Methods of local perfusion for treating fungal infections

Abstract

Described herein are methods and kits for topically treating or preventing fungal infection in a patient in need thereof. The methods may include topically administering multiple doses of at least one antifungal agent in solution to a human patient by irrigating the at least one antifungal agent in a wound. The administration provides the patient with continuous topical antifungal therapy for at least 24 hours, at least 48 hours, at least 72 hours, or at least 96 hours.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 63 / 486,186, filed February 21, 2023, U.S. Provisional Application No. 63 / 493,577, filed March 31, 2023, U.S. Provisional Application No. 63 / 519,923, filed August 16, 2023, U.S. Provisional Application No. 63 / 596,130, filed November 3, 2023, and U.S. Provisional Application No. 63 / 613,533, filed December 21, 2023, the contents of each of which are incorporated by reference in their entirety.

[0002] The present disclosure relates generally to methods, kits, dosages, and concentrations for perfusion of antifungal agents to living tissue. In particular, the disclosure relates to methods, kits, dosages, and concentrations for topical perfusion of antifungal agents in and at wounds, including surgical wounds, traumatic wounds, wounds caused or exacerbated by infection, and wounds containing infected medical devices. [Background technology]

[0003] Musculoskeletal wounds are common, painful experiences ranging in severity from minor abrasions and lacerations to major surgical or traumatic wounds involving severe injuries to the skin, subcutaneous tissue, and bone. Treatment of minor wounds may be partially addressed with local treatment. However, treatment of severe wounds may involve surgical intervention, repeated debridement, delayed healing, and subsequent wound closure (including prolonged exposure of the wound to fungal contamination from the skin or environment). Patients with prolonged wound exposure over the postoperative period are more likely to develop fungal infections, which can be difficult to treat and can impair the patient's functional status and quality of life. Chronic fungal infections are debilitating and potentially life-threatening.

[0004] The use of systemic antifungal therapy for the treatment of localized fungal infections in deep or complex wounds is typically unsuccessful, but topical administration of antifungal agents is very difficult to administer over long periods of time and protect healing wounds.

[0005] In view of the above, there is a substantial unmet clinical need for topical antifungal therapy of wounds (e.g., at therapeutic concentrations for extended periods of time). There is also an unmet need for new methods for topical delivery of antifungal agents for extended periods of time, either alone or in combination with additional antimicrobial agents. Summary of the Invention

[0006] According to some embodiments of the disclosed subject matter, treatment methods, dosages, and concentrations of topical antifungal therapy, including perfusion, are provided for the treatment of various wounds.

[0007] Provided herein are methods for treating or preventing localized fungal infections in patients in need of treatment. The methods may include locally administering multiple doses of at least one antifungal agent in solution to a human patient by perfusing the at least one antifungal agent in a wound. The administration provides continuous local antifungal therapy to the patient for at least 24 hours, at least 48 hours, at least 3 days, 4 days, 5 days, 6 days, at least 7 days, or at least 10 days, or longer. The administration provides a serum concentration of the at least one antifungal agent that is below the maximum safe serum concentration level of the at least one antifungal agent in a human patient. In some examples, the administration provides a total daily dose that is below the established FDA-approved intravenous dose of the antifungal agent.

[0008] The perfusion includes alternating injection and aspiration cycles. The injection and aspiration cycles may be continuous or staggered (e.g., at different times). The perfusion device may be configured to automatically control the perfusion. The perfusion may include immersing the localized infection site with at least one antifungal agent during a time interval between each alternating injection and aspiration cycle. The time interval may be equal to or less than the half-life, duration of activity, or PK / PD of the at least one antifungal agent. For example, the time interval may be less than 5 minutes, about 5 to about 60 minutes, about 10 to about 180 minutes, or about 30 to about 120 minutes. The aspiration cycle may be less than 60 minutes, less than 30 minutes, or less than 15 minutes.

[0009] In some embodiments, the perfusion is performed at least twice in a 24 hour period, at least four times in a 24 hour period, at least eight times in a 24 hour period, at least 16 times in a 24 hour period, or continuously over a 24 hour period.

[0010] The antifungal agent may optionally include two or more antifungal agents. In some embodiments, at least one antifungal agent is an azole derivative selected from the group consisting of fluconazole, isavuconazole, posaconazole, voriconazole, and combinations thereof. In some embodiments, the method may optionally include monitoring the serum concentration of the antifungal agent. In certain embodiments, the topically administered dose of the antifungal agent is at least 100 mg in a 24-hour period, the topically administered dose of the antifungal agent is at a concentration of at least 80 mcg / mL to 2 mg / mL, and the administration provides a serum concentration of the antifungal agent of less than 5 mcg / mL in the human patient. In another embodiment, the topically administered dose of the antifungal agent is at least 200 mg, 400 mg, 600 mg, 800 mg, or 1,200 mg in a 24-hour period, the topically administered dose of the antifungal agent is at a concentration of at least 80 mcg / mL to 2 mg / mL, and administration provides a serum concentration of the antifungal agent in a human patient of less than 5 mcg / mL. In another embodiment, the topically administered dose of fluconazole is at least 800 mg in a 24-hour period, the topically administered dose of the antifungal agent in a 24-hour period exceeds the recommended daily dose of the antifungal agent administered intravenously or systemically to an adult human patient over a 24-hour period, or the topically administered daily dose of the antifungal agent is 100 mg to 2,000 mg in a 24-hour period, and administration provides a serum concentration of the antifungal agent in a human patient of less than 5 mcg / mL. In another embodiment, the topically administered dose of the antifungal agent is at least 500 mg to 1,500 mg in a 24 hour period, and the serum concentration of the antifungal agent is less than 2.5 mcg / mL in a human patient, or the serum concentration of the antifungal agent is less than 1 mcg / mL in a human patient.

[0011] In one example, the topically administered dose of voriconazole is at least 100 mg in a 24-hour period, the topically administered dose of voriconazole is at a concentration of at least 80 mcg / mL to 2 mg / mL, and administration provides a serum concentration of voriconazole of less than 5 mcg / mL in a human patient. In another embodiment, the topically administered dose of voriconazole is at least 200 mg, 400 mg, 600 mg, 800 mg, or 1,200 mg in a 24-hour period, the topically administered dose of voriconazole is at a concentration of at least 80 mcg / mL to 2 mg / mL, and administration provides a serum concentration of voriconazole of less than 5 mcg / mL in a human patient. In another embodiment, the topically administered dose of fluconazole is at least 800 mg in a 24-hour period, and the topically administered dose of voriconazole in a 24-hour period exceeds the recommended daily dose of intravenously or systemically administered voriconazole in an adult human patient over a 24-hour period, or the topically administered daily dose of voriconazole is between 100 mg and 2,000 mg in a 24-hour period, and administration provides a serum concentration of voriconazole of less than 5 mcg / mL in the human patient. In another embodiment, the topically administered dose of voriconazole is at least 500 mg and 1,500 mg in a 24-hour period, and the serum concentration of voriconazole is less than 2.5 mcg / mL in the human patient, or the serum concentration of voriconazole is less than 1 mcg / mL in the human patient.

[0012] In various instances, the total daily dose of an antifungal agent administered locally by perfusion is equal to or less than the established FDA-approved intravenous dose of said antifungal agent.

[0013] In some embodiments, the antifungal agent is amphotericin B or a lipid formulation thereof. In some embodiments, the antifungal agent is an echinocandin selected from the group consisting of anidulafungin, caspofungin, and micafungin.

[0014] In various embodiments, the wound is the site of a localized fungal infection, for example, a topical wound, a diabetic ulcer, a traumatic wound, a surgical wound, a subcutaneous surgical wound, or a subcutaneous surgical wound containing an implanted medical device. The implanted medical device may be an orthopedic implant such as a joint replacement prosthesis. In some embodiments, antifungal perfusion therapy may be provided at least 1 cm, 2 cm, 3 cm, 5 cm, 10 cm, or 15 cm from the wound (e.g., a localized radius of antifungal therapy in centimeters from the center of the wound or the center of topical administration). Perfusion therapy may occur within the periphery of a superficial or subcutaneous wound (e.g., within the two-dimensional surface periphery of the wound or the three-dimensional periphery of the wound).

[0015] In some embodiments, the method may further include topically administering at least one additional therapeutic agent to treat a condition other than a fungal infection. Administering an antifungal agent along with the additional therapeutic agent may minimize the risk of secondary fungal infection when treating a condition other than a fungal infection. The at least one additional therapeutic agent may be at least one antimicrobial agent. The at least one antimicrobial agent may be one or more antibiotics, two or more antibiotics, or two or more antimicrobial agents of different classes. In some embodiments, the two or more antibiotics may include vancomycin and tobramycin, vancomycin and gentamicin, daptomycin and tobramycin, or daptomycin and gentamicin. The two or more antibiotics may be administered simultaneously, sequentially, or at different times. In some embodiments, the at least one antifungal agent is fluconazole, and the fluconazole and vancomycin are administered simultaneously, and the tobramycin or gentamicin is administered sequentially relative to the co-administered agents. The serum concentrations of fluconazole, vancomycin, and tobramycin remain below the recommended safe serum concentration of each administered agent throughout the entire administration period. In another embodiment, at least one antifungal agent is fluconazole, the fluconazole and gentamicin are administered simultaneously, and the vancomycin or daptomycin is administered sequentially to the co-administered fluconazole and gentamicin. The serum concentrations of each of the fluconazole, vancomycin or daptomycin, and gentamicin remain below the recommended safe serum concentration of each administered agent throughout the entire administration period. In other embodiments, fluconazole is administered once daily with a dwell period of about 4 to about 6 hours, followed by administration of two or more other therapeutic agents, such as vancomycin and lidocaine. In some examples, the vancomycin and lidocaine may be administered over a period of about 18 hours.

[0016] In some embodiments, the at least one antifungal agent is administered sequentially with the at least one antimicrobial agent. In other embodiments, the at least one antifungal agent is administered simultaneously with the at least one antimicrobial agent. The topical administration may be provided for 1 to 10 days, 2 to 10 days, 3 to 10 days, at least 1 day, at least 2 days, or at least 3 days. In some embodiments, the at least one antifungal agent is in a solution comprising saline.

[0017] In some embodiments, the concentration of the at least one antifungal agent exceeds the maximum recommended concentration of the at least one antifungal agent. Local administration can include perfusing the wound by soaking the wound locally with at least one antifungal agent, and aspirating the at least one antifungal agent after a certain period of time. Because the antifungal agent is perfused locally, it can be administered at different concentrations over different periods than would typically be administered orally, via IV, or topically.

[0018] Further provided herein is a kit for managing a localized fungal infection in a human patient, which may include at least one antifungal agent, a perfusion device configured to locally perfuse a localized site of fungal infection with at least one dose of the at least one antifungal agent, and instructions for administering the at least one dose of the at least one antifungal agent to provide continuous localized antifungal therapy to a patient for at least 24 hours, at least 48 hours, at least 72 hours, at least 96 hours, or longer.

