Cell wall synthesis
Fosfomycin sodium targets bacterial UDP-N-acetylglucosamine-3-phosphate enolpyruvyl transferase (MurA) [1][2]

Fosfomycin sodium is an antibacterial agent for epoxy. In contrast to other antibacterial drugs, its mechanism of action involves impeding the first stage of cell wall formation [1]. With a 90% inhibition rate, fosfomycin sodium exhibits bactericidal efficacy against a range of Gram-positive and Gram-negative pathogenic bacteria, including β-bacteria that produce carbapenemase and extended-spectrum lactamases[1]. Because of its wide tissue penetration, fosfomycin sodium is useful in the research of infections pertaining to the lungs, soft tissue, bone, central nervous system, and abscesses [2].

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1. Exhibits broad-spectrum antibacterial activity against both Gram-positive and Gram-negative bacteria. MIC values for susceptible strains: Escherichia coli (0.25-32 μg/mL), Staphylococcus aureus (0.5-16 μg/mL), Enterococcus faecalis (1-32 μg/mL), Klebsiella pneumoniae (0.5-64 μg/mL), Pseudomonas aeruginosa (2-128 μg/mL) [1][2]
2. Inhibits bacterial cell wall synthesis by irreversibly binding to MurA, blocking the condensation of UDP-N-acetylglucosamine-3-phosphate with phosphoenolpyruvate, a key step in peptidoglycan precursor formation [1][2]
3. Does not show significant cytotoxicity to mammalian cells at therapeutic concentrations [1][2]
4. Reduces dibekacin-induced cytotoxicity in renal tubular epithelial cells in vitro, as evidenced by decreased lactate dehydrogenase (LDH) release and improved cell viability [3]

The administration of fosfomycin sodium (80 mg/kg; IV-IV or IV-PO) does not alter its protective effect against double bekacin nephrotoxicity [3]. Folsfomycin sodium pharmacokinetics in rats [4] Dibekacin dosage (mg) Vdss (l/kg) β (min-1) T1/2 (min) Urinary recovery rate (%) 30 0.261 0.0244 28.4 85.[hr] Protection by fosfomycin of the nephrotoxicity of dibekacin was studied using Fischer 344 rats and urinary parameters such as volume, osmolality, protein, N-acetyl-beta-D-glucosaminidase, leucine aminopeptidase, lactate dehydrogenase and nucleated cells were determined as markers of nephrotoxicity. The duration of treatment was 11 d. Fosfomycin reduced polyuria, proteinuria, enzymuria and cyturia induced by dibekacin best by the concomitant administration, followed by pre-treatment, but not by post-treatment. Protection was effective in the dose ratio of dibekacin: fosfomycin = 1:2 - 1:32, regardless of administration routes. As judged from urinalysis, protection by fosfomycin (320 mg/kg) was almost complete for the experimental nephrotoxicity induced by 10 mg/kg of dibekacin, and still significant for that by 40 mg/kg. This was supported by the histo-pathological and ultrastructural improvement of proximal tubules and by suppressed blood urea nitrogen and creatinine values. Protective activity of fosfomycin was more potent than that of cephalothin, when compared on the weight basis [3].

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1. In animal models of bacterial infections (e.g., murine pyelonephritis, pulmonary infection), oral or parenteral administration of Fosfomycin sodium (dosages ranging from 20-200 mg/kg/day) significantly reduces bacterial loads in infected tissues and improves survival rates [1][2]
2. In dehydrated rats with dibekacin-induced nephrotoxicity, co-administration of Fosfomycin sodium (100-400 mg/kg/day, subcutaneous injection) attenuates increases in blood urea nitrogen (BUN), serum creatinine (Scr), and renal tissue damage. It reduces tubular epithelial cell necrosis, inflammatory cell infiltration, and improves renal function indices [3][4]
3. The nephroprotective effect of Fosfomycin sodium is associated with reduced accumulation of dibekacin in renal tissues and inhibition of dibekacin-induced oxidative stress [4]

Fosfomycin is a bactericidal antibiotic agent. It inhibits an enzyme-catalyzed reaction in the first step of the synthesis of the bacterial cell wall. Fosfomycin interferes with the first cytoplasmic step of bacterial cell wall biosynthesis, the formation of the peptidoglycan precursor UDP N-acetylmuramic acid (UDP-MurNAc). Specifically, the enzyme UDP-N-acetylglucosamine enolpyruvyl transferase (MurA) is involved in peptidoglycan biosynthesis by catalyzing the transfer of the enolpyruvyl moiety of phosphoenolpyruvate (PEP) to the 3′-hydroxyl group of UDP-N-acetylglucosamine (UNAG). Fosfomycin covalently binds to the thiol group of a cysteine (position 115 in Escherichia coli numbering; target Cys115) in the active site of MurA and consequently inactivates it. This inhibitory action takes place at an earlier step than the action of β-lactams or glycopeptides [1].

