In recent years, the incidence of infected wounds is steadily increasing, and so is the clinical as well as economic interest in effective therapies. These combine reduction of pathogen load in the wound with general wound management to facilitate the healing process. The success of current therapies is challenged by harsh conditions in the wound microenvironment, chronicity, and biofilm formation, thus impeding adequate concentrations of active antimicrobials at the site of infection. Inadequate dosing accuracy of systemically and topically applied antibiotics is prone to promote development of antibiotic resistance, while in the case of antiseptics, cytotoxicity is a major problem. Advanced drug delivery systems have the potential to enable the tailor-made application of antimicrobials to the side of action, resulting in an effective treatment with negligible side effects. This review provides a comprehensive overview of the current state of treatment options for the therapy of infected wounds. In this context, a special focus is set on delivery systems for antimicrobials ranging from semi-solid and liquid formulations over wound dressings to more advanced carriers such as nano-sized particulate systems, vesicular systems, electrospun fibers, and microneedles, which are discussed regarding their potential for effective therapy of wound infections. Further, established and novel models and analytical techniques for preclinical testing are introduced and a future perspective is provided. Graphical abstract

Abbreviations: (HPLC) AbstractReliable application of neutral protamine Hagedorn (NPH) insulin requires previous resuspension of the suspension by tipping over the cartridge 20 times. This procedure is considered annoying by patients. The goal of this investigation was to assess the efficiency of the mixing procedure when performed less frequently than recommended. Neutral protamine Hagedorn insulin cartridges from five different manufacturers (sanofi-aventis, Lilly, Berlin-Chemie, B. Braun, and Novo Nordisk) were emptied with doses of 28 IU in the morning and the evening over 5 days. While the first dose was obtained after a regular resuspension procedure (20× tipping over), the consecutive doses were obtained after 3, 6, 10, or 20 mixing procedures (12 cartridges per experimental series, two doses/day). Insulin concentrations of doses 1, 2, 6, and 10 were determined by highpressure liquid chromatography. Between dosing, cartridges were stored at room temperature in a horizontal position. Comparable insulin concentrations were seen in the first correctly prepared doses. Pronounced and substantial deviations from the selected dose were observed with most of the cartridges, in particular when resuspending only 3 and 6 times. Mean absolute percentage deviations when tipping 3 times and maximally observed overdoses were: Insuman basal: 1.1 ± 1.0%/4 IU, Humulin N: 2.6 ± 3.4%/19 IU, Berlinsulin H basal: 4.4 ± 6.0%/26 IU, Insulin B. Braun basal: 10.4 ± 8.9%/38 IU, and Protaphane: 4.7 ± 4.1%/19 IU (all p < 0.05 vs Insuman basal). Only one cartridge with three metal mixing bullets (sanofi-aventis) was resuspended efficiently with only a few mixing procedures. All other cartridges with fewer bullets were shown to deliver potentially harmful doses if used for treatment when the mixing procedure was less frequent than demanded in the instructions for use.