Nano-Mupirocin Injection: Parenterally Active Mupirocin

Background: Mupirocin, an antibiotic with a unique mechanism of action (inhibition of isoleucyl-tRNA synthetase) is limited to topical use due to its rapid systemic elimination. Computational methods identified mupirocin as a good candidate for delivery via nano-liposomes. Mupirocin loaded in nano-liposomes, termed Nano-mupirocin, is aimed to enable mupirocin parenteral efficacy by protecting it in the circulation and passively targeting it to the infected tissue due to the enhanced permeability and retention effect. Mupirocin is active in vitro against “serious and urgent threats” including methicillin-resistant S. aureus (MRSA), S. pneumoniae and N. gonorrhoeae.

Methods: The efficacy of free vs Nano-mupirocin injection was tested in three animal models: 1) mice necrotizing fasciitis caused by M14 group A streptococci 2) rabbit endocarditis due to MRSA 3) mice osteomyelitis caused by S. aureus. The pharmacokinetic (PK) profiles were tested in healthy mice and in the rabbits endocarditis model.
The distribution of mupirocin was determined in the wounds in necrotizing fasciitis and in the tibia in osteomyelitis model.

Results: In the rabbit endocarditis model, animals treated with Nano-mupirocin at 25 mg/kg, IV, bid for 3 days showed 57% survival vs no survival in the free mupirocin and untreated groups. In the mice necrotizing fasciitis model, Nano-mupirocin administered either prophylactically at 15, 25 and 50 mg/kg or 5 h after the bacterial challenge (at 50 mg/kg) resulted in 100% survival vs 44% and 38% mortality in the control and free mupirocin groups, respectively. Nano-mupirocin in the osteomyelitis model showed increase in body weight vs decrease in the free and blank liposomes groups and serum IL-6 levels resembled uninfected mice compared with high levels in the free and blank liposomes groups.
The PK profile of Nano-mupirocin showed much higher exposure and longer half-life compared to the free drug. Consistent with the PK data, Nano-mupirocin was detected in the wounds as well as in the tibia while no mupirocin was detected in the free mupirocin group.

Conclusions: We demonstrate that parenetral Nano-mupirocin is therapeutically efficacious. The prolonged plasma PK profile enables mupirocin accumulation in the infection site to exert its therapeutic activity. Our studies indicate that Nano-mupirocin may be a novel parenteral antibiotic.