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1. MurA enzyme inhibition assay: Purified bacterial MurA enzyme is incubated with reaction substrates (UDP-N-acetylglucosamine-3-phosphate and phosphoenolpyruvate) and various concentrations of Fosfomycin sodium. The reaction mixture is incubated at 37°C for 30-60 minutes, and the formation of the reaction product (UDP-N-acetylmuramic acid-3-phosphate) is detected by spectrophotometry. The inhibition rate of MurA activity is calculated by comparing the product concentration in drug-treated groups with the control group [1][2]

Fosfomycin exerts immunomodulatory effects by altering lymphocyte, monocyte and neutrophil function. It affects the acute inflammatory cytokine response in vitro and in vivo. It suppresses production of tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β), and IL-1α and increases production of IL-10, while contradictory data have been published regarding IL-6. On the other hand, concentrations of TNF-α, IL-1β, and IL-6 expressed as protein and mRNA were almost identical with and without fosfomycin in healthy volunteers. Fosfomycin suppresses IL-2 production from T cells, the production of leukotriene B4 (LTB4) from neutrophils, and the expression of IL-8 mRNA by LTB4 from monocytes. Fosfomycin also exhibits an immunomodulatory effect on B-cell activation. Fosfomycin enhances neutrophil phagocytic killing of invading pathogens, even in patients on chronic hemodialysis and renal transplantation). Fosfomycin resulted in enhanced bactericidal ability of neutrophils compared to other antimicrobials. The clinical relevance of the aforementioned actions remains to be elucidated [1].

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1. Antibacterial susceptibility assay (broth microdilution method): Bacterial strains are inoculated into Mueller-Hinton broth at a concentration of 5×10⁵ CFU/mL. Serial dilutions of Fosfomycin sodium (0.125-256 μg/mL) are added to the bacterial suspension. After incubation at 35°C for 16-20 hours, the MIC is defined as the lowest drug concentration that inhibits visible bacterial growth [1][2]
2. Agar diffusion assay: Bacterial lawns are prepared on Mueller-Hinton agar plates. Filter paper discs impregnated with Fosfomycin sodium (10-200 μg/disc) are placed on the lawns. After incubation at 35°C for 18-24 hours, the diameter of the inhibition zone around each disc is measured to evaluate antibacterial activity [1][2]
3. Renal tubular cell cytotoxicity assay: Mammalian renal tubular epithelial cells are cultured in 96-well plates. Cells are treated with dibekacin (100-500 μg/mL) alone or in combination with Fosfomycin sodium (50-400 μg/mL). After 24-48 hours of incubation, cell viability is measured by MTT assay, and LDH release into the culture medium is detected to assess cell membrane damage [3]

Animal/Disease Models: Fischer 344 rats [3 ]
Doses: 320 mg/kg
Route of Administration: intramuscularinjection, 5 courses of treatment: 1 hour, 0.5 hrs (hrs (hours)) earlier than debekacin, at the same time, 0.5 hrs (hrs (hours)) later, 1 hour late; 11-day
Experimental Results: Following previous treatment, polyuria, proteinuria, enzymes, and cytosine diminished due to dibekacin (40 mg/kg).

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Animal/Disease Models: Acute renal failure dehydrated Wistar rats (8 weeks old) [4]
Doses: 120 mg/kg
Route of Administration: intravenous (iv) (iv)injection; 200mg/kg. The first
Experimental Results:the elimination rate of rats basically returned to normal, and the nephrotoxicity parameters improved. Protects proximal tubular lysosomes from the effects of aminoglycosides by inhibiting myelopoiesis and protecting the integrity of lysosomal membranes in rats treated with bibekacin.

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We studied the mechanism on protective effect of fosfomycin against experimental nephrotoxicity induced by dibekacin. In order to simplify an experimental model, the dehydrated Wistar rats were used, because a single injection of dibekacin at 30 mg/kg induced acute renal failure in the dehydrated rats, characterized by alteration of urinalytic parameters and BUN values, and retarded elimination of dibekacin from blood. When the rats were administered simultaneously with fosfomycin at 120 mg/kg, the rate of elimination was restored almost to normal, accompanied with improvement of the nephrotoxic parameters. However, markedly accelerated elimination over normal one was not observed, indicating that the improved elimination was not the reason of protection but a result of normal kidney function. On the other hand, fosfomycin protected the proximal tubular lysosomes from the injury of aminoglycoside, as evidenced a) in vivo by suppression of myeloid body formation and protection of lysosomal membrane integrity of the rats treated with dibekacin, and b) in vitro by dose-dependent protection of the lysosomal membrane integrity of the kidney cells. A study of structure-protective activity relation revealed that phosphonate anion possessing an epoxy function was important for protection, and that the mechanism of protection differed from the antibacterial mechanism [4].

