Fosfomycin is an antibiotic that has seen renewed interest due to a global rise in difficult-to-treat bacterial infections. Discovered in the 1960s, the drug is now being repurposed to combat pathogens resistant to modern antibiotics. Among the most concerning is Klebsiella pneumoniae, a bacterium commonly associated with hospital-acquired infections, including pneumonia, bloodstream infections, and urinary tract infections. Many strains of K. pneumoniae have evolved into “superbugs,” capable of evading multiple classes of antimicrobial agents. The medical community is increasingly exploring Fosfomycin as a therapeutic option against these highly resistant strains, especially since the pipeline for new antibiotics remains limited.
Understanding the Klebsiella Resistance Challenge
The difficulty in treating Klebsiella pneumoniae stems from its diverse mechanisms for neutralizing antibiotics. The primary challenge is the production of powerful enzymes known as beta-lactamases, which break down beta-lactam antibiotics, including penicillins and cephalosporins. These enzymes include Extended-Spectrum Beta-Lactamases (ESBLs), which render many common antibiotics ineffective. A more concerning development is the emergence of Carbapenemase-Producing Organisms (CPOs). Klebsiella strains can produce carbapenemases, such as KPC, NDM-1, and VIM, which hydrolyze and inactivate carbapenems, often considered last-resort antibiotics.
Beyond enzymatic destruction, Klebsiella can also modify its cell structure to prevent drug entry. The bacterium alters or loses outer membrane proteins, specifically porins like OmpK35 and OmpK36, which act as channels for antibiotic molecules. A reduction in the number or function of these porins physically restricts the amount of drug that reaches its target inside the cell. Furthermore, some strains can increase the activity of efflux pumps, cellular mechanisms that actively pump the antibiotic out of the bacterial cell.
Fosfomycin’s Unique Mode of Action
Fosfomycin’s effectiveness stems from its distinctive mechanism of action, which targets a step in cell wall synthesis unaffected by other antibiotic classes. This small-molecule, epoxy-phosphonate compound functions as a structural analog of phosphoenolpyruvate (PEP), a naturally occurring molecule in bacteria. Fosfomycin targets the enzyme UDP-N-acetylglucosamine-3-enolpyruvyl transferase, known as MurA.
MurA catalyzes the very first committed step in the biosynthesis of peptidoglycan, the polymer that forms the bacterial cell wall. This initial reaction involves the transfer of an enolpyruvyl moiety from PEP to UDP-N-acetylglucosamine (UDP-GlcNAc). Fosfomycin mimics PEP and irreversibly binds to the MurA enzyme. This covalent attachment permanently inactivates MurA, halting the peptidoglycan assembly line and leading to bacterial death.
This unique point of attack allows Fosfomycin to bypass common resistance mechanisms like ESBLs and carbapenemases. The drug must be actively transported into the bacterial cell, primarily via the GlpT (glycerol-3-phosphate) or UhpT (hexose phosphate) transport systems, before it can inhibit the intracellular MurA target.
Administration and Approved Applications
Fosfomycin is available in two distinct formulations, tailored to different clinical applications concerning Klebsiella infections.
Oral Formulation (Fosfomycin Trometamol)
The oral formulation, Fosfomycin trometamol, is most commonly used for acute, uncomplicated urinary tract infections (UTIs). It is rapidly absorbed, achieving low bloodstream concentrations but extremely high, sustained concentrations in the urine. This makes it highly effective for eradicating multi-drug-resistant Klebsiella causing cystitis, provided the infection is confined to the bladder. The trometamol salt improves oral bioavailability, which typically ranges from 30% to 40%. Due to its poor systemic concentration, the oral form is not adequate for treating systemic or complicated Klebsiella infections outside the urinary tract.
Intravenous Formulation (IV)
For more severe, systemic Klebsiella infections, such as pneumonia, bacteremia, or complicated UTIs, the intravenous (IV) formulation is required. Administered as a disodium salt, the IV route achieves significantly higher plasma concentrations necessary to penetrate deep-seated infection sites. Fosfomycin is a small, hydrophilic molecule with low protein binding, allowing it to distribute well into various body tissues, including the lungs, bone, and even the cerebrospinal fluid (CSF) in cases of meningeal inflammation. The IV dosing regimen is typically higher and more frequent, often administered every six to eight hours, to maintain therapeutic concentrations in the plasma and target tissues.
Strategies for Overcoming Resistance
Although Fosfomycin has a unique mechanism, Klebsiella can still develop specific resistance against it. The most prevalent mechanism involves acquiring the fosA gene, often carried on mobile genetic elements like plasmids. This gene encodes a metallo-glutathione S-transferase enzyme that chemically modifies and inactivates the Fosfomycin molecule before it reaches the MurA target. The presence of fosA is concerning because it is frequently found on the same plasmids that carry genes for carbapenemases, linking resistance to multiple drug classes.
Another resistance mechanism involves mutations or deficiencies in the bacterial transport systems, GlpT and UhpT, which are essential for Fosfomycin uptake. If the bacterium loses the function of these transporters, the drug cannot enter in sufficient quantities to inhibit MurA. These transporter-related resistance mechanisms often result from chromosomal mutations.
To mitigate resistance and enhance efficacy against highly resistant Klebsiella strains, Fosfomycin is rarely used as monotherapy for systemic infections. The current clinical strategy favors combination therapy, pairing Fosfomycin with another antibiotic to create a synergistic effect. Common combinations include Fosfomycin with carbapenems, aminoglycosides (like amikacin), or polymyxins (like colistin). This approach prevents resistance emergence by attacking the bacterium through two different pathways simultaneously, significantly improving the chances of a successful clinical outcome.