Controlled release of ciprofloxacin and ceftriaxone from a single ototopical administration of antibiotic-loaded polymer microspheres and thermoresponsive gel.

Acute otitis media (AOM) is the main indication for pediatric antibiotic prescriptions, accounting for 25% of prescriptions. While the use of topical drops can minimize the administered dose of antibiotic and adverse systemic effects compared to oral antibiotics, their use has limitations, partially due to low patient compliance, high dosing frequency, and difficulty of administration. Lack of proper treatment can lead to development of chronic OM, which may require invasive interventions. Previous studies have shown that gel-based drug delivery to the ear is possible with intratympanic injection or chemical permeation enhancers (CPEs). However, many patients are reluctant to accept invasive treatments and CPEs have demonstrated toxicity to the tympanic membrane (TM). We developed a novel method of delivering therapeutics to the TM and middle ear using a topical, thermoresponsive gel depot containing antibiotic-loaded poly(lactic-co-glycolic acid) microspheres. Our in vitro and ex vivo results suggest that the sustained presentation can safely allow therapeutically relevant drug concentrations to penetrate the TM to the middle ear for up to 14 days. Animal results indicate sufficient antibiotic released for treatment from topical administration 24h after bacterial inoculation. However, animals treated 72h after inoculation, a more clinically relevant treatment practice, displayed spontaneous clearance of infection as is also often observed in the clinic. Despite this variability in the disease model, data suggest the system can safely treat bacterial infection, with future studies necessary to optimize microsphere formulations for scaled up dosage of antibiotic as well as further investigation of the influence of spontaneous bacterial clearance and of biofilm formation on effectiveness of treatment. To our knowledge, this study represents the first truly topical drug delivery system to the middle ear without the use of CPEs

Endophthalmitis Prophylaxis Using a Single Drop of Thermoresponsive Controlled-Release Microspheres Loaded with Moxifloxacin in a Rabbit Model

Citation: Mammen A, Romanowski EG, Fedorchak MV, Dhaliwal DK, Shanks RM, Kowalski RP. Endophthalmitis prophylaxis using a single drop of thermoresponsive controlled-release microspheres loaded with moxifloxacin in a rabbit model. Trans Vis Sci Tech. 2016;5(6):12, doi: 10.1167/tvst.5.6.12 Purpose: Postsurgical endophthalmitis is a sight-threatening problem. We introduce a simple approach by using a single application of thermoresponsive controlledrelease microspheres, loaded with moxifloxacin, to prevent bacterial endophthalmitis in a rabbit endophthalmitis prevention model. Methods: We separated 24 rabbits into 3 treatment groups in which topical drop treatment was placed onto the conjunctival cul-de-sac: (1) a single drop of controlledrelease microspheres containing moxifloxacin, (2) a single drop of controlled-release microspheres without moxifloxacin, and (3) multiple topical treatment with moxifloxacin alone every 15 minutes for 1 hour. All rabbits were challenged, 1 hour after microspheres drop placement and immediately after the fifth topical dose of moxifloxacin, with anterior chamber injections of Staphylococcus aureus. Rabbits in the topical moxifloxacin group also were treated after challenge and four additional times over the next 24 hours. After 24 hours, the rabbits were clinically evaluated for endophthalmitis and the animals were euthanized to culture for intraocular S. aureus. The treatment groups were compared statistically for bacterial endophthalmitis. Results: No eyes had endophthalmitis, based on clinical presentation and/or positive culture, in the groups with controlled-release microspheres loaded with moxifloxacin (0/8, 0%) or multiple drops of topical moxifloxacin (0/8, 0%). In contrast, 8 of 8 eyes (100%; P ¼ 0.0001), had endophthalmitis among eyes treated with controlled-release microspheres drops without moxifloxacin. Conclusion: A single drop of controlled-release microspheres loaded with moxifloxacin was successful in preventing endophthalmitis. Further clinical studies will be required to confirm the full potential of controlled-release anti-infective loaded microspheres to prevent endophthalmitis. Translational Relevance: This study presents a simple method of prophylaxis to prevent postsurgical endophthalmitis

Modeling and Hemofiltration Treatment of Acute Inflammation

The body responds to endotoxins by triggering the acute inflammatory response system to eliminate the threat posed by gram-negative bacteria (endotoxin) and restore health. However, an uncontrolled inflammatory response can lead to tissue damage, organ failure, and ultimately death; this is clinically known as sepsis. Mathematical models of acute inflammatory disease have the potential to guide treatment decisions in critically ill patients. In this work, an 8-state (8-D) differential equation model of the acute inflammatory response system to endotoxin challenge was developed. Endotoxin challenges at 3 and 12 mg/kg were administered to rats, and dynamic cytokine data for interleukin (IL)-6, tumor necrosis factor (TNF), and IL-10 were obtained and used to calibrate the model. Evaluation of competing model structures was performed by analyzing model predictions at 3, 6, and 12 mg/kg endotoxin challenges with respect to experimental data from rats. Subsequently, a model predictive control (MPC) algorithm was synthesized to control a hemoadsorption (HA) device, a blood purification treatment for acute inflammation. A particle filter (PF) algorithm was implemented to estimate the full state vector of the endotoxemic rat based on time series cytokine measurements. Treatment simulations show that: (i) the apparent primary mechanism of HA efficacy is white blood cell (WBC) capture, with cytokine capture a secondary benefit; and (ii) differential filtering of cytokines and WBC does not provide substantial improvement in treatment outcomes vs. existing HA devices