[0019] The at least one antifungal agent in the kit may be fluconazole. The perfusion device may be configured to locally administer a total dose of fluconazole of 100 mg or more in a 24-hour period. In some embodiments, the at least one antifungal agent is fluconazole, and the kit further includes at least one antimicrobial agent. The at least one antifungal agent may be in a solution containing saline. For example, 2 mg / mL of fluconazole may be provided in a solution of sodium chloride. The at least one antifungal agent may be in a concentrated form for reconstitution in a solution containing saline.

[0020] The perfusion device may be configured not to be removed from the patient until administration is complete. In some embodiments, the perfusion device is configured to be applied to the wound or localized site of fungal infection for more than 48 hours, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, or at least 10 days. In some embodiments, the perfusion device is not a sponge. In some embodiments, the perfusion device includes a local perfusion component (e.g., an irrigation tubing, a fenestrated implant, a dressing, a sponge, a drain, a cannula, or a suction tubing). Further provided herein is a method of treating a localized fungal infection in a wound of a human patient. The method may include locally administering to the human patient by perfusion repeated doses of at least two therapeutic agents from separate sources without interruption to change sources. One of the two or more therapeutic agents is at least one antifungal agent and / or one of the two or more therapeutic agents is at least one antimicrobial agent. In some embodiments, the two or more therapeutic agents may be administered sequentially, simultaneously, or at different times.

[0021] These and other aspects will now be described in detail with reference to the following drawings. [Brief explanation of the drawings]

[0022] [Figure 1A]FIG. 1A shows an example of a therapeutic delivery system and kit. [Figure 1B] FIG. 1B shows a detailed view of the therapeutic delivery system and kit of FIG. 1A. DETAILED DESCRIPTION OF THE INVENTION

[0023] Detailed Description The disclosed subject matter generally relates to topically administered antifungal agents for improved treatment or prevention of fungal infection in infected wounds. Dosages and methods for safely administering repeated or cyclic doses and concentrations of antifungal agents are disclosed herein. Methods for administering doses of antifungal agents at concentrations higher than previously implemented systemic therapy levels while maintaining systemic exposure below safe systemic concentration limits are also disclosed. The methods described herein fulfill the needs described above. For example, the methods described herein offer new opportunities for previously unattainable safe and effective local delivery of therapeutic agents, such as antifungals, via the perfusion administration route, maximizing the effectiveness of topical antifungal agents and minimizing the risks associated with exposure of wounds to concentrated antifungal agents and the environment during treatment. Additionally, the methods described herein reduce side effects typically associated with topical antifungal agents, such as irritation, itching, or systemic inflammatory responses.

[0024] Successful topical antifungal therapy depends on the specific antifungal agent used and the exposure of the wound to the antifungal agent, including the dose, concentration, and duration of exposure, which are prescribed based on the antifungal agent's mechanism of action and pharmacodynamic target. The effectiveness of antifungal agents in clinical settings is determined by the patient's response to the treatment and confirmation of effective eradication of the infection. Antifungal agents are commonly used topically for a wide range of indications, and local injection of antifungal agents in solution has been reported to treat fungal infections in certain organs (e.g., lungs, kidneys, and bladder). However, because injections are unidirectional (none of the injected antifungal agent is aspirated or washed away from the infection site), the unidirectional injection dose is completely absorbed into the tissues and bloodstream, and local and systemic toxicity considerations limit the local dose and concentration that can be safely administered via injection. Complications of commonly used topical antifungal agents can be life-threatening. For example, complications of amphotericin B toxicity include anaphylaxis and renal failure. Complications of fluconazole toxicity include anaphylaxis, hepatotoxicity, clinical hepatitis, myalgia, seizures, acute kidney injury, thrombotic thrombocytopenic purpura, and, in rare cases, death. Thus, the disclosed methods may enable the administration of antifungal agents to patients who are otherwise contraindicated or precluded from treatment with antifungal agents. For example, the patient may be taking immunosuppressants or may have cancer, renal failure, or other conditions that affect the systemic absorption of antifungal agents. Thus, provided herein are methods for treating fungal infections in a human patient in need of treatment, where the patient has renal failure, cancer, immunosuppression, or a combination thereof. Without being bound by theory, the immunosuppression in the human patient may be due to a pathology (e.g., an autoimmune disease in the human patient) or due to the immunosuppressant administered to the human patient. Also provided herein are methods for treating fungal infections in a human patient in need of treatment that are free of, or substantially free of, the risk of ototoxicity to the human patient. Also provided herein are methods of treating a fungal infection in a human patient in need thereof, which methods pose no or substantially no risk of nephrotoxicity to the human patient.

[0025] The present disclosure represents a significant improvement and departure from previous methods, as it involves delivering one or more safe and effective doses of at least one antifungal agent via perfusion (e.g., injection and subsequent aspiration) to a local wound (e.g., traumatic wound, surgical wound, ulcer) in a human patient in need of delivery. Severe complications from the use of systemic antifungal agents may be substantially reduced or eliminated by the use of local antifungal agents. Such safe and effective local antifungal therapy via perfusion is achieved by local perfusion, i.e., injecting a sufficiently high concentration of antifungal agent, allowing sufficient time for the antifungal agent to soak the wound for effectiveness, and then aspirating the antifungal agent from the wound frequently enough to maintain safe systemic exposure to the antifungal agent (e.g., avoiding local and systemic toxicity). This perfusion cycle can then be repeated within a time frame before the antifungal agent's effectiveness wears off. Thus, in some embodiments, one or more doses of at least one antifungal agent, at or above the minimum effective dose, delivered to a localized wound may be bidirectional rather than unidirectional. The bidirectional infusion and aspiration cycles of irrigation therapy may be continuous or staggered.

[0026] In certain embodiments, topical cyclic administration provides a patient with continuous topical antifungal therapy over a period of time, which may include continuous topical exposure to therapeutic concentrations of at least one antifungal agent over said period of time.

[0027] The period for continuous local antifungal therapy may be at least 24 hours, at least 48 hours, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, or at least 10 days. Local administration of an antifungal agent may allow a patient to complete therapy for an underlying surgical procedure more quickly, reduce the number of surgeries a patient needs, or reduce the time a patient receives antimicrobial therapy. For example, local administration of an antifungal agent by perfusion may have a shorter therapy time (i.e., on the order of days) compared to therapy times (i.e., on the order of weeks) when topical, IV, or oral agents are administered. In some embodiments, local administration of an antifungal agent shortens the therapy time by at least 1 week, at least 2 weeks, at least 3 weeks, or at least 4 weeks. In some embodiments, topical administration of the antifungal agent reduces mortality in human patients by at least 50%, at least 40%, at least 30%, at least 25%, at least 20%, at least 15%, at least 10%, at least 5%, at least 4%, at least 3%, at least 2%, or at least 1% over a predetermined time frame (e.g., 1 week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, or 12 months). In some embodiments, topical administration of the antifungal agent reduces the risk of fungal reinfection in a human patient by at least 50%, at least 40%, at least 30%, at least 25%, at least 20%, at least 15%, at least 10%, at least 5%, at least 4%, at least 3%, at least 2%, or at least 1% (e.g., 1 week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, or 12 months).

[0028] In some embodiments, local administration may be at a rate faster than that which is safe for systemic administration. For example, the antifungal agent may be infused for a period exceeding the safe intravenous administration limit of fluconazole, which is 200 mg / hour. The disclosed local perfusion method may safely administer at least one antifungal agent at a rate of at least 200 mg / 30 minutes, or at least 200 mg / 10 minutes, or at least 200 mg / 5 minutes, or at least 200 mg / minute every hour, thereby increasing the exposure period to the at least one antifungal agent at its maximum concentration and increasing the pharmacodynamic target of MIC / AUC or MBEC / AUC.

[0029] In another embodiment, the present disclosure improves upon previous methods by providing concentrations and doses of locally administered antifungal agents that exceed recommended safe systemic concentrations and doses, but do not provide unsafe systemic plasma concentration levels in human patients. Irrigation may include bathing the site of localized fungal infection with at least one antifungal agent in the time interval between each alternating injection and aspiration cycle.

[0030] In other examples, the immersion time may be a fixed time of 5 minutes or more, 10 minutes or more, 20 minutes or more, 30 minutes or more, 60 minutes or more, 120 minutes or more, 180 minutes or more, or 240 minutes or more. In other examples, the immersion time may be less than 180 minutes, less than 120 minutes, less than 60 minutes, less than 30 minutes, or less than 20 minutes. In other examples, the immersion time interval between each injection and aspiration cycle may be less than 5 minutes, 5 to 60 minutes, about 10 to about 180 minutes, about 30 to about 120 minutes, or about 60 to about 90 minutes. Aspiration cycles may be less than 180 minutes, less than 120 minutes, less than 90 minutes, less than 60 minutes, or less than 30 minutes. As the concentration of the at least one antifungal agent increases, the time between the injection and aspiration phases of perfusion may decrease to maintain a safe serum concentration.

[0031] The present disclosure further provides methods for maintaining an effective concentration of at least one antifungal agent at or above the minimum effective dose at the site of a localized wound in a human patient by repeating the perfusion cycle two or more times, three or more times, four or more times, five or more times, six or more times, seven or more times, eight or more times, nine or more times, ten or more times, eleven or more times, or twelve or more times per day, even hourly or more frequently. In other examples, the perfusion is performed at least two times, at least four times, at least eight times, at least sixteen times, or continuously over a 24-hour period. Continuous perfusion includes successive infusion and aspiration cycles with no time between the previous and subsequent infusions.

[0032] The effectiveness of unidirectional infusion methods is limited by potential toxicity due to sustained concentrations of antifungal agents delivered to achieve a pharmacodynamic target. Local perfusion tailored to the specific pharmacodynamics and pharmacokinetics of each antifungal agent overcomes this limitation. Several classes of antifungal agents may be suitable for local wound perfusion, including, but not limited to, azole derivatives (fluconazole, isavuconazole, posaconazole, voriconazole, and combinations thereof), amphotericin B or its lipid formulation, and echinocandins (anin, caspofungin, and micafungin). Those skilled in the art will appreciate that the perfusion methods provided herein can be used to administer each of the aforementioned antifungal agents and provide safe and effective antifungal therapy for wounds by adjusting the volume, concentration, immersion time, drainage time, and cycle frequency to best suit the pharmacodynamics and pharmacokinetics of the administered antifungal agent.

