.1128/AAC.01446-21 -
Archivos Espanoles de Urologia Aug 2022Fosfomycin has been with us for more than 50 years; however the history of its discovery is largely unknown. The objective of this article is to recover and make known... (Review)
Review
INTRODUCTION AND OBJECTIVES
Fosfomycin has been with us for more than 50 years; however the history of its discovery is largely unknown. The objective of this article is to recover and make known its lost history.
MATERIAL AND METHODS
Retrospective review study on the history of the discovery of fosfomycin based on articles and documents located in Medline/PubMed and Google between 1945 and 2020. For the search of articles in PubMed the MeSH keywords fosfomycin OR fosfomycin history, fosfomycin discovery, , and in Google the free terms; fosfomycin, fosfomycin history, fosfomycin discovery, were used. All the papers found were reviewed and those containing any historical review of interest to this research were selected for study.
RESULTS
We found 3500 articles on fosfomycin, of which 32 (0.9%) dealt with some aspect related to its discovery, and 21 corresponded to its history (0.6%), divided between 13 publications and 7 press releases, 8 to the genus (0.2%) and 3 to fosfomycin (0.1%).
CONCLUSIONS
The story of the discovery of fosfomycin begins with the finding of the bacterium in a soil sample from mount Montgó between Dénia and Jávea (Alicante). There is little published literature and the existing one is mostly incomplete. Some medical publications and press releases have made it possible to recover its history.
Topics: Fosfomycin; Humans; Soil; Streptomyces
PubMed: 36138496
DOI: 10.56434/j.arch.esp.urol.20227506.72