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 solubil ity (less than or equal to 1 mg/ml) were encapsulated by fibrin (composed o f fibrinogen, thrombin, Factor XIIIa and calcium chloride) and examined. El ectron microscopy revealed fibrin-caged, tetracycline crystals that were 0. 26 to 2.8 mu m in size and bound within the reticular matrix. Antibiograms documented that S. aureus ATCC 27659 was resistant to erythromycin (ERY), p enicillin 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 dis k diffusion assay, produced zones of growth inhibition after 18-24 h at 37 degrees C in vitro, indicating renewed susceptibility of S. aureus ATCC 276 59 to these ABs. ERY, PEN and TET were unable to overcome resistance at con centrations up to 10 mg/ml, In vivo, intraperitoneal (i.p.) injection of 15 0 mg/kg STR delivered from fibrin resulted in 100% survival of rats with MD R S. aureus peritonitis as compared with control rats receiving i.p. STR (1 50 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.