[0033] This method allows for the administration of a total daily dose of at least one antifungal agent that is greater than the recommended dose for safe systemic administration.In one example, the locally administered dose of the antifungal agent in 24 hours exceeds the recommended daily systemic dose of the antifungal agent for adult human patients over 24 hours.The recommended daily dose can be the dose recommended for administration to adult human patients via intravenous, oral, or injection.The daily dose or total amount can also be the sum of multiple doses administered during the period. In some embodiments, the daily dose / amount provided by topical administration may be 10 mg / day or more, 50 mg / day or more, 100 mg / day or more, 200 mg / day or more, 300 mg / day or more, 400 mg / day or more, 500 mg / day or more, 600 mg / day or more, 700 mg / day or more, 800 mg / day or more, 900 mg / day or more, 1000 mg / day or more, 1500 mg / day or more, 2000 mg / day or more, 2500 mg / day or more, 3000 mg / day or more, 4000 mg / day or more, or 5000 mg / day or more of at least one antifungal agent. In some examples, the antifungal agent may be administered topically for at least 12 hours, and the daily dose / amount provided by topical administration may be about half of the amount that would be administered topically over 24 hours.

[0034] In other embodiments, the method allows for the administration of multiple doses of at least one antifungal agent in solution to a human patient by perfusing at least one antifungal agent in the wound. The administration provides the patient with continuous local antifungal therapy for 4 hours, 8 hours, 12 hours, 16 hours, 20 hours, or 24 hours. In some instances, the administration provides a total daily dose that is equal to or less than the established FDA-approved intravenous dose of the antifungal agent.

[0035] In some examples, the topically administered dose (total amount) of fluconazole, isavuconazole, posaconazole, or voriconazole is at least 100 mg, at least 150 mg, at least 200 mg, at least 250 mg, at least 300 mg, at least 400 mg, at least 500 mg, at least 550 mg, at least 600 mg, at least 700 mg, at least 800 mg, at least 900 mg, at least 1000 mg, at least 1500 mg, at least 2000 mg, at least 2500 mg, or at least 3000 mg in a 24-hour period. In other examples, the topically administered daily dose of fluconazole is between 100 mg and 3,000 mg, between 200 mg and 1,500 mg, or between 1,000 mg and 3,000 mg in a 24-hour period. In other embodiments, the maximum daily dose provided by topical administration of anidulafungin, caspofungin, or micafungin may be greater than 50 mg / day, greater than 100 mg / day, greater than 200 mg / day, greater than 300 mg / day, greater than 400 mg / day, greater than 500 mg / day, greater than 750 mg / day, or greater than 1,000 mg / day. In one example, the topically administered dose of micafungin is at least 100 mg, or at least 800 mg, at least 200 mg, or at least 400 mg in a 24-hour period. In one example, the topically administered dose / amount of amphotericin B is at least 15 mg, at least 25 mg, at least 50 mg, at least 100 mg, at least 250 mg, at least 500 mg, or at least 750 mg in a 24-hour period.

[0036] Table 1 provides exemplary topical antifungal dosage and concentration ranges. Table 1 provides exemplary topical concentrations in a 1200 mL solution for antifungal irrigation therapy (when administered at 50 mL / hour). In additional examples, the administered volume may be less than or greater than 50 cc, and the resulting concentrations will be proportionally greater or less than those set forth in Table 1. [Table 1]

[0037] The volume of the antifungal agent administered locally may be sufficient to allow the entire surface of the wound to be exposed throughout the entire soaking period. The volume of the dose administered for each soaking step may be about 5cc, about 10cc, about 20cc, about 30cc, about 40cc, about 50cc, about 60cc, about 70cc, about 80cc, about 90cc, about 100cc, or more than 100cc. In some embodiments, continuous antifungal treatment may be provided within a subcutaneous wound volume of at least 5cc, at least 10cc, 25cc, 50cc, 75cc, or 100cc, or may be provided at a depth of at least 1cm, 2cm, 3cm, 5cm, 10cm, or 15cm below the skin (e.g., small or large anatomical joint cavities, or small or large surgical wounds). In other examples, continuous antifungal treatment may be delivered locally / superficially to the local wound bed, up to the superficial layer.

[0038] Perfusion may be performed once or more per day, twice or more per day, five or more per day, ten or more per day, fifteen or more per day, twenty or more per day, twenty-one or more per day, or twenty-two or more per day. In one example, an antifungal agent may be perfused at the wound site every hour for 20 to 22 hours. In some examples, two or more antifungal agents may be perfused at the wound site simultaneously or sequentially. Two or more antifungal agents may be perfused at different frequencies. For example, one may be perfused hourly for 12 to 24 hours, and a second may be perfused once or twice a day.

[0039] The daily dose of the at least one antifungal agent may substantially exceed the maximum recommended daily systemic dose of the at least one antifungal agent. Substantially exceeding the maximum recommended daily systemic dose of the at least one antifungal agent may include a daily dose that exceeds the maximum recommended daily systemic dose by at least 110%, at least 125%, at least 150%, at least 175%, at least 200%, at least 225%, at least 250%, at least 275%, at least 300%, at least 400%, at least 500%, at least 600%, at least 700%, at least 800%, at least 900%, at least 1,000% or more.

[0040] In some embodiments, at least one antifungal agent is fluconazole. The concentration of fluconazole administered locally may be at least 0.2 mg / mL, at least 0.4 mg / mL, at least 0.8 mg / mL, or at least 1.6 mg / mL. The maximum recommended daily systemic dose of fluconazole is 400 mg / day. The daily dose of fluconazole administered locally may be 100 mg to 200 mg, 200 mg to 400 mg, 400 mg to 800 mg, 800 mg to 1,200 mg, 1,200 mg to 1,600 mg, or more than 1,600 mg. The total dose of fluconazole administered over the entire administration day may be in the range of about 1 g to 2 g, about 2 g to 4 g, about 4 g to 8 g, about 8 g to 12 g, about 12 g to 16 g, or more than 16 g.

[0041] Despite the high concentrations administered locally, an advantage of the disclosed methods is that the serum concentration of the antifungal agent is maintained at a level below the maximum safe level. Thus, the patient benefits from a high concentration of the antifungal agent at the site of infection while maintaining safe serum levels and minimizing side effects to the patient. The serum concentration is the concentration of the antifungal agent in the patient's blood serum from an intravenous sample anywhere in the body and is used to monitor systemic toxicity. The maximum safe serum concentration of the antifungal agent may be about 50 mcg / mL. In some examples, the serum concentration of the antifungal agent when administered according to the disclosed methods is less than 10 mcg / mL, less than 5 mcg / mL, less than 4 mcg / mL, less than 3 mcg / mL, less than 2.5 mcg / mL, less than 2 mcg / mL, or less than 1 mcg / mL. In one example, the maximum safe serum concentration of voriconazole may be about 50 mcg / mL. In some examples, the serum concentration of fluconazole when administered according to the disclosed methods is less than 5 mcg / mL, less than 4 mcg / mL, less than 3 mcg / mL, less than 2.5 mcg / mL, less than 2 mcg / mL, or less than 1 mcg / mL.

[0042] In some embodiments, the method may optionally include monitoring the serum concentration of the antifungal agent. In at least one embodiment, the serum level or concentration of the antifungal agent is undetectable. In some embodiments, administration provides a serum concentration of the antifungal agent of less than 5 mcg / mL, less than 2.5 mcg / mL, less than 1.25 mcg / mL, or a serum concentration of the antifungal agent below the limit of detection or quantitation of the testing method used in the human patient. In one example, the topically administered dose of voriconazole is at a concentration of at least 100 mcg / mL, and administration provides a serum concentration of voriconazole of less than 0.5 mcg / mL in the human patient, below the limit of detection or quantitation. In another example, the topically administered dose of voriconazole is at a concentration of at least 800 mcg / mL, and administration provides a serum concentration of voriconazole of less than 5 mcg / mL in the human patient. In yet another example, the topically administered daily dose of voriconazole is 100 mg to 3,000 mg in a 24 hour period, and the administration provides a serum concentration of fluconazole of less than 5 mcg / mL in a human patient.

[0043] The methods described herein may locally treat fungal infections in wounds in patients in need of treatment. The radius of the wound may be at least 1 cm, at least 5 cm, at least 10 cm, or at least 15 cm from the center of the wound (or the site of topical administration). In some instances, perfusion may occur within the two-dimensional or three-dimensional perimeter of the wound. In some instances, the wound may be a topical wound or a subcutaneous wound. For example, fungal infections may involve superficial fungi, subcutaneous fungi, or a combination thereof, most commonly including Candida albicans, Candida parapsilosis, and Aspergillus, and more rarely including dimorphic fungi, pigmented yeasts, black fungi, and other filamentous fungi. In other instances, the wound may be a chronic wound. Chronic wounds encompass a wide variety of wounds, which may be categorized as traumatic wounds, surgical wounds, ulcers of various causes, and burns. Traumatic wounds include abrasions and lacerations, penetrating wounds, compound fractures, and blast injuries. Chronic surgical wounds can occur in any surgical field and include deep surgical wounds, including incisional wounds and fistulas. Chronic ulcers include pressure ulcers, diabetic foot ulcers, vasculitic ulcers, arterial ulcers, and venous stasis ulcers. Chronic burn wounds can occur in any part of the body and can vary greatly in size and severity. Previously surgically treated surgical wounds and traumatic wounds may also contain implanted medical devices within the wound. For example, the surgical wound may be a subcutaneous surgical wound, and in some cases, the subcutaneous surgical wound may contain an implanted medical device. In some cases, the implanted medical device may be an orthopedic implant, such as a joint replacement prosthesis.

[0044] In some embodiments, the method may treat or prevent persistent infection, reinfection, or patient mortality. In one example, the method may prevent the occurrence of persistent infection by completely eradicating the fungal infection after administration is completed. In another example, the method may prevent reinfection by topically administering an antifungal agent after a previous antifungal infection has been treated to prevent further infection. In yet another example, the method may prevent mortality or reduce the likelihood of mortality by treating or preventing fungal infection in a wound.

[0045] In some embodiments, the method may further include topically administering at least one additional therapeutic agent for the treatment of conditions other than fungal infection. Chronic wounds are frequently complicated by the presence of polymicrobial infections. Musculoskeletal infections are often polymicrobial and biofilm-forming, and pathogen identification is typically achieved using tissue culture 7 to 14 days after treatment initiation. In a significant minority of cases, the pathogen is never identified by tissue culture methods; recent studies employing genetic sequencing techniques have identified multiple organisms in both culture-negative cases and cases in which a single pathogen was identified by tissue culture. In some instances, the at least one additional therapeutic agent is at least one antimicrobial agent. Therefore, administering one or more antimicrobial agents in addition to an antifungal agent may provide additional benefits in topical wound management.

