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Preventing Nephrotoxicity of Vancomycin and Attenuating Deep Tissue Infections by Methicillin-Resistant
Anushri Warang1, Filip Garrett2, Madhavi P Gavini3
1Department of Internal Medicine, University of Missouri, Columbia, MO 65211, United States.
Abstract:
Methicillin-resistant Staphylococcus aureus (MRSA) is a major pathogen causing wound infections. The use of vancomycin, a glycopeptide antibiotic, is a last resort treatment against MRSA. However, systemic administration of vancomycin causes nephrotoxicity. Currently, no effective strategies are available to deliver the high molecular weight drug vancomycin topically across the outermost layer of the epidermis, the stratum corneum, to treat deep tissue infections by MRSA. We reported previously on the use of localized, needle-free transdermal delivery of high molecular weight antibiotics by the Droplette micromist technology device (DMTD) to successfully treat deep tissue infections by gram-negative bacteria. We hypothesized that DMTD delivery of vancomycin would successfully attenuate deep tissue infections by MRSA without causing nephrotoxicity. A mouse model (n = 15 per experimental group) for deep skin wound infection by MRSA was treated with vancomycin (300 mg/kg; 3 treatments) delivered via either transdermal DMTD delivery or systemic delivery by intraperitoneal (IP) injection. Saline-treated mice with MRSA infection were used as a positive control for untreated MRSA infection. The number of colony-forming units of MRSA in the skin wound tissue 2 days post-infection was determined to evaluate attenuation of MRSA infection. Histopathological scoring of kidney tissues was used to evaluate vancomycin-induced nephrotoxicity. Both IP- and DMTD-delivered vancomycin attenuated MRSA deep skin infection similarly as compared to saline-treated control (P < .001), but hematoxylin and eosin staining of kidney tissues revealed acute tubular necrosis evidenced by vacuolization of tubular cells, tubular lumen dilation, and tubular cell necrosis only in the mice that received IP-delivered vancomycin. These results confirm that transdermal delivery of vancomycin by the DMTD successfully attenuates deep skin infection by MRSA without causing nephrotoxicity. This novel drug delivery device can have a significant impact on wound care in general, but especially in the austere environment of battlefield hospitals.
Insights
Localized transdermal delivery of vancomycin using the Droplette micromist technology device (DMTD) effectively treats Methicillin-resistant Staphylococcus aureus (MRSA) wound infections. This method achieves similar infection reduction as systemic delivery but avoids vancomycin-induced kidney damage.
Area of Science:
- Pharmacology and Drug Delivery
- Infectious Diseases
- Dermatology
Background:
- Methicillin-resistant Staphylococcus aureus (MRSA) is a significant cause of wound infections, often requiring vancomycin as a last resort.
- Systemic vancomycin administration is associated with nephrotoxicity, and effective topical delivery across the stratum corneum for deep infections remains a challenge.
- Previous studies demonstrated the Droplette micromist technology device (DMTD) for transdermal delivery of antibiotics against gram-negative bacteria.
Purpose of the Study:
- To investigate the efficacy of DMTD-delivered vancomycin in treating deep skin wound infections caused by MRSA.
- To evaluate whether transdermal vancomycin delivery via DMTD mitigates the nephrotoxicity associated with systemic administration.
Main Methods:
- A mouse model of deep skin wound infection by MRSA was established.
- Vancomycin was administered via transdermal DMTD or intraperitoneal (IP) injection (300 mg/kg; 3 treatments).
- MRSA burden in wound tissue and kidney histopathology were assessed to determine infection attenuation and nephrotoxicity.
Main Results:
- Both IP and DMTD vancomycin treatments significantly attenuated MRSA infection compared to saline controls (P < .001).
- Histopathological analysis revealed acute tubular necrosis in kidneys of mice receiving IP vancomycin, but not in those treated with DMTD.
- DMTD delivery successfully delivered vancomycin transdermally, reducing MRSA infection without causing observable kidney damage.
Conclusions:
- Transdermal vancomycin delivery using the DMTD is an effective strategy for attenuating deep MRSA skin infections.
- DMTD-mediated vancomycin delivery avoids the nephrotoxicity associated with systemic administration, offering a safer treatment option.
- This novel drug delivery approach holds promise for advanced wound care, particularly in resource-limited or battlefield settings.
