Urinary Pharmacokinetic and Pharmacodynamic Profiles of Fosfomycin against Extended-Spectrum β-Lactamase-Producing Escherichia coli with Canine Ex Vivo Modeling: A Pilot Study

Abstract

Fosfomycin is a candidate drug for extended-spectrum β-lactamase (ESBL)-producing bacteria, but its efficacy is yet to be investigated in dogs. This study investigated the urinary pharmacokinetic/pharmacodynamic (PK/PD) profile of fosfomycin orally administered at 80 mg/kg to six healthy dogs to assess its efficacy for canine urinary tract infections (UTIs) caused by ESBL-producing bacteria. Four strains of ESBL-producing Escherichia coli (ESBL-EC) characterized by fosfomycin minimum inhibitory concentrations (MICs) of 0.5, 1, 2, and 32 µg/mL were used. Urine samples for the measurement of urinary drug concentrations and urinary bactericidal titers (UBTs) were obtained after drug administration. The urinary concentrations (µg/mL, mean ± SE) were 1348.2 ± 163.5, 1191.6 ± 260.2, and 661.1 ± 190.4 at 0–4, 4–8, and 8–12 h, respectively, after drug administration. The mean urinary area under the curve during the test period (AUC0–12) of fosfomycin was estimated to be 12,803.8 µg·h/mL. The UBTs for all tested strains fluctuated closely with urine concentration during the test period (r = 0.944–1.000), and the area under the UBT-versus-time curve correlated with the urinary AUC/MIC of each strain (r = 0.991). According to the optimal urinary PK/PD target value, fosfomycin at 80 mg/kg twice daily may be suitable for the treatment of canine UTIs caused by ESBL-EC presenting MIC ≤ 128 µg/mL.

Plasma and Urine Pharmacokinetics of Oral Fosfomycin Tromethamine in Dogs

“…The kidney and liver functions, as well as the urinalysis results, of all subjects in the three treatments, were normal, indicating no signs of renal toxicity. These findings are consistent with previous studies conducted on dogs, where a single dose of Fosfomycin was administered [ 34 ], as well as studies where Fosfomycin disodium was administered for three consecutive days [ 20 ]. However, this study was examined in dogs with a single dose that might not be sufficient to completely represent ‘s adverse effects.…”

“…From their early study in dogs, the authors investigated the plasma PK of Fosfomycin sodium at 40 and 80 mg/kg [ 20 ] and the urine PK of Fosfomycin at 80 mg/kg [ 34 ]. However, a PK study of oral Fosfomycin tromethamine, a recommended oral formulation for bacterial cystitis, in both plasma and urine samples, has not been reported.…”

Fosfomycin Resistance in Bacteria Isolated from Companion Animals (Dogs and Cats)

“…Even though it is occasionally used by veterinarians for decades and in several countries, it Is still considered a second-line antibiotic. It is not approved for veterinary use in many countries, and therefore knowledge of its pharmacokinetic and pharmacodynamic properties among professionals is rather insufficient [ 19 ]. Moreover, it is currently categorized as a critically important antimicrobial for human medicine and thus its use is rather disapproved, especially in European Union [ 20 , 21 ].…”

“…Moreover, it is currently categorized as a critically important antimicrobial for human medicine and thus its use is rather disapproved, especially in European Union [ 20 , 21 ]. Nevertheless, a small number of protocols have been suggested, with promiscuous results, in several livestock and domestic species such as broiler chickens [ 22 , 23 ], dogs [ 19 , 24 ], pigs [ 25 , 26 ], cattle [ 27 ], and horses [ 28 ]. Contrarily, acute renal insufficiency and failure have been referred to after administration in cats [ 29 , 30 ].…”