[0046] Broad-spectrum systemic antibiotic therapy is the standard first-line treatment for localized infections, especially when pathogens have not yet been identified or may be polymicrobial. In cases of infections in the presence of implanted devices, such as periprosthetic joint infections (PJIs), breast implant infections (BIIs), or fracture-related infections (FRIs), broad-spectrum therapy that exceeds the biofilm bactericidal concentration (BBC) or minimum biofilm eradication concentration (MBEC) for all identified or potential pathogens is preferred. Preclinical studies to quantify the BBC and MBEC of antibiotics for pathogens found in localized human infections have not been comprehensive. Given the large number of potential antibiotics and known pathogens, the BBC and MBEC values ​​identified to date generally significantly exceed the safe systemic dosages and concentrations of the tested antimicrobial agents, making practical clinical application of such studies unlikely. In many studies where studies to establish MBEC values ​​were limited to clinically recommended dosages or concentrations, the concentrations of antimicrobial agents tested were not found to eradicate biofilms of specific organisms, and the MBEC for the specific antibiotic and strain tested remained unknown. Therefore, local irrigation of antimicrobial agents at concentrations above the MBEC for common wound infections while maintaining safe serum concentrations is desirable.

[0047] Broad-spectrum antibiotic therapy for localized infections generally includes a glycopeptide (e.g., vancomycin HCl) for coverage of gram-positive bacteria and an aminoglycoside (e.g., gentamicin or tobramycin sulfate) for coverage of gram-negative bacteria. Examples of safe dosages and systemic concentrations of these and other antibiotics are shown in Table 2. [Table 2]

[0048] In polymicrobial infections, the pathogens involved may include Gram-positive and Gram-negative bacteria, fungi, or any combination of these pathogens. In such cases, and in culture-negative infections (i.e., where no pathogen is identified), it is best practice to administer multiple antimicrobial agents to provide the broadest possible coverage. In addition to adequate and safe antibiotic therapy, what is clinically needed is a systemically safe antifungal therapy that provides local biofilm eradication under highly variable clinical conditions.

[0049] Antifungal therapy for localized infections may include azole derivatives from the group consisting of fluconazole, isavuconazole, posaconazole, voriconazole, and combinations thereof; amphotericin B or its lipid formulation; or an echinocandin selected from the group consisting of anidulafungin, caspofungin, and micafungin. Examples of safe dosages and systemic concentrations of these antifungal agents are shown in Table 3. [Table 3]

[0050] The at least one antibacterial agent may be administered locally by perfusion in a manner similar to the perfusion of the at least one antifungal agent. The at least one antifungal agent may be administered sequentially and / or simultaneously with the at least one antibacterial agent. In some embodiments, the at least one antibacterial agent is at least one antibiotic. Various antibiotics used to treat infections and biofilms may be used with the disclosed methods. In some embodiments, the at least one antibacterial agent is two or more antibiotics. Two or more antibiotics may be administered sequentially. In some instances, a first antibiotic may be administered simultaneously with the at least one antifungal agent, and a second antibiotic may be administered sequentially after the administration of the first antibiotic and the at least one antifungal agent.

[0051] Drug-drug interactions between the administered at least one antifungal agent and at least one antibiotic may be minimal or nonexistent. Because the agents are administered locally via perfusion, they are removed locally before significant systemic absorption or metabolism occurs. Therefore, there is little opportunity for either agent to interact systemically with each other or with other medications the patient is taking. The disclosed method may provide combinations of antifungal agents, antibiotics, anesthetics, analgesics, or other drugs that cannot otherwise be combined systemically. For example, local administration of a combination of at least one antifungal agent and at least one antibacterial agent may not be nephrotoxic or ototoxic to the patient.

[0052] The at least one antibiotic may be selected from vancomycin, daptomycin, tobramycin, gentamicin, or other antibiotics known in the art. In some embodiments, the two or more antibiotics may include vancomycin and tobramycin, and the at least one antifungal agent may be fluconazole. In one example, fluconazole and vancomycin may be administered simultaneously, and tobramycin may be administered sequentially with respect to the simultaneously administered fluconazole and vancomycin, while the serum concentrations of each of the fluconazole, vancomycin, and tobramycin remain below the recommended safe serum concentrations of each of the fluconazole, vancomycin, and tobramycin throughout the entire administration period.

[0053] As a route of administration, irrigation is defined as administration to soak or irrigate an open wound or body cavity. By controlling the irrigation dose, i.e., concentration, volume, and length of exposure (soaking or irrigation), a novel method for treating or preventing localized fungal infections in human patients in need of treatment or prevention has been developed. The irrigation concentration or total irrigation dose of antifungal agents may exceed the manufacturer's recommended concentration. Furthermore, the dose and concentration required to achieve the BBC or MBEC for biofilm-forming organisms varies depending on the organism, the maturity of the biofilm, the location of the biofilm, the implant or tissue to which the biofilm is attached, the dilution and absorption rate of the antifungal agent at the irrigation site, and other factors. In one aspect, provided herein is a method for treating or preventing localized fungal infections in wounds in human patients in need of treatment or prevention. The novel method described herein involves the continuous administration of one or more antimicrobial agents, preferably at least one antifungal agent, via the irrigation route of administration. Optimal efficacy of this novel method is achieved when the dose and concentration of each antimicrobial agent are administered based on the pharmacodynamics and pharmacokinetics of the administered drug. In certain embodiments of the present invention, one or more of the agents administered by perfusion are administered at a dose and / or concentration that exceeds the previously established safe systemic dose and / or concentration of that agent(s), while still providing a safe systemic (serum) concentration of that agent(s). Non-limiting examples of antifungal agents include fluconazole, isavuconazole, posaconazole, voriconazole, amphotericin B or its lipid formulation, anidulafungin, caspofungin, micafungin, and combinations thereof.

[0054] The daily dose of at least one antifungal agent may include a single administration or multiple administrations within the day. For example, the daily dose may be administered as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 administrations within the day. In some examples, the daily dose of at least one antifungal agent and at least one additional antimicrobial agent may be administered consecutively and / or simultaneously for at least 1, at least 2, at least 5, at least 10, at least 15, at least 20, or at least 24 administrations. Dosing may be every 30 minutes or less, about every hour, about every 2 hours, about every 3 hours, about every 4 hours, about every 5 hours, about every 6 hours, about every 7 hours, about every 8 hours, about every 9 hours, about every 10 hours, about every 12 hours, about every 18 hours, or about every 24 hours.

[0055] A daily dose may also include multiple doses in which at least one antifungal agent is administered sequentially with at least one antibiotic, with at least one dose of combination therapy for fungal and bacterial wound infections considered to be the entirety of both sequential doses. Alternatively, a daily dose may include a single daily dose of at least one antimicrobial agent, with the daily dose of combination therapy including single or multiple doses within the same day. In some embodiments, at least one antifungal agent may be administered simultaneously with at least one additional antimicrobial agent, followed by sequential administration of at least one additional antimicrobial agent to provide both antifungal and broad-spectrum antibacterial coverage. Specifically, one embodiment may include the administration of tobramycin (or gentamicin) and the co-administration of fluconazole and vancomycin (or daptomycin) sequentially. This particular perfusion regimen is tailored to the pharmacodynamic targets of each administered drug, specifically, tobramycin Cmax / MIC, vancomycin AUC / MIC, and fluconazole AUC / MIC. Another embodiment may involve sequential administration of amphotericin B and at least one antimicrobial agent (eg, tobramycin).

[0056] Alternatively, the daily dose may comprise a single daily administration of at least one antifungal agent, followed by a series of multiple doses of at least one additional therapeutic agent for the remainder of the day. In one embodiment, the single daily dose comprises simultaneous administration of fluconazole and tobramycin, with a 2-hour soak followed by 30 minutes of suction, and the series of multiple doses comprises continuous administration of vancomycin irrigation, with a 30-minute soak followed by 30 minutes of suction, repeated for the remainder of the day, at which point the single daily simultaneous administration of fluconazole and tobramycin is repeated to begin a new day of combination therapy.

[0057] Wound irrigation may involve soaking the wound tissue with an antifungal agent for about 10 minutes to about 180 minutes, about 30 minutes to about 180 minutes, about 30 minutes to about 45 minutes, about 30 minutes to about 60 minutes, about 60 minutes to about 90 minutes, about 60 minutes to about 120 minutes, or about 120 minutes to about 180 minutes. In various examples, wound irrigation may involve soaking the wound tissue with the antibiotic for 30 minutes, 60 minutes, 90 minutes, 120 minutes, 150 minutes, or 180 minutes. For fluconazole, a 30-minute soak time may be optimal. In other cases, the optimal soak time depends on the administered concentration and may be adjusted to administer a high concentration for effective fungal eradication while maintaining a safe level of systemic exposure as determined by serum concentrations such as creatinine or other serum levels.

[0058] Administration of the topical antifungal agent, with or without an additional antimicrobial agent, may be performed for one or more days to provide the necessary treatment or prophylaxis. Perfusion may be performed for 1 or more days, 2 or more days, 3 or more days, 4 or more days, 5 or more days, 6 or more days, 7 or more days, 8 or more days, 9 or more days, 10 or more days, 14 or more days, or 30 or more days. Topical administration may be repeated for an additional period of up to 10 days (e.g., changing the perfusion device between repeated administration periods).

[0059] Further provided herein is a method for treating or preventing localized fungal infection in a wound of a human patient in need thereof by locally administering repeated doses of at least two therapeutic agents from separate sources to the human patient by perfusion without interruption for changing sources. In one embodiment, one of the two or more therapeutic agents is at least one antifungal agent. In another embodiment, one of the two or more therapeutic agents is at least one antifungal agent and at least one additional antimicrobial agent. In some instances, the two or more therapeutic agents are administered sequentially, simultaneously, or in combination. The at least one additional antimicrobial agent may be at least one antibiotic or at least two antibiotics. For example, the at least one antifungal agent is fluconazole, and the at least two antibiotics are vancomycin and tobramycin. Fluconazole and vancomycin may be administered simultaneously from a first source, and tobramycin may be administered sequentially with the simultaneously administered fluconazole and vancomycin from a second source. The fluconazole and vancomycin are administered from a common source. In a further embodiment, the at least two therapeutic agents administered sequentially may be administered without manual intervention to switch between the first and second sources.

[0060] Further provided herein is a method of treating or preventing fungal infection of a localized wound in a human patient by locally administering to the human patient by perfusion at least one antifungal agent at a concentration that exceeds the recommended concentration or maximum recommended daily dose of the at least one antifungal agent, whereby said local administration by perfusion provides a serum concentration that is less than the maximum safe serum concentration of said at least one antifungal agent.

[0061] In certain embodiments, the method may include topically administering to a human patient at least one antifungal agent at a dose that substantially exceeds the recommended safe dose of the antifungal agent, and providing a serum concentration that is less than or equal to the maximum safe serum concentration of the antifungal agent. In some embodiments, the recommended safe dose is the maximum recommended systemic daily dose.

