Fosfomycin for the Treatment of Resistant Gram‐Negative Bacterial Infections

Abstract

The antimicrobial agent fosfomycin was discovered in 1969, at a time when bacteria had not yet developed extended-spectrum β-lactamases or carbapenemases. Decades later, it is not uncommon for gram-negative organisms to be multidrug-resistant and even pan-resistant to available antibiotic regimens, leaving clinicians with few therapeutic alternatives. Because fosfomycin has been shown to retain activity against these virulent pathogens, there is renewed interest in its use as a therapeutic agent. Fosfomycin formulations including fosfomycin disodium and the newer tromethamine salt are less toxic than other alternatives and are attractive options for resistant gram-negative and gram-positive infections. Oral fosfomycin tromethamine is approved for urinary tract infections in the United States, and an intravenous formulation is also available outside of the United States for systemic disease. The bactericidal action of fosfomycin occurs at an earlier step in cell wall synthesis than that of β-lactam antibiotics. From an in vitro standpoint, fosfomycin generally has high activity against ESBL- and carbapenemase-producing Enterobacteriaceae; multidrug-resistant Pseudomonas aeruginosa susceptibility appears to be more dependent on the local antibiogram. Fosfomycin formulations have a large volume of distribution, penetrate biofilms, and concentrate in the urine. Both oral and intravenous fosfomycin formulations are effective for a wide range of gram-negative infections and disease severities; however, clinical studies are limited. Fosfomycin formulations are well-tolerated, and mild gastrointestinal distress is the most common adverse effect. The primary limitations of fosfomycin are the lack of established regimens for complicated infections and the lack of availability of the intravenous formulation in the United States. Further study of this promising agent seems warranted in the current climate of antibiotic resistance.

Pharmacodynamic and pharmacokinetic considerations in the treatment of critically Ill patients infected with carbapenem-resistant Enterobacteriaceae

“…63,69 This method of administration bypasses the limited bioavailability of oral formulations and allows for considerably higher concentrations in plasma and tissues. The breakpoint set by EUCAST for fosfomycin against Enterobacteriaceae is 32 mg/mL, 70 which is a concentration achievable in many body tissues including the lungs and interstitial spaces. [70][71][72][73] There is wide variation in the dosing regimens described in the limited reports of intravenous fosfomycin for CRE infections, ranging up to 24 g of drug daily divided 3 or 4 times a day.…”

“…The breakpoint set by EUCAST for fosfomycin against Enterobacteriaceae is 32 mg/mL, 70 which is a concentration achievable in many body tissues including the lungs and interstitial spaces. [70][71][72][73] There is wide variation in the dosing regimens described in the limited reports of intravenous fosfomycin for CRE infections, ranging up to 24 g of drug daily divided 3 or 4 times a day. 74,75 Optimal pharmacodynamic targets for fosfomycin are unclear; historically it has been considered a time-dependent agent, but some recent pharmacodynamic studies with fosfomycin against E. coli have shown the fAUC/MIC ratio to be most predictive of efficacy.…”

“…[76][77][78][79][80] Though it is generally well tolerated, it should be noted that the intravenous formulation (fosfomycin disodium) contains 330 mg of sodium per gram of fosfomycin, which could be problematic in patients with heart failure. 70 A study of IV fosfomycin for UTIs for approval in the United States is currently being conducted (NCT02753946).…”

Beyond Susceptible and Resistant, Part III: Treatment of Infections due to Gram-Negative Organisms Producing Carbapenemases

“…35 Fosfomycin has shown potent in vitro activity against MDR Gram-negative bacteria, including KPCproducing organisms. 36 In a retrospective study conducted by Neuner et al 37 assessing treatment of MDR UTIs, 92% of the carbapenem-resistant K pneumoniae were susceptible to fosfomycin in vitro, although only 46% showed microbiological cure.…”

Overview on fosfomycin and its current and future clinical significance

“…However, clinical studies to assess the efficacy of fosfomycin are limited [34]. Based on the fact that fosfomycin monotherapy with intravenous formulation should be prohibited due to the prompt emergence of resistance during therapy, the choice of the appropriate adjunctive antibiotic should be carefully investigated and must be individualized for each patient's condition [9,17].…”