Pharmacokinetics cut-off determination for fosfomycin in healthy horses

Though not approved for horses in the USA yet, this has been a useful antibiotic for horses in Japan.
DrO

Pharmacokinetics/pharmacodynamics cut-off determination for fosfomycin using Monte Carlo simulation in healthy horses
J Vet Med Sci. 2024 Feb 12. doi: 10.1292/jvms.23-0476. Online ahead of print.
Authors
Taisuke Kuroda 1 , Yohei Minamijima 2 , Hidekazu Niwa 3 , Hiroshi Mita 1 , Norihisa Tamura 1 , Kentaro Fukuda 1 , Pierre-Louis Toutain 4 5 , Minoru Ohta 1
Affiliations

1 Clinical Veterinary Medicine Division, Equine Research Institute, Japan Racing Association.
2 Drug Analysis Department, Laboratory of Racing Chemistry.
3 Microbiology Division, Equine Research Institute, Japan Racing Association.
4 Comparative Biomedical Sciences, The Royal Veterinary College.
5 Intheres, Ecole Nationale Vétérinaire de Toulouse.

PMID: 38346727
DOI: 10.1292/jvms.23-0476

Abstract

Fosfomycin (FOM) is an approved veterinary medicinal product for large animals in Japan, but Clinical breakpoint (CBP) for antimicrobial susceptibility test (AST) is not defined for animals. This study aimed at conducting a pharmacokinetics/pharmacodynamics (PK/PD) analysis to determine the PK/PD cutoff for the CBP in horses. Drug concentrations following single intravenous administration (IV) of 20 mg/kg body weight (BW) FOM in nine horses were measured using liquid chromatography/mass spectrometry. The data were modelled using a nonlinear mixed-effects model, followed by Monte Carlo simulations. A 90% probability of target attainment for a PK/PD target of the ratio of Area Under the free plasma concentration-time curve divided by the minimal inhibitory concentration (MIC) >24 hr was set as PK/PD cut-off. The PK/PD cutoff for FOM 20 mg/kg BW q12 hr IV was estimated with the MIC value of ≤16.0 mg/L, and this regimen was considered effective against E. coli (MIC90; 16.0 mg/L) in healthy horses based on the MIC90 values of the wild population. Owing to the relevance of FOM to human health, veterinarians should use q 12 hr FOM 20 mg /kg against E. coli infections with an MIC <16 µg/mL, as suggested by our PK/PD cutoff after AST.

Keywords: Escherichia coli; antimicrobial susceptibility testing; fosfomycin; horse; pharmacokinetics/pharmacodynamics (PK/PD) cutoff.

Excerpted from Wikipedia and taken from experience with humans:
Despite its name (ending in -omycin) Fosfomycin is not a macrolide, but a member of a novel class of phosphonic antibiotics.

Fosfomycin is bactericidalFosfomycin has broad antibacterial activity against both Gram-positive and Gram-negative pathogens, with useful activity against E. faecalis, E. coli, and various Gram-negatives such as Citrobacter and Proteus. Given a greater activity in a low-pH milieu, and predominant excretion in active form into the urine, fosfomycin has found use for the prophylaxis and treatment of UTIs caused by these uropathogens. Of note, activity against S. saprophyticus, Klebsiella, and Enterobacter is variable and should be confirmed by minimum inhibitory concentration testing. Activity against extended-spectrum β-lactamase-producing pathogens, notably ESBL-producing E. coli, is good to excellent, because the drug is not affected by cross-resistance issues.

Development of bacterial resistance under therapy is a frequent occurrence and makes fosfomycin unsuitable for sustained therapy of severe infections. Mutations that inactivate the nonessential glycerophosphate transporter render bacteria resistant to fosfomycin.

Prescribing fosfomycin together with at least another active drug reduces the risk of developing bacterial resistance. Fosfomycin acts synergistically with many other antibiotics, including aminoglycosides, carbapenems, cephalosporins, daptomycin and oritavancin.

• This topic was modified 1 year ago by Robert Oglesby DVM.