[0062] In one method, 50 cc of fluconazole at a concentration of 400 mcg / mL may be administered hourly for 22 hours for 7 days, simultaneously with vancomycin at a concentration of 2,500 mcg / mL and consecutively with 50 cc of tobramycin (administered once daily at a concentration of 1,600 mcg / mL). The daily doses in this method are 440 mg of fluconazole, 80 mg of tobramycin, and 3,000 mg of vancomycin, for a total dose of about 3.08 g of fluconazole, about 0.56 g of tobramycin, and about 21 g of vancomycin, with fixed dose ratios of 5.5:1 and 0.18:1 for fluconazole to tobramycin and vancomycin, respectively. The maximum dose and concentration that may be administered are pharmacokinetically calculated based on known values ​​of selected daily exposure and pharmacokinetic parameters, and such dose and concentration may be empirically adjusted before or during administration for patients with abnormal antibiotic absorption or excretion.

[0063] In one method, one or more antifungal agents may be administered at a known safe dose at a concentration(s) that exceeds the known safe concentration of such antifungal agent while providing a clinically established safe systemic level of the antifungal agent. This is achieved by irrigating the wound less frequently per day at a higher concentration, thereby administering a daily dose that remains within known safety limits. In another method, one or more antifungal agents may be administered at a concentration(s) within known safety limits at a daily dose that exceeds the known safe daily dose, while providing a clinically established safe systemic level of the one or more antifungal agents. This is achieved by irrigating the wound more frequently per day, within known safe concentration limits, thereby administering a daily dose that exceeds known safety limits. In either case, safe serum levels may be maintained by adjusting the soak and drain times for each dosing cycle to limit systemic absorption of each dose of one or more antifungal agents.

[0064] When two or more therapeutic agents are administered in the methods described herein, they may be administered at a fixed dose ratio of less than, greater than, or equal to 1:1, although it may be beneficial to administer the therapeutic agents at a fixed dose ratio that exceeds previously established maximum dose ratios. For example, based on the 5th and 95th percentiles of patient weight in the United States, the minimum and maximum recommended daily systemic doses of vancomycin are approximately 1,200 g and 7,500 g, respectively, and the minimum and maximum recommended daily systemic doses of tobramycin are approximately 200 g and 1,250 g, respectively. The resulting recommended fixed dose ratio of vancomycin to tobramycin is therefore 6:1. The methods disclosed herein describe the administration of antibiotics that are at or above the MBEC for the target organism while maintaining safe systemic levels of the antibiotic. In such cases, the fixed dose ratio may exceed known systemic dose ratios. In one method, the vancomycin to tobramycin dose ratio is 40:1. In another method, the vancomycin to tobramycin fixed dose ratio is 125:1. In yet another method, the fixed dose ratio of vancomycin to tobramycin is 10:1. In some embodiments, similar ranges of fixed dose ratios are provided for the two antifungal agents. In other embodiments, similar ranges of fixed dose ratios are provided for at least one antifungal agent and at least one antibiotic.

[0065] Due to incompatibility of certain therapeutic agents or differences in their pharmacodynamic targets, not all therapeutic agents may be administered simultaneously. For example, tobramycin is administered for an optimal concentration-dependent target with an optimal exposure at therapeutic concentrations of 2 hours, whereas vancomycin is administered for an optimal pharmacodynamic target of AUC / MIC or total daily exposure. An additional advantage of the methods and perfusion administration routes described herein is that they allow for simultaneous or sequential administration of multiple solutions above therapeutic targets from multiple sources without interruption or input from the patient or user to change the source of incompatible therapeutic agents.

[0066] Although the doses and concentrations and methods described herein may be described in the context of a particular wound, other wounds or conditions are also contemplated. For example, if a method is described as being useful for use in periprosthetic joint infections, the method may also be used in other infected wounds, such as breast implant infections, fracture-related infections, diabetic ulcers, osteomyelitis, surgical site infections, etc. The antifungal agents and methods described herein may be configured for use in a variety of localized wounds and treatment sites other than those specifically listed herein.

[0067] The treatment methods described herein may be performed manually (e.g., injection with a syringe and removal of fluid via gravity drain), semi-automatically (e.g., injection with a syringe pump and aspiration with an active drainage device), or automatically (e.g., via a custom-built perfusion delivery system). The perfusion delivery system may control perfusion (e.g., delivery and removal of a topical antifungal agent) according to a set protocol comprising one or more sequential stages for delivery one or more time periods, one or more times per day.

[0068] Also provided herein is a perfusion device for treating or preventing localized wounds in a human patient in need thereof. The perfusion device may be configured to automatically control perfusion. The perfusion device may be configured to locally administer a daily dose of at least one antifungal agent for up to 24 hours without interruption or input from the patient or user. In certain embodiments, the perfusion device may be configured to include two or more independent sources of therapeutic agent from which the perfusion device draws therapeutic agent according to various cycle times and frequencies described herein. In some embodiments, the perfusion device delivers therapeutic agent sequentially, simultaneously, alternately, or cyclically from the independent sources without any human intervention to change sources, connect the perfusion device to each source, or access or control the flow of therapeutic agent according to various cycle times and frequencies. In one example, a first independent source (e.g., a solution bag) may contain at least one antifungal agent, and a second independent source (e.g., a solution bag) may contain at least one antibiotic. In another example, the first independent source may include at least one antifungal agent and at least one antibiotic, and the second independent source may include at least one antibiotic or at least one other therapeutic agent.

[0069] In some embodiments, the perfusion device may further include a suction component. The suction component may be configured to apply suction to the wound or surrounding area to remove any previously administered therapeutic agent from the infection site. For example, the suction component may be configured to apply a vacuum of at least -50 mmHg to the tissue of the wound.

[0070] Further disclosed herein are kits for treating or preventing localized fungal infections in wounds of human patients. The kits may include at least one antifungal agent, a treatment delivery system and / or an irrigation device configured to locally irrigate (inject and aspirate) a series of doses of the at least one antifungal agent, and instructions for administration. The instructions may include instructions for administering at least one dose of the at least one antifungal agent to provide continuous antifungal therapy to the patient over at least 24 hours. It is further contemplated that the instructions may include steps for administering at least one antifungal agent and / or at least one antibiotic according to any of the methods disclosed herein. In some embodiments, the at least one antifungal agent in the kit may include at least one antifungal agent and at least one additional antimicrobial agent, and in some embodiments, the at least one antimicrobial agent in the kit may include at least one antibiotic and / or at least one pain management agent (e.g., an anesthetic or analgesic).

[0071] In some examples, at least one antifungal agent and / or at least one antibiotic may be provided in undiluted form in a vial or other container. The end user may then combine the at least one antifungal agent and / or at least one antibiotic with saline or other biocompatible fluid in one or more fluid reservoirs at a desired concentration when the antifungal agent(s) and / or antibiotic(s) are ready for administration. In other examples, the antifungal agent(s) and / or antibiotic(s) may be provided in saline and stored in a fluid reservoir, such as a bag. In various embodiments, a kit may include at least one antifungal agent and one or more antibiotics, along with any combination of a therapy delivery system, a perfusion device, a fluid reservoir, any other components required for the therapy delivery system or perfusion device to function properly, and instructions for administering the antifungal agent(s) and antibiotic(s). In some instances, the kit may be provided separately to the end user, such that the separate components of the kit arrive at the end user at different times and may then be assembled by the end user prior to administration to a patient. The at least one antifungal agent and / or at least one antibiotic may be provided in a solution comprising saline. The solution may further comprise one or more buffering agents. For example, the solution may comprise sodium bicarbonate. In other instances, the solution may further comprise dextrose or other excipients required for effective storage and administration of the antifungal agent and / or the antibiotic or pain management agent.

[0072] In some embodiments, the at least one antifungal agent may be fluconazole, and the at least one antibiotic may be vancomycin, daptomycin, and / or tobramycin. The therapeutic delivery system and / or perfusion device is configured to locally administer a daily dose of at least one antifungal agent and / or at least one antibiotic to the wound via perfusion. The therapeutic delivery system and / or perfusion device does not include a sponge, which requires intervention by the user to remove the sponge after a certain period of time. The therapeutic delivery system and / or perfusion device may be configured with multiple control functions to complete administration from two or more therapeutic agent sources over a one-day period without interruption or input from the patient or other users. In some examples, the multiple control functions include two or more infusion pumps or two or more control valves, each independently operated by the therapeutic delivery system.

[0073] The treatment delivery system and / or perfusion device may further include a local perfusion component applied onto or within the wound to be treated. In some examples, the local perfusion component may include a fenestrated infusion tube, an implantable fenestrated device, a drain, a dressing, a sponge, a cannula, or a suction tube. In some examples, the perfusion apparatus including the local perfusion component is configured to not be removed from the patient until administration is complete. The treatment delivery system and / or perfusion device includes a local perfusion component that remains in place for up to 10 days. For example, the treatment delivery system and / or perfusion device is configured to be applied to the local site (wound) of fungal infection for more than 48 hours, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, or at least 10 days. In other examples, the perfusion apparatus is configured to be applied to the local site (wound) of fungal infection for 24 hours, less than 48 hours, less than 3 days, less than 4 days, less than 5 days, less than 6 days, less than 7 days, or less than 10 days.

[0074] Therapeutic delivery systems and / or perfusion devices may be configured to administer two or more agents (antifungal and / or other therapeutic agents) from multiple sources without interruption or intervention by the user. In one example, the perfusion device is configured to locally administer a total dose of fluconazole of 200 mg or more, a total dose of tobramycin of 50 mg or more, and a total dose of vancomycin of 2,000 mg or more in a 24-hour period without interruption or human intervention.

[0075] 1A-1B illustrate an example of a therapy delivery system 100 and perfusion device 107 capable of providing controlled delivery of at least one antifungal agent to a treatment site 102 (e.g., an infection in a periprosthetic space, a bone segment, or a wound area). The therapy delivery system 100 and perfusion device 107 may be included in whole or in part in a kit. Generally, the therapy delivery system 100 may include a (portable) disposable device to allow adjustment of the distance between the therapy delivery system 100 and the treatment site 102 of a patient (e.g., a patient suffering from an infection treatable with fluid perfusion). In the example shown in FIG. 1A, the therapy delivery system 100 provides perfusion to a treatment site 102 comprising an perfusable volume (e.g., a joint space or a bone segment). The system 100 may include a fluid delivery system 104A, a fluid collection system 104B, and a control system 106. The fluid delivery system 104A may include one or more fluid reservoirs 108A, B. In some examples, one or more fluid reservoirs 108A, 108B may contain at least one antifungal agent and / or one or more antibiotics provided by the kit. For example, fluid reservoir 108A may contain an antifungal agent such as fluconazole, isavuconazole, posaconazole, or voriconazole in a saline solution, and fluid reservoir 108B may contain an antibiotic such as vancomycin, daptomycin, or tobramycin in a saline solution. In other examples, fluid reservoir 108B may contain a second antifungal agent. The fluid collection system 104B may include one or more collection fluid canisters 109.

