Exploration of the Pharmacokinetic-Pharmacodynamic Relationships for Fosfomycin Efficacy Using an In Vitro Infection Model

Abstract

c Fosfomycin, a phosphonic class antibiotic with a broad spectrum of antibacterial activity, has been used outside the United States since the early 1970s for the treatment of a variety of infections. In the United States, an oral (tromethamine salt) formulation is used for uncomplicated urinary tract infections. Recently, there has been interest in the use of an intravenous solution (ZTI-01) for the treatment of a broad range of infections associated with multidrug-resistant bacteria. In this era of multidrugresistant bacteria with few treatment options, it is critical to understand the pharmacokinetic-pharmacodynamic (PK-PD) determinants for fosfomycin efficacy. Since such data are limited, a one-compartment in vitro infection model was used to determine the PK-PD index associated with efficacy and the magnitude of this measure necessary for various levels of effect. One challenge isolate (Escherichia coli ATCC 25922, for which the fosfomycin agar MIC is 0.5 mg/liter and the broth microdilution MIC is 1 mg/liter) was evaluated in the dose fractionation studies, and two additional clinical E. coli isolates were evaluated in the doseranging studies. Mutation frequency studies indicated the presence of an inherently fosfomycin resistant E. coli subpopulation (agar MIC ‫؍‬ 32 to 64 mg/liter) within the standard starting inoculum of a susceptibility test. Due to the presence of this resistant subpopulation, we identified the percentage of the dosing interval that drug concentrations were above the inherent resistance inhibitory concentration found at baseline to be the PK-PD index associated with efficacy (r 2 ‫؍‬ 0.777). The magnitudes of this PK-PD index associated with net bacterial stasis and 1-and 2-log 10 CFU/ml reductions from baseline at 24 h were 11.9, 20.9, and 32.8, respectively. These data provide useful information for modernizing and optimizing ZTI-01 dosing regimens for further study. In 1969, Hendlin and colleagues reported the discovery of phosphonomycin (later renamed fosfomycin) in a Streptomyces fradiae culture (1). Fosfomycin antibacterial activity is dependent upon its entry into the cell through the L-alpha-glycerophosphate transport and hexose monophosphate systems, which are glucose-6-phosphate dependent (2). Once it is inside the bacterial cell, fosfomycin inhibits peptidoglycan synthesis by the inactivation of UDP-N-acetylglucosamine-3-enolpyruvyltransferase (MurA) (3). Through this mechanism of action, fosfomycin has a broad spectrum of in vitro activity against a variety of clinically important Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus, and Gram-negative pathogens, including extended-spectrum-␤-lactamase (ESBL)-producing members of the family Enterobacteriaceae and carbapenem-resistant Enterobacteriaceae (CRE) (4, 5).While oral fosfomycin has long been utilized as single-dose therapy for uncomplicated urinary tract infections (6), there has been considerable recent interest in the use of this agent in both intravenous (IV) and oral formulations for t...

Fosfomycin: Mechanism and Resistance

“…As there is interest in use of parenteral fosfomycin for treatment of indications in addition to uncomplicated UTI, recent hollow fiber pharmacokinetic/pharmacodynamic (PK/PD) studies were undertaken by the Ambrose group (VanScoy et al 2015) to determine the PK/PD index for IV fosfomycin and to determine requirements for stasis, and 1-and 2-log reductions of colony-forming units. The results showed that, at least for the E. coli isolates studied, there was a large resistant subpopulation from the inception of infection.…”

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

“…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 The pharmacodynamics of fosfomycin may differ by species. [76][77][78] The emergence of resistance to fosfomycin has been demonstrated in vitro in studies in both Enterobacteriaceae and Pseudomonas species.…”

“…[76][77][78] The emergence of resistance to fosfomycin has been demonstrated in vitro in studies in both Enterobacteriaceae and Pseudomonas species. [76][77][78] This resistance may be suppressed by combining fosfomycin with other agents. [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.…”

“…[76][77][78] This resistance may be suppressed by combining fosfomycin with other agents. [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).…”

“…76,77 The pharmacodynamics of fosfomycin may differ by species. [76][77][78] The emergence of resistance to fosfomycin has been demonstrated in vitro in studies in both Enterobacteriaceae and Pseudomonas species. [76][77][78] This resistance may be suppressed by combining fosfomycin with other agents.…”