Fosfomycin is an antibiotic first discovered in 1969 from the bacterium Streptomyces fradiae. Chemically, it is a unique phosphonic acid derivative featuring a highly reactive epoxide ring, meaning it is not structurally related to any other established class of antibiotics. Classified as a bactericidal agent, it kills bacteria directly through a singular mechanism of action. This has led to its re-emergence as a valuable option for treating infections, especially as resistance to other drugs increases globally.
Understanding How Fosfomycin Works
Fosfomycin exerts its bactericidal effect by targeting the initial step in bacterial cell wall synthesis, specifically the peptidoglycan structure. The drug acts as an analog of phosphoenolpyruvate (PEP), allowing it to inhibit the enzyme UDP-N-acetylglucosamine-enolpyruvyltransferase, also known as MurA.
MurA catalyzes the transfer of an enolpyruvyl group from PEP, a foundational reaction in cell wall construction. Fosfomycin irreversibly inhibits MurA by covalently binding to a cysteine residue in the active site. This covalent bond forms when the drug’s reactive epoxide ring opens upon nucleophilic attack.
By inactivating MurA, fosfomycin prevents the formation of the essential peptidoglycan precursor, UDP-N-acetylmuramic acid. Without this precursor, the bacterial cell cannot construct its cell wall, leading to structural disruption and cell death. Since it interferes at an early stage, distinct from agents like penicillin, it lacks cross-resistance with other antibiotic classes.
How the Body Processes Fosfomycin
Fosfomycin pharmacokinetics depend heavily on the formulation administered. The most common oral form is fosfomycin trometamol, which improves absorption in the small intestine. Bioavailability is approximately 34% to 58%, though food can slightly reduce this amount.
Once absorbed, fosfomycin exhibits minimal plasma protein binding. Its low molecular weight and hydrophilic nature allow effective distribution into tissues, including the central nervous system, bone, and soft tissues. The drug is not significantly metabolized by the liver.
The primary route of elimination is through the kidneys, excreted virtually unchanged in the urine by glomerular filtration. This results in high and prolonged concentrations in the urinary tract, crucial for effectiveness against urinary pathogens. Although the serum half-life is short (1.5 to 3.6 hours), the urine concentration remains bactericidal for up to 48 hours.
The Range of Susceptible Bacteria
Fosfomycin has a broad spectrum of activity against both Gram-positive and Gram-negative bacteria. This coverage is valuable given increasing antibiotic resistance. Among Gram-negative organisms, it shows strong activity against common urinary tract pathogens, including Escherichia coli and Klebsiella pneumoniae.
Its activity extends to many multidrug-resistant (MDR) strains of Enterobacterales, such as those producing extended-spectrum beta-lactamases (ESBLs). For Gram-positive bacteria, fosfomycin is active against Enterococcus faecalis and Staphylococcus aureus, including methicillin-resistant S. aureus (MRSA). High susceptibility rates are often seen for MRSA and E. coli isolates.
Susceptibility is variable among different species, and resistance is intrinsic to some organisms. Certain species like Pseudomonas aeruginosa and some Klebsiella strains naturally possess resistance mechanisms, such as the fosA gene. Susceptibility testing is important to confirm the drug’s utility in treating specific infections.
Targeted Treatments and Administration
The primary clinical application for oral fosfomycin trometamol is the treatment of uncomplicated lower urinary tract infections (UTIs), or cystitis, in adult women. The resulting high and sustained urine concentrations make it highly effective at the infection site. The standard regimen is a single 3-gram oral dose, which simplifies patient adherence.
Intravenous (IV) formulations, typically the disodium salt, are available for more serious or complicated infections. The IV drug treats conditions beyond the urinary tract, such as pyelonephritis, complicated soft tissue infections, or infections caused by MDR organisms. In these cases, it is often administered in a multiple-dose regimen and used in combination with other antibiotics to maximize efficacy.
Bacterial resistance remains a concern. Resistance can arise through acquired genes like fosA, which inactivates the drug, or mutations impairing antibiotic uptake. To mitigate this, especially in non-urinary tract infections, fosfomycin is often used in combination therapy to exploit synergistic effects. Its distinctive mechanism makes it an excellent partner drug, as its resistance is not linked to resistance mechanisms for most other antibiotic classes.