Subverting bacterial resistance using high dose, low solubility antibiotics in fibrin.

Antibiotics (ABs) delivered from fibrin were evaluated for control of multi-drug resistant (MDR) Staphylococcus aureus. ABs having low aqueous solubility (< or = 1 mg/ml) were encapsulated by fibrin (composed of fibrinogen, thrombin, Factor XIIIa and calcium chloride) and examined. Electron microscopy revealed fibrin-caged, tetracycline crystals that were 0.26 to 2.8 microns in size and bound within the reticular matrix. Antibiograms documented that S. aureus ATCC 27659 was resistant to erythromycin (ERY), penicillin G (PEN), streptomycin (STR), sulfamethoxazole-trimethoprim (SXT) and tetracycline (TET). However, low solubility formulations of STR (10 mg/ml) or SXT (0.5 mg/ml), delivered from fibrin and evaluated by the agar disk diffusion assay, produced zones of growth inhibition after 18-24 h at 37 degrees C in vitro, indicating renewed susceptibility of S. aureus ATCC 27659 to these ABs. ERY, PEN and TET were unable to overcome resistance at concentrations up to 10 mg/ml. In vivo, intraperitoneal (i.p.) injection of 150 mg/kg STR delivered from fibrin resulted in 100% survival of rats with MDR S. aureus peritonitis as compared with control rats receiving i.p. STR (150 mg/kg) in 0.9% saline. The results demonstrate that some low solubility ABs delivered from fibrin are efficacious in controlling infection mediated by MDR S. aureus.