[0076] In some examples, the control system 106 can control the flow of fluid from the fluid reservoirs 108A, B toward the treatment site 102 and / or draw fluid away from the treatment site 102 toward the fluid recovery system 104B. For example, the control system 106 can include one or more of a vacuum pressure source, a pump, or any other means for moving fluid through the system 100. In some examples, one means for moving fluid may be used for both infusing and withdrawing fluid from the treatment site 102. In other examples, one means may be used for infusing and another means for withdrawing. The system may be configured to deliver fluid percutaneously to a perfusion device positioned within the treatment area (e.g., infected tissue and / or infected joint, such as the hip, knee, shoulder, wrist, ankle, etc.). Although not shown, one or more other medical devices may assist, coordinate with, and / or operate in parallel with the therapy delivery system 100 to provide therapy for the patient (including the treatment site 102).

[0077] In one example, a perfusion device 107 can be configured to fluidly couple to a therapy delivery system 100, as shown in FIG. 1A. The therapy delivery system 100 can be coupled to a syringe or another manual component for delivering and withdrawing fluid from a treatment site. In some embodiments, the perfusion device 107 can have a porous component 103. The porous component 103 of the perfusion device 107 can be configured to fill spaces and / or openings in the treatment site and allow fluid exiting the tubing to flow through the porous component 103 to the treatment site 102.

[0078] Treatment system 100 may be configured to fluidly couple to an irrigation device 107 that can provide controlled delivery of fluid (e.g., antibiotics, saline, local anesthetic) to a treatment site 102 (e.g., an infected joint such as a knee or hip) during, for example, I&D, DAIR, double DAIR, or other procedures described elsewhere herein, or other types of healing, including wound and post-surgical healing.

[0079] In example contexts, the therapy delivery system 100 may be used to deliver at least one antifungal agent and / or one or more antibiotics to an infected joint (e.g., hip, knee, shoulder, wrist, ankle) or any type of living tissue that can be treated using controlled fluid irrigation. Examples of treatments include debridement, antibiotic, and periprosthetic joint infection treatment protocols such as implant retention (DAIR) and exchange arthroplasty, irrigation of surgical incisions and traumatic wounds, or irrigation for osteomyelitis and septic arthritis. While the applications may be described in the context of a particular treatment site (e.g., an infected joint) and its connection to that site, it should be understood that other treatment sites are contemplated and that the manner in which the system interfaces with these various sites may vary.

[0080] 1A-1B, the fluid delivery system 104A includes two or more fluid reservoirs 108A, 108B.

[0081] Each of the fluid reservoirs 108A, 108B has a specific volume and may store a specific fluid type to be delivered during a respective treatment phase. The contents of the fluid reservoirs may be switched, such that an antifungal agent may be stored in the first fluid reservoir 108B or the second fluid reservoir 108A, and one or more antibiotics may be stored in the second fluid reservoir 108A or the first fluid reservoir 108B. In some examples, the fluid reservoirs may also contain a combination of at least one antifungal agent and an antibiotic. The fluid reservoirs may be provided as part of a kit or may be provided separately and combined with one or more antifungal agents and one or more antibiotics of the kit prior to use.

[0082] For example, the first fluid reservoir 108A may contain or store a first fluid, which may include at least one antifungal agent, such as fluconazole, isavuconazole, posaconazole, or voriconazole. The first fluid may be delivered from the first fluid reservoir 108A to the treatment site 102 according to a respective fluid delivery protocol. The fluid delivery protocol may be included in the kit's instructions. The protocol may define the concentration of the at least one antifungal agent, the volume of antifungal agent fluid to be delivered, the duration of antifungal agent fluid delivery, and a pre-delivery vacuum, which may be performed at a set pressure (e.g., -125 mmHg) for a set vacuum time (e.g., approximately 30 minutes). The total volume of antifungal agent fluid delivered may vary depending on the length of time and the total time for first fluid delivery, soaking, and removal. Delivery of the antifungal agent fluid is followed by a soaking protocol to allow the treatment site 102 to soak in the delivered fluid. The duration of the antifungal fluid immersion protocol may be between 15 and 45 minutes, for example, approximately 30 minutes. The antifungal fluid may be removed from the treatment site 102 by the fluid recovery system 104B. The duration of the second fluid removal from the treatment site 102 may be approximately 30 minutes.

[0083] The second fluid reservoir 108B may store a second fluid, which may include an antibiotic, such as tobramycin, vancomycin, or daptomycin, or a second antifungal agent, such as fluconazole, isavuconazole, posaconazole, or voriconazole. The total volume of the second fluid delivered may vary depending on the length of time and the total time for the first fluid delivery, soaking, and removal. Delivery of the second fluid is followed by a soaking protocol to allow the treatment site 102 to soak with the delivered fluid. The duration of the second fluid soaking protocol may be between 15 and 45 minutes, for example, approximately 30 minutes. The second fluid may be removed from the treatment site 102 by the fluid recovery system 104B. The duration of antibiotic fluid removal from the treatment site 102 may be approximately 30 minutes.

[0084] The fluid recovery system 104B can direct fluid from the treatment site 102 to the recovery fluid canister 109. In some examples, the control system 106 can create a vacuum within the recovery fluid canister 109 to remove fluid from the treatment site 102 to the recovery fluid canister 109 via the vacuum line 113A. For example, a pump can be activated by the control system 106 to create a vacuum within at least the recovery fluid canister 109. In other examples, a vacuum pressure source, a syringe, gravity, a pump, or any other mechanism for moving fluid into or out of the treatment site 102 is contemplated. The recovery fluid canister 109 can include a disposable canister having a known volume (e.g., 2000 mL). The recovery fluid canister 109 recovers antibiotic solution or other fluids (e.g., wound exudate) that accumulate during vacuum-induced evacuation of fluid from the treatment site 102. The material of canister 109 is preferably translucent or transparent so that during use a user can assess the level of contents within canister 109. The material of canister 109 is also preferably capable of holding a vacuum at maximum vacuum levels without deforming or restricting flow.

[0085] Definition: In various embodiments, the description will be made with reference to the drawings. However, certain embodiments may be practiced without one or more of these specific details or in combination with other known methods and configurations. In this description, many specific details, such as specific doses, fixed dose combinations, and concentrations, are presented to provide a thorough understanding of the present invention. In other instances, specific doses, fixed dose combinations, and concentrations are not described in detail to avoid unnecessarily obscuring the description. References throughout this specification to "doses," "fixed dose ratios," "concentrations," and the like, mean that a particular method or described feature is included in at least one novel method of treatment. Thus, the appearance of phrases such as "a method of treatment" in various places throughout this specification does not necessarily refer to the same method of treatment. Furthermore, specific antibiotics, doses, fixed dose combinations, ratios, and concentrations may be combined in any suitable manner in one or more novel methods of treatment.

[0086] Where a range of values ​​is provided, each value between the upper and lower limits of that range is specifically contemplated and described herein.

[0087] As used herein, the term "about" refers to a range of values ​​that includes the specified value and that one of ordinary skill in the art would consider reasonably similar to the specified value. In embodiments, "about" refers to within a standard deviation using measurements generally accepted in the art. In embodiments, "about" refers to a range that spans + / - 10% of the specified value and may include the specified value. For example, endpoints may be within 10%, 8%, 5%, 3%, 2%, or 1% of the recited value. Furthermore, for convenience and brevity, a numerical range of "about 50 mg / mL to about 80 mg / mL" should also be understood to provide support for the range "50 mg / mL to 80 mg / mL." Endpoints may be based on variability permitted by appropriate regulatory agencies, such as the FDA, USP, etc.

[0088] As used herein, the term "substantially" means a value that one of ordinary skill in the art would consider significantly greater than the specified value. In some embodiments, "substantially" means at least 25% more than the specified value, or at least 125% of the specified value.

[0089] As used herein, the terms "safe" and "recommended" mean recommended by a medical authority, such as a manufacturer, the FDA, or other similar regulatory body. In some instances, the maximum dose or serum level may be based on peer-reviewed medical literature (e.g., Rybak et al., "Therapeutic Monitoring of Vancomycin in Adult Patients: A Consensus Review of the American Society of Health-System Pharmacists, the Infections Diseases Society of America, and the Society of Infectious Diseases Pharmacists," ASHP Therapeutic Position Statements, pp. 685-700, 2009) or recommended by a professional medical organization or association. In additional instances, the maximum recommended daily systemic dose and / or maximum safe serum concentration may be provided on the label or instructions for use of a particular antifungal or antibiotic.

[0090] As used herein, the terms "maximum recommended daily dose," "maximum recommended daily systemic dose," and "maximum recommended systemic daily dose" may be used interchangeably. In some instances, the systemic daily dose may be a daily dose administered by intravenous injection.

[0091] While this specification contains many specific details, these should not be construed as limitations on the scope of what is or may be claimed, but rather as descriptions of features specific to particular methods. Some methods described herein may be practiced in combination in a single method. Conversely, various features described in the context of a single method may be practiced individually, separately in multiple methods, or in any suitable subcombination of novel methods. Furthermore, while a method may be described herein as including a particular combination of antibiotics, dosages, or concentrations, and even originally claimed as such, one or more features from the claimed combination may, in some cases, be omitted from the combination, and the claimed combination may be intended as a subcombination or a variation of the subcombination. Similarly, although the sequential administration of multiple antibiotics is described herein in a particular order or for a particular duration, this should not be construed as requiring that the method be performed in a particular sequential order or for a particular duration, or that all elements of the sequence be performed, to achieve the desired results. Only a few examples and methods are disclosed. Variations, modifications, and enhancements to the described and other methods may be made based on what is disclosed.

[0092] In the above description and claims, phrases such as "at least one" or "one or more" may be followed by a connected list of one or more elements, antibiotics, combinations, doses, or concentrations. The term "and / or" may also appear in lists of two or more such elements. Unless otherwise implicitly or explicitly contradicted by the context in which it is used, such phrases are intended to mean any of the listed elements individually, or any of the listed elements in combination with any of the other listed elements. For example, the phrases "at least one of A and B," "one or more of A and B," and "A and / or B" are intended to mean "A only, B only, or a combination of A and B," respectively. A similar interpretation is intended for lists containing more than two items. For example, the phrases "at least one of A, B, and C," "one or more of A, B, and C," and "A, B, and / or C" are intended to mean "A only, B only, C only, a combination of A and B, a combination of A and C, a combination of B and C, or a combination of A, B, and C," respectively.

[0093] Use of the term "based on" above and in the claims is intended to mean "based at least in part on," thereby allowing for unrecited features or elements.

