Antibiotic abscess penetration: fosfomycin levels measured in pus and simulated concentration-time profiles

Abstract

The present study was performed to evaluate the ability of fosfomycin, a broad-spectrum antibiotic, to penetrate into abscess fluid. Twelve patients scheduled for surgical or computer tomography-guided abscess drainage received a single intravenous dose of 8 g of fosfomycin. The fosfomycin concentrations in plasma over time and in pus upon drainage were determined. A pharmacokinetic model was developed to estimate the concentration-time profile of fosfomycin in pus. Individual fosfomycin concentrations in abscess fluid at drainage varied substantially, ranging from below the limit of detection up to 168 mg/liter. The fosfomycin concentrations in pus of the study population correlated neither with plasma levels nor with the individual ratios of abscess surface area to volume. This finding was attributed to highly variable abscess permeability. The average concentration in pus was calculated to be 182 +/- 64 mg/liter at steady state, exceeding the MIC(50/90)s of several bacterial species which are commonly involved in abscess formation, such as streptococci, staphylococci, and Escherichia coli. Hereby, the exceptionally long mean half-life of fosfomycin of 32 +/- 39 h in abscess fluid may favor its antimicrobial effect because fosfomycin exerts time-dependent killing. After an initial loading dose of 10 to 12 g, fosfomycin should be administered at doses of 8 g three times per day to reach sufficient concentrations in abscess fluid and plasma. Applying this dosing regimen, fosfomycin levels in abscess fluid are expected to be effective after multiple doses in most patients.

FIG. 1.

Individual fosfomycin concentrations in plasma (open circles) and abscess fluid (solid circles) after a single dose of 8 g. Solid lines indicate fitted concentration-time curves for plasma. Dotted lines show simulated abscess fluid concentration-time curves obtained from the solutions to equation 1 after adjustment to the respective data. Plasma PK results were available for 11 patients. For abscesses, results for 10 abscesses were used because the C_a(t_i)s were below the LOD for 3 abscesses.

FIG. 2.

Simulated drug concentrations in plasma (solid lines) and abscess fluid (dotted lines) for three patients after multiple intravenous administrations of 8 g fosfomycin over 30 min and a dosing interval of 8 h. The patients with the minimum (a), median (b), and the maximum (c) C_max,a were chosen. The three patients with a C_a(t_i) below the LOD were not considered. The horizontal dotted line at 32 mg/liter represents a common MIC₅₀ of relevant bacterial pathogens.