Parenteral Fosfomycin for the Treatment of Multidrug Resistant Bacterial Infections: The Rise of the Epoxide

Abstract

Fosfomycin was initially discovered in 1969 but has recently gained renewed interest for the treatment of multidrug‐resistant (MDR) bacterial infections, particularly in the United States. Its unique mechanism of action, bactericidal activity, broad spectrum of activity, and relatively safe and tolerable adverse effect profile make it a great addition to the dwindling antibiotic armamentarium. Fosfomycin contains a three‐membered epoxide ring with a direct carbon to phosphorous bond that bypasses the intermediate oxygen bond commonly present in other organophosphorous compounds; this structure makes the agent unique from other antibiotics. Despite nearly 50 years of parenteral fosfomycin use in Europe, fosfomycin has retained stable activity against most pathogens. Furthermore, fosfomycin demonstrated in vitro synergy in combination with other cell wall–active antibiotics (e.g., β‐lactams, daptomycin). These combinations may offer respite for severe infections due to MDR gram‐positive and gram‐negative bacteria. The intravenous (IV) formulation is currently under review in the United States, and apropos, this review collates more contemporary evidence (i.e., studies published between 2000 and early 2019) in anticipation of this development. The approval of IV fosfomycin provides another option for consideration in the management of MDR infections. Its unique structure will give rise to a promising epoxide epoch in the battle against MDR bacteria.

In Vitro Susceptibility of Multi-Drug Resistant Klebsiellapneumoniae Strains Causing Nosocomial Infections to Fosfomycin. A Comparison of Determination Methods

“…An extensive literature presents i.v. fosfomycin as a viable treatment option for patients with systemic infections with Enterobacterales producing both ESBL and CPE [ 1 , 3 , 4 , 13 , 41 , 42 ]. As early as in 2010, Falagaset et al reported the satisfactory sensitivity of multidrug-resistant Klebsiella pneumoniae to fosfomycin [ 1 ].…”

“…It is nearly completely (95%) excreted unchanged in the urine within 24 h, and its half-life is relatively long (4–8 h). Due to its different chemical structure and characteristic mechanism of action, for the time being, there is no cross-resistance observed with other antibiotics commonly used in clinical practice [ 4 , 5 , 6 ]. Fosfomycin’s effective penetration into bacterial biofilm was also confirmed, in particular into the biofilm produced by the P seudomonas aeruginosa and Staphylococcus aureus strains [ 7 , 8 ].…”

“…Multidrug-resistant Klebsiella pneumoniae strains are among the pathogens posing a major therapeutic problem [ 1 , 3 , 4 ]. Klebsiella bacilli have undergone a unique evolution over the last few decades.…”

Two-component signaling pathways modulate drug resistance of

“…The molecular structure of Fosfomycin, a broad-spectrum antibiotic in clinical trials, is similar to phosphoenolpyruvate. Instead of being metabolized by the body, the antibiotic is excreted in its original form, thus it is widely used for the treatment of osteomyelitis due to its lower toxicity and fewer side effects (46). This type of antibiotic may be transported into the cytoplasm via the bacterial phosphohexose transporter to exert its antibiotic effects through competitively binding to UDP-N-acetylglucosamine-3-O-enolpyruvate transferase (encoded by the murA gene), inhibiting the synthesis of the peptidoglycan precursor, as well as interfering with the synthesis of the cell wall (47).…”

Evaluation of Intravenous Fosfomycin Disodium Dosing Regimens in Critically Ill Patients for Treatment of Carbapenem-Resistant Enterobacterales Infections Using Monte Carlo Simulation

“…In addition, the physiochemical properties were concerned. IVFOS is a hydrophilic drug, with a volume distribution of around 20 to 40 L; it is negligibly protein-bound, and results in almost total renal elimination [7,8]. Results from several population pharmacokinetic studies showed that fosfomycin was a significant variable of plasma concentration, and large interindividual with intraindividual pharmacokinetic variabilities [9][10][11].…”