Fosfomycin: Pharmacological, Clinical and Future Perspectives

Abstract

Fosfomycin is a bactericidal, low-molecular weight, broad-spectrum antibiotic, with putative activity against several bacteria, including multidrug-resistant Gram-negative bacteria, by irreversibly inhibiting an early stage in cell wall synthesis. Evidence suggests that fosfomycin has a synergistic effect when used in combination with other antimicrobial agents that act via a different mechanism of action, thereby allowing for reduced dosages and lower toxicity. Fosfomycin does not bind to plasma proteins and is cleared via the kidneys. Due to its extensive tissue penetration, fosfomycin may be indicated for infections of the CNS, soft tissues, bone, lungs, and abscesses. The oral bioavailability of fosfomycin tromethamine is <50%; therefore, oral administration of fosfomycin tromethamine is approved only as a 3-gram one-time dose for treating urinary tract infections. However, based on published PK parameters, PK/PD simulations have been performed for several multiple-dose regimens, which might lead to the future use of fosfomycin for treating complicated infections with multidrug-resistant bacteria. Because essential pharmacological information and knowledge regarding mechanisms of resistance are currently limited and/or controversial, further studies are urgently needed, and fosfomycin monotherapy should be avoided.

Unexpected activity of oral fosfomycin against resistant strains ofEscherichia coliin murine pyelonephritis

“…Several limitations of our study, due to experimental conditions, should be taken into account when extrapolating the data as they could limit the probability for selection of fosfomycin-resistant mutants in vivo: i) bacterial loads in kidneys before fosfomycin treatment were moderate, and no spontaneous mortality is observed in this model; ii) duration of fosfomycin treatment was limited to 24h, a short duration of time to select for resistant mutants; however, it must be acknowledge that this is very similar to the situation in human after an oral single dose of fosfomycin; iii) the fosfomycin dosing regimen used in the present study generated an AUC 0-24h that corresponded approximately to what would be obtained in human after two doses of oral fosfomycin-tromethamine (15, 16, 18), as repeated oral doses is a dosing regimen that is under investigation for other situations than cystitis in women (19); iv) finally, we did not perform a group of end-of-treatment control mice which would have help to analyze the relative part of spontaneous bacterial clearance from the kidneys and the antibacterial effect of fosfomycin.…”

“…Fosfomycin has been approved for decades as an injectable antibiotic for the treatment of systemic infections due to both Gram-positive cocci and Gram-negative bacilli, including severe infections (4, 15, 16). More recently, an oral formulation, fosfomycin-tromethamine, has rapidly become the first-line empirical treatment recommended worldwide as a single dose for acute uncomplicated lower UTIs (6, 7).…”

“…Single-dose plasma pharmacokinetic studies were performed on eight-week-old CBA female mice (weight 20–23 g) in order to determine the therapeutic regimen that best reproduced peak and trough plasma levels obtained in humans with a daily oral-dose of 3 grams of fosfomycin-tromethamine (20 and 5 μg/ml, respectively) (15, 18, 19). Dosing interval was chosen accordingly to reproduce area under the concentrationtime curve (AUC) in the range of that obtained in humans with a single oral-dose of 3 grams of fosfomycin-tromethamine (ie up to 228 mg.h/liter, as compared with a range of 1400 to 1800 mg.h/L in human with the iv route) (13, 15, 18) since fosfomycin AUC/MIC ratio is the PK/PD index most closely linked to in vivo efficacy (24). This regimen was determined as 100 mg/kg every 4 h (15, 18, 19).…”

“…Dosing interval was chosen accordingly to reproduce area under the concentrationtime curve (AUC) in the range of that obtained in humans with a single oral-dose of 3 grams of fosfomycin-tromethamine (ie up to 228 mg.h/liter, as compared with a range of 1400 to 1800 mg.h/L in human with the iv route) (13, 15, 18) since fosfomycin AUC/MIC ratio is the PK/PD index most closely linked to in vivo efficacy (24). This regimen was determined as 100 mg/kg every 4 h (15, 18, 19). Total drug concentrations were utilized in PK/PD analyses, as fosfomycin is not bound to plasma protein (15, 18).…”

Fosphomycin: Current Scenario and Susceptibility Pattern in Urinary Isolates of a Teaching Hospital

“…[5][6][7][8][9] Fosfomycinis a bactericidal, broad spectrum antibiotic. [10] it does not undergo hepatic metabolism, and is primarily eliminated as unchanged drug by the kidneys through glomerular filtration. About 90% of the administered dose is eliminated in the kidneys.…”