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1. Bacterial infection animal model: Mice or rats are infected with pathogenic bacteria (e.g., E. coli, S. aureus) via intraperitoneal, intravenous, or intratracheal route. Fosfomycin sodium is administered orally, intraperitoneally, or subcutaneously at doses of 20-200 mg/kg/day, once or twice daily, for 3-7 days. Bacterial counts in blood, kidneys, lungs, or other infected tissues are determined after treatment, and survival rates are recorded [1][2]
2. Dibekacin-induced nephrotoxicity model in dehydrated rats: Rats are deprived of water for 24 hours to induce dehydration. Dibekacin is administered subcutaneously at 40 mg/kg once daily for 3 days to induce nephrotoxicity. Fosfomycin sodium is given subcutaneously at 100, 200, or 400 mg/kg/day, 30 minutes before dibekacin administration, for 3 consecutive days. Blood samples are collected to measure BUN and Scr levels, and renal tissues are harvested for histopathological examination [3][4]
3. Renal tissue drug accumulation assay: Rats are treated as described in the nephrotoxicity model. After the last dose, renal tissues are homogenized, and the concentrations of dibekacin and Fosfomycin sodium in homogenates are quantified by chromatographic methods to analyze the effect of Fosfomycin sodium on dibekacin accumulation [4]

1. Absorption: The oral bioavailability of fosfomycin sodium taken on an empty stomach is 30-40%, which can be increased to 50-60% when taken with food. After oral administration of 1 gram, the peak plasma concentration (Cmax) of 20-40 μg/mL can be reached in 1-2 hours [1][2]
2. Distribution: It is widely distributed in various tissues and body fluids, including the kidneys, lungs, muscles, bones and cerebrospinal fluid (CSF). After parenteral administration, the CSF concentration can reach 10-30% of the plasma concentration [1][2]
3. Metabolism: It is metabolized very little in the body; more than 90% of the drug is excreted unchanged [1][2]
4. Excretion: It is mainly excreted by the kidneys. The elimination half-life (t1/2) of healthy adults is 2-4 hours, while that of patients with renal impairment is prolonged to 6-8 hours [1][2]. 5. Renal clearance: approximately 120-150 mL/min, similar to glomerular filtration rate [1].
Absorption, distribution and excretion
Fosfomycin is a low molecular weight hydrophilic drug. After oral administration, fosfomycin is rapidly absorbed in the small intestine and widely distributed in tissues. Oral bioavailability is 34-58%. Co-administration with food reduces its gastrointestinal absorption to approximately 30%. The reported AUC is 145-228 mg·h/L, and Cmax is 26.1 (±9.1) mcg/mL. Fosfomycin is almost completely excreted by the kidneys. Co-administration with food, renal impairment and advanced age may reduce the clearance of fosfomycin. In healthy subjects, the volume of distribution (Vd) of fosfomycin is approximately 0.3 L/kg. Due to changes in vascular endothelial cells, the Vd can increase by up to 50% in critically ill patients. One study reported a clearance/expenditure (CL/F) of fosfomycin in healthy volunteers of 17 ± 4.7 L/h. Fosfomycin is not metabolized and is primarily excreted unchanged in the urine. The mean elimination half-life of fosfomycin is 5.7 (± 2.8) hours.

1. Acute toxicity: The LD50 of sodium fosfomycin in mice and rats is >2000 mg/kg (oral or subcutaneous administration)[1][2] 2. Chronic toxicity: Long-term (up to 6 months) administration of up to 500 mg/kg/day in animals did not cause significant organ toxicity[1][2] 3. Nephrotoxicity: At therapeutic doses, no significant nephrotoxicity was observed in healthy animals or humans. Instead, it protects the kidneys from dibekacin-induced nephrotoxicity by reducing the accumulation of dibekacin in the kidneys and alleviating oxidative stress [3][4]
4. Gastrointestinal toxicity: Mild and transient diarrhea, nausea, or vomiting may occur in humans (incidence <10%), and no serious gastrointestinal adverse reactions have been reported in animal studies [1][2]
5. Plasma protein binding: <10% in both humans and animals [1][2]
6. Drug interactions: Reduces the accumulation and nephrotoxicity of aminoglycosides (e.g., dibekacin) in the kidneys without affecting their antibacterial activity [3][4]

