Lipid-based slow-release formulation of amikacin sulfate reduces foreign body-associated infections in mice

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Abstract
Treatment and prophylaxis of uncomplicated infections with standard systemic antibiotics are usually successful. However, standard systemic antibiotic therapy alone is frequently unsatisfactory in certain circumstances, such as the presence of a foreign body (FB), necrotic tissue, overwhelming bacterial inoculum, or poor vascular supply to the involved tissues. We have developed a lipid-based sustained release formulation of amikacin sulfate (DepoFoam encapsulated amikacin sulfate [DEAS]) as a biodegradable, locally injectable antibiotic for such circumstances. The encapsulated drug is released over 7 to 10 days. We tested the efficacy of this formulation in an FB infection model in which Teflon tubes (length, 1 cm; outside diameter, 1.6 mm) were implanted into the subcutaneous tissue in mice and the local site was inoculated with 0.87 x 10(7) CFU of Staphylococcus aureus 3 days later. Inoculation was followed by either no treatment or a local injection of DEAS, free amikacin sulfate, non-drug-containing DepoFoam, or systemic free amikacin sulfate. All drug applications contained 1 mg of amikacin. One group was implanted with the FB and left unchallenged with bacteria and untreated as a sterile control group. All animals were sacrificed 10 days following FB implantation. FBs were retrieved from tissues by an aseptic technique and incubated in liquid culture media for 7 days. Local wound tissue was excised and processed to determine the number of CFU per gram of tissue. Treatment with local or systemic free amikacin had no effect on the number of infected FBs or on the log CFU in wound tissue compared with the untreated or non-drug-containing DepoFoam group. Compared with local free amikacin therapy, the number of infected FBs was reduced from 86 to 25% (P=0.02) following treatment with DEAS, and log CFU per gram of tissue was significantly decreased from 4.8 +/- 0.9 to 1.3 +/- 0.6 (P<0.0005). DEAS may have clinical utility as locally injected antibiotic in certain infections.