[0094] As used herein, the terms "comprises," "comprising," "containing," "having," and the like may have the meanings ascribed to them in U.S. patent law, and may also mean "includes," "including," and the like, and are generally construed as open-ended terms. The terms "consisting of" or "consists of" are closed-ended terms and include only those components, structures, steps, etc. specifically recited in conjunction with the term, and in accordance with U.S. patent law. "Consisting essentially of" or "consists essentially of" have the meanings generally ascribed to them by U.S. patent law. In particular, this term is generally open-ended, except to permit the inclusion of additional items, materials, components, steps, or elements that do not materially affect the basic and novel characteristics or function of the item(s) with which it is used. For example, trace elements that are present in a composition but do not affect the properties or characteristics of the composition are permitted to be present under the expression "consisting essentially of," even if they are not explicitly listed in the list of items following the term "consisting essentially of." When open-ended terms such as "comprising" or "including" are used herein, it is understood that direct support for the phrase "consisting essentially of" as well as the phrase "consisting of" should also be provided, as if explicitly stated, and vice versa.

[0095] As used herein, first, second, third, etc. are used to characterize and distinguish various elements of the present invention. The use of numerical terms may be used to distinguish one agent from another. The use of such numerical terms does not imply a sequence or order unless clearly indicated by context. Such numerical references may be used interchangeably without departing from the teachings of the embodiments and variations herein.

[0096] The inventions disclosed herein may be packaged in a single package of multiple therapeutic agents, or may be packaged together in multiple packages of combinations of therapeutic agents for use individually or together, and such use may be administered simultaneously, sequentially, cyclically, or sequentially (in a particular sequence which may include repeated use of one or more individual or combinations of therapeutic agents) according to specific instructions. All methods described herein may be performed in any suitable order unless otherwise indicated herein or clearly contradicted by context. The use of any and all examples or exemplary language (e.g., "such as") provided herein is intended merely to better clarify the invention and does not impose a limitation on the scope of any claims. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention. Implementation

[0097] Embodiment 1: A method of treating or preventing a fungal infection, said method comprising topically administering to a human patient multiple doses of at least one antifungal agent in solution by perfusing said at least one antifungal agent at a wound, wherein said administering provides continuous topical antifungal therapy to said patient for at least 24 hours.

[0098] Embodiment 2: The method of embodiment 1, wherein said administering provides a serum concentration of said at least one antifungal agent in said human patient that is less than or equal to a maximum safe level of serum concentration of said at least one antifungal agent.

[0099] Embodiment 3: The method of embodiment 1, wherein said administering provides continuous topical antifungal therapy to said patient for at least 48 hours.

[0100] Embodiment 4: The method of embodiment 3, wherein said administering provides continuous topical antifungal therapy to the patient for at least 3 days, 4 days, 5 days, 6 days, at least 7 days, or at least 10 days.

[0101] Embodiment 5: The method of embodiment 1, wherein said perfusion comprises alternating injection and aspiration cycles.

[0102] Embodiment 6: The method described in embodiment 5, wherein the injection and aspiration cycles are consecutive.

[0103] Embodiment 7: The method according to embodiment 5, wherein the injection and aspiration cycles are performed staggered.

[0104] Embodiment 8: The method described in embodiment 5, wherein the perfusion device is configured to automatically control the perfusion.

[0105] Embodiment 9: The method described in embodiment 5, wherein said irrigation comprises immersing the local fungal infection site with said at least one antifungal agent in the time intervals between each of the alternating injection and suction cycles.

[0106] Embodiment 10: The method of embodiment 9, wherein the total daily dose of the antifungal agent administered locally by perfusion is equal to or less than the established FDA-approved intravenous dose of the antifungal agent.

[0107] Embodiment 11: The method described in embodiment 9, wherein the time interval is from about 10 minutes to about 180 minutes.

[0108] Embodiment 12: The method described in embodiment 9, wherein the time interval is from about 30 minutes to about 120 minutes.

[0109] Embodiment 13: The method described in embodiment 9, wherein the suction cycle is less than 60 minutes.

[0110] Embodiment 14: The method described in embodiment 1, wherein said perfusion is performed at least twice in 24 hours.

[0111] Embodiment 15: The method described in embodiment 1, wherein the perfusion is performed at least four times in 24 hours.

[0112] Embodiment 16: The method described in embodiment 1, wherein the perfusion is performed at least 8 times in 24 hours.

[0113] Embodiment 17: The method described in embodiment 1, wherein the perfusion is performed at least 16 times in 24 hours.

[0114] Embodiment 18: The method of embodiment 1, wherein said perfusion is performed continuously for 24 hours.

[0115] Embodiment 19: The method of embodiment 1, wherein the at least one antifungal agent is an azole.

[0116] Embodiment 20: The method of embodiment 19, wherein the azole is selected from the group consisting of fluconazole, isavuconazole, posaconazole, voriconazole, and combinations thereof.

[0117] Embodiment 21: The method described in embodiment 1, wherein the amount of the antifungal agent administered topically in 24 hours is at least 100 mg.

[0118] Embodiment 22: The method of embodiment 21, wherein the dose of the antifungal agent administered topically is at a concentration of at least 80 mcg / mL, and wherein said administration provides a serum concentration of fluconazole in the human patient of less than 5 mcg / mL.

[0119] Embodiment 23: The method of embodiment 21, wherein the amount of the antifungal agent administered topically in 24 hours is at least 200 mg, 400 mg, 800 mg, 1,200 mg, or 1,600 mg.

[0120] Embodiment 24: The method of embodiment 21, wherein the dose of the antifungal agent administered locally is at a concentration of at least 600 mcg / mL, and wherein said administration provides a serum concentration of the antifungal agent in the human patient of less than 5 mcg / mL.

[0121] Embodiment 25: The method described in embodiment 21, wherein the amount of the antifungal agent administered topically in 24 hours is at least 1,200 mg.

[0122] Embodiment 26: The method described in embodiment 21, wherein the amount of the antifungal agent administered locally over a 24-hour period exceeds the recommended daily dose of the antifungal agent administered intravenously or systemically to an adult human patient over a 24-hour period.

[0123] Embodiment 27: The method of embodiment 21, wherein the amount of the antifungal agent topically administered in 24 hours is between 100 mg and 3,000 mg, and wherein said administration provides a serum concentration of the antifungal agent in the human patient of less than 5 mcg / mL.

[0124] Embodiment 28: The method described in embodiment 21, wherein the amount of the antifungal agent administered topically in 24 hours is at least 500 mg to 1,500 mg.

[0125] Embodiment 29: The method of embodiment 21, wherein the serum concentration of the antifungal agent in the human patient is less than 2.5 mcg / mL.

[0126] Embodiment 30: The method of embodiment 29, wherein the serum concentration of the antifungal agent in the human patient is less than 1.25 mcg / mL.

[0127] Embodiment 31: The method of embodiment 1, wherein the antifungal agent is fluconazole or voriconazole.

[0128] Embodiment 32: The method of embodiment 31, wherein the amount of fluconazole or voriconazole administered topically in 24 hours is at least 100 mg.

[0129] Embodiment 33: The method of embodiment 32, wherein the dose of fluconazole or voriconazole administered topically is at a concentration of at least 80 mcg / mL, and said administration provides a serum concentration of fluconazole or voriconazole in the human patient of less than 5 mcg / mL.

[0130] Embodiment 34: The method of embodiment 32, wherein the amount of fluconazole or voriconazole administered topically in 24 hours is at least 200 mg, 400 mg, 800 mg, 1,200 mg, or 1,600 mg.

[0131] Embodiment 35: The method of embodiment 32, wherein the dose of fluconazole or voriconazole administered topically is at a concentration of at least 600 mcg / mL, and said administration provides a serum concentration of fluconazole or voriconazole in the human patient of less than 5 mcg / mL.

[0132] Embodiment 36: The method of embodiment 32, wherein the amount of fluconazole or voriconazole administered topically in 24 hours is at least 1,200 mg.

[0133] Embodiment 37: The method of embodiment 32, wherein the amount of fluconazole or voriconazole administered topically over a 24-hour period exceeds the recommended daily dose of fluconazole or voriconazole administered intravenously or systemically to an adult human patient over a 24-hour period.

[0134] Embodiment 38: The method of embodiment 32, wherein the amount of fluconazole or voriconazole administered topically over a 24-hour period is 100 mg to 3,000 mg, and said administration provides a serum concentration of fluconazole or voriconazole in the human patient of less than 5 mcg / mL.

[0135] Embodiment 39: The method described in embodiment 32, wherein the amount of fluconazole or voriconazole administered topically in 24 hours is at least 500 mg to 1,500 mg.

[0136] Embodiment 40: The method of embodiment 32, wherein the serum concentration of fluconazole or voriconazole in the human patient is less than 2.5 mcg / mL.

[0137] Embodiment 41: The method of embodiment 40, wherein the serum concentration of fluconazole or voriconazole in the human patient is less than 1.25 mcg / mL.

[0138] Embodiment 42: The method of embodiment 1, wherein the at least one antifungal agent is amphotericin B or a lipid formulation thereof.

[0139] Embodiment 43: The method of embodiment 1, wherein the at least one antifungal agent is an echinocandin.

[0140] Embodiment 44: The method of embodiment 43, wherein the echinocandin is selected from the group consisting of anidulafungin, caspofungin, micafungin, and combinations thereof.

[0141] Embodiment 45: The method described in embodiment 44, wherein the amount of the echinocandin administered topically over 24 hours is at least 50 mg.

[0142] Embodiment 46: The method described in embodiment 1, wherein the wound is a superficial wound.

[0143] Embodiment 47: The method described in embodiment 46, wherein the superficial wound is a diabetic ulcer.

[0144] Embodiment 48: The method of embodiment 1, wherein the wound is a traumatic wound.

[0145] Embodiment 49: The method of embodiment 48, wherein the traumatic wound comprises an implantable medical device.

[0146] Embodiment 50: The method described in embodiment 1, wherein the wound is a surgical wound.

[0147] Embodiment 51: The method described in embodiment 50, wherein the surgical wound is a subcutaneous surgical wound.

[0148] Embodiment 52: The method described in embodiment 51, wherein the subcutaneous surgical wound contains an implantable medical device.

[0149] Embodiment 53: The method of embodiment 52, wherein the implantable medical device is an orthopedic implant.

[0150] Embodiment 54: The method described in embodiment 53, wherein the orthopedic implant is a joint replacement prosthesis.

[0151] Embodiment 55: The method described in embodiment 52, wherein local administration of the at least one antifungal agent reduces the treatment time of the implantable medical device.

[0152] Embodiment 56: The method described in embodiment 55, wherein the treatment time is reduced by at least 1 day to 10 days compared to the treatment time of the implantable medical device without local administration of at least one antifungal agent.

[0153] Embodiment 57: The method described in embodiment 1, wherein the wound is a site of a localized fungal infection.

[0154] Embodiment 58: The method of embodiment 57, wherein the topical antifungal therapy is provided up to at least 15 cm from the wound.