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Hepatotoxicity>
A small number of patients (1-2%) may experience elevated serum transaminases after a single oral dose of fosfomycin, but the incidence is similar to that of the control drug. Antibiotics. However, elevated serum enzymes are listed as a potential adverse reaction in the fosfomycin product information. In addition, a small number of clinically significant cases of fosfomycin-related liver injury have been reported. These cases have a rapid onset, usually occurring within one week after a single oral dose or within the first week after intravenous treatment, with liver enzyme elevations presenting as mixed or hepatocellular. Liver injury is usually mild and self-limiting, and there is currently no conclusive evidence that fatal acute liver failure, chronic hepatitis, or bile duct disappearance syndrome is associated with fosfomycin. The number of cases described is too small to establish a typical clinical pattern, but immune allergy features and autoimmune markers appear to be uncommon. Probability score: D (likely a rare cause of clinically significant liver injury). Effects during pregnancy and lactation. ◉ Overview of use during lactation: Limited information suggests that fosfomycin is present in low concentrations in breast milk, and that infants are unlikely to absorb it well due to its binding with calcium in breast milk. No adverse effects on breastfed infants are unlikely. ◉ Effects on breastfed infants: No relevant published information was found as of the revision date. ◉ Effects on lactation and breast milk: No relevant published information was found as of the revision date.

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Protein Binding
Fosfomycin binds very little to plasma proteins.

[1]. Fosfomycin. Clin Microbiol Rev. 2016 Apr. 29(2):321-47.

[2]. Fosfomycin: Pharmacological, Clinical and Future Perspectives. Antibiotics (Basel). 2017 Oct 31. 6(4):24.

[3]. Protective effect of fosfomycin on the experimental nephrotoxicity induced by dibekacin. J Pharmacobiodyn. 1982 Sep. 5(9):659-69.

[4]. Mode of protective action of fosfomycin against dibekacin-induced nephrotoxicity in the dehydrated rats. J Pharmacobiodyn. 1982 Dec. 5(12):941-50.

1. Fosfomycin sodium is a broad-spectrum bactericidal antibiotic, first isolated from Streptomyces fradiae in 1969[1][2]. 2. It is approved for the treatment of uncomplicated urinary tract infections (UTIs), complicated urinary tract infections, lower respiratory tract infections, skin and soft tissue infections, and other bacterial infections caused by susceptible strains[1][2]. 3. Its unique mechanism of action (inhibition of early cell wall synthesis) reduces cross-resistance with other antibiotic classes, making it effective against multidrug-resistant bacteria (MDRs), such as extended-spectrum β-lactamase (ESBL)-producing Escherichia coli[1][2]. 4. It has a protective effect against nephrotoxicity caused by aminoglycosides, attributed to its competitive inhibition of aminoglycoside uptake by renal tubular epithelial cells[4]. 5. It is safe for patients. Contraindicated in pregnant women, children, and elderly patients (dosage adjustment required in patients with renal insufficiency)[1][2].

C3H5NA2O4P

182.02

181.972

C, 19.80; H, 2.77; Na, 25.26; O, 35.16; P, 17.02

26016-99-9

Fosfomycin calcium;26016-98-8;Fosfomycin tromethamine;78964-85-9;Fosfomycin;23155-02-4

73491

White to off-white solid powder

342.7ºC at 760 mmHg

>300°C

1.34E-05mmHg at 25°C

Streptomyces spp.

0.785

0

4

0

10

127

2

P([C@]1([H])[C@@]([H])(C([H])([H])[H])O1)(=O)([O-])[O-].[Na+].[Na+]

QZIQJIKUVJMTDG-JSTPYPERSA-L

InChI=1S/C3H7O4P.2Na/c1-2-3(7-2)8(4,5)6;;/h2-3H,1H3,(H2,4,5,6);;/q;2*+1/p-2/t2-,3+;;/m0../s1

Phosphonic acid, (3-methyloxiranyl)-, disodium salt, (2R-cis)- (9CI)

Disodium fosfomycin; Disodium phosphonomycin; Forocyle S; Fosfomycin sodium; MK 955; MK955; MK-955; Phosphonomycin disodium salt

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Water : 36~125 mg/mL(686.74 mM )

Solubility in Formulation 1: 100 mg/mL (549.39 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication.

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 (Please use freshly prepared in vivo formulations for optimal results.)