[0155] Embodiment 59: The method described in embodiment 1, wherein the perfusion occurs within the periphery of a superficial or subcutaneous wound.

[0156] Embodiment 60: The method of embodiment 1, further comprising topically administering at least one additional therapeutic agent for the treatment of a condition other than a fungal infection.

[0157] Embodiment 61: The method described in embodiment 60, wherein the at least one additional therapeutic agent is at least one antimicrobial agent.

[0158] Embodiment 62: The method described in embodiment 61, wherein the at least one antimicrobial agent is two or more antibiotics.

[0159] Embodiment 63: The method of embodiment 62, wherein the two or more antibiotics comprise vancomycin and tobramycin.

[0160] Embodiment 64: The method of embodiment 62, wherein the two or more antibiotics are administered sequentially.

[0161] Embodiment 65: The method described in embodiment 64, wherein the at least one antifungal agent is fluconazole.

[0162] Embodiment 66: The method of embodiment 65, wherein the fluconazole and vancomycin are administered simultaneously and the tobramycin is administered sequentially to the fluconazole and vancomycin, which are administered simultaneously.

[0163] Embodiment 67: The method of embodiment 65, wherein the serum concentrations of each of the fluconazole, vancomycin, and tobramycin remain below the recommended safe serum concentrations of each of the fluconazole, vancomycin, and tobramycin throughout the administration period.

[0164] Embodiment 68: The method described in embodiment 61, wherein the at least one antifungal agent is amphotericin B.

[0165] Embodiment 69: The method of embodiment 68, wherein the amphotericin B is administered sequentially with the at least one antimicrobial agent.

[0166] Embodiment 70: The method described in embodiment 69, wherein the at least one antimicrobial agent is tobramycin.

[0167] Embodiment 71: The method of embodiment 61, wherein the at least one antifungal agent is administered sequentially with the at least one antimicrobial agent.

[0168] Embodiment 72: The method described in embodiment 61, wherein the at least one antifungal agent is administered simultaneously with the at least one antimicrobial agent.

[0169] Embodiment 73: The method of embodiment 61, wherein there is no drug-drug interaction between the at least one antifungal agent and the at least one antimicrobial agent.

[0170] Embodiment 74: The method of embodiment 1, wherein the topical administration is provided for 1 day to 10 days.

[0171] Embodiment 75: The method of embodiment 1, wherein the at least one antifungal agent is in a solution comprising saline.

[0172] Embodiment 76: The method described in embodiment 75, wherein the solution further comprises dextrose.

[0173] Embodiment 77: The method described in embodiment 1, wherein the concentration of the at least one antifungal agent exceeds the maximum recommended concentration of the at least one antifungal agent.

[0174] Embodiment 78: The method described in embodiment 77, wherein the local administration comprises irrigating the local wound by soaking with the at least one antifungal agent, and aspirating the at least one antifungal agent after a period of time.

[0175] Embodiment 79: The method of embodiment 1, wherein the patient experiences reduced side effects after topical administration of the at least one antifungal agent compared to topical administration.

[0176] Embodiment 80: The method of embodiment 79, wherein the patient's irritation, itching, or systemic inflammatory response is reduced.

[0177] Embodiment 81: The method of embodiment 1, wherein the patient has immunosuppression, cancer, renal failure, or a combination thereof.

[0178] Embodiment 82: The method described in embodiment 81, wherein said immunosuppression in said human patient results from an autoimmune disease of said human patient or from an immunosuppressant drug administered to said human patient.

[0179] Embodiment 83: The method according to embodiment 1, wherein persistent or recurrent fungal infection in said patient is prevented.

[0180] Embodiment 84: The method of embodiment 1, wherein there is no or substantially no risk of ototoxicity to the human patient.

[0181] Embodiment 85: The method of embodiment 1, wherein there is no or substantially no risk of nephrotoxicity to said human patient.

[0182] Embodiment 86: A kit for administering topical antifungal therapy in a human patient, comprising: at least one antifungal agent; a therapeutic delivery system and / or perfusion device configured to locally perfuse a localized fungal infection site with at least one dose of said at least one antifungal agent in solution; instructions for administering at least one dose of said at least one antifungal agent to provide continuous topical antifungal therapy to said patient for at least 24 hours; Includes a kit.

[0183] Embodiment 87: The kit described in embodiment 86, wherein the at least one antifungal agent is fluconazole.

[0184] Embodiment 88: A kit described in embodiment 87, wherein the perfusion device is configured to locally administer a total amount of fluconazole of 100 mg or more in 24 hours.

[0185] Embodiment 89: The kit described in embodiment 86, wherein the kit further comprises at least one antimicrobial agent.

[0186] Embodiment 90: A kit described in embodiment 89, wherein the at least one antifungal agent is provided as a solution in a first independent source and the first antimicrobial agent is provided in a second independent source.

[0187] Embodiment 91: A kit described in embodiment 89, wherein a second antimicrobial agent is provided in a first independent source together with the at least one antifungal agent.

[0188] Embodiment 92: The kit described in embodiment 89, wherein an anesthetic or analgesic is provided in a second, independent source together with the first antimicrobial agent.

[0189] Embodiment 93: A kit described in embodiment 86, wherein the perfusion device is configured not to be removed from the patient until administration is complete.

[0190] Embodiment 94: A kit described in embodiment 93, wherein the perfusion device is configured to be applied to a local fungal infection site for more than 48 hours.

[0191] Embodiment 95: The kit described in embodiment 93, wherein the perfusion device is configured to be applied to a local fungal infection site for at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, or at least 10 days.

[0192] Embodiment 96: The kit described in embodiment 86, wherein the at least one antifungal agent is in a solution comprising saline.

[0193] Embodiment 97: A kit described in embodiment 86, wherein the perfusion device includes a local perfusion component that remains in place for up to 10 days.

[0194] Embodiment 98: A method for treating or preventing a localized fungal infection in a wound of a human patient, said method comprising locally administering to said human patient by perfusion, without interruption to change sources, repeated doses of at least two therapeutic agents from separate sources, wherein one of said two or more therapeutic agents is at least one antifungal agent.

[0195] Embodiment 99: The method of embodiment 98, wherein the two or more therapeutic agents are administered sequentially.

[0196] Embodiment 100: The method described in embodiment 98, wherein the two or more therapeutic agents are administered simultaneously.

[0197] Embodiment 101: A method for treating or preventing a localized fungal infection in a human patient in need thereof, said method comprising locally administering to said human patient by perfusion, without interruption to change sources, repeated doses of two therapeutic agents from separate sources, wherein one of said two or more therapeutic agents is at least one antifungal agent and at least one antimicrobial agent.

[0198] Embodiment 102: The method described in embodiment 101, wherein the at least one antimicrobial agent is at least one antibiotic.

[0199] Embodiment 103: The method described in embodiment 102, wherein the at least one antimicrobial agent is at least two antibiotics.

[0200] Embodiment 104: The method described in embodiment 103, wherein the at least one antifungal agent is fluconazole and the at least two antibiotics are vancomycin and tobramycin.

[0201] Embodiment 105: The method of embodiment 104, wherein the fluconazole and vancomycin are administered simultaneously and the tobramycin is administered sequentially to the fluconazole and vancomycin, which are administered simultaneously.

[0202] Embodiment 106: The method of embodiment 105, wherein the fluconazole and vancomycin are administered from a common source.

[0203] Embodiment 107: A method for treating or preventing a localized fungal infection in a human patient in need thereof, said method comprising locally administering at least one antifungal agent and at least two antimicrobial agents to said human patient by perfusion.

[0204] Embodiment 108: The method described in embodiment 107, wherein the at least one antifungal agent is fluconazole and the at least two antimicrobial agents are vancomycin and tobramycin.

Claims

1. 1. A method for treating or preventing a fungal infection, said method comprising topically administering multiple doses of at least one antifungal agent in solution to a human patient by perfusing said at least one antifungal agent at a wound, said administration providing continuous topical antifungal therapy to said patient for at least 24 hours.

2. 10. The method of claim 1, wherein said administering provides a serum concentration of said at least one antifungal agent in said human patient that is less than or equal to a maximum safe level of serum concentration of said at least one antifungal agent.

3. 10. The method of claim 1, wherein said administration provides continuous topical antifungal therapy to said patient for at least 48 hours.

4. 4. The method of claim 3, wherein the administration provides continuous topical antifungal therapy to the patient for at least 3 days, 4 days, 5 days, 6 days, at least 7 days, or at least 10 days.

5. The method of claim 1 , wherein the perfusion comprises alternating infusion and aspiration cycles.

6. The method of claim 5 , wherein the injection and aspiration cycles are consecutive.

7. 6. The method of claim 5, wherein the injection and aspiration cycles are staggered.

8. The method of claim 5 , wherein the perfusion device is configured to automatically control the perfusion.

9. 6. The method of claim 5, wherein the irrigation comprises bathing the localized fungal infection site with the at least one antifungal agent during the time interval between each alternating injection and aspiration cycle.

10. 10. The method of claim 9, wherein the total daily dose of the antifungal agent administered locally by perfusion is equal to or less than the established FDA-approved intravenous dose of the antifungal agent.

11. 10. The method of claim 9, wherein the time interval is from about 10 minutes to about 180 minutes.

12. 10. The method of claim 9, wherein the time interval is from about 30 minutes to about 120 minutes.

13. 10. The method of claim 9, wherein the suction cycle is less than 60 minutes.

14. 10. The method of claim 1, wherein the perfusion is performed at least twice in a 24-hour period.

15. 10. The method of claim 1, wherein the perfusion is performed at least four times in a 24-hour period.

16. 10. The method of claim 1, wherein the perfusion is performed at least 8 times in 24 hours.

17. 10. The method of claim 1, wherein the perfusion is performed at least 16 times in a 24-hour period.

18. 10. The method of claim 1, wherein the perfusion is performed continuously for 24 hours.

19. 10. The method of claim 1, wherein the at least one antifungal agent is an azole.

20. 20. The method of claim 19, wherein the azole is selected from the group consisting of fluconazole, isavuconazole, posaconazole, voriconazole, and combinations thereof.

21. 10. The method of claim 1, wherein the amount of the antifungal agent administered topically over a 24-hour period is at least 100 mg.

22. 22. The method of claim 21, wherein the dose of the antifungal agent administered topically is at a concentration of at least 80 mcg / mL, and said administration provides a serum concentration of fluconazole in the human patient of less than 5 mcg / mL.

23. 22. The method of claim 21, wherein the amount of the antifungal agent administered topically in 24 hours is at least 200 mg, 400 mg, 800 mg, 1,200 mg, or 1,600 mg.

24. 22. The method of claim 21, wherein the dose of the antifungal agent administered locally is at a concentration of at least 600 mcg / mL, and said administration provides a serum concentration of the antifungal agent in the human patient of less than 5 mcg / mL.

25. 22. The method of claim 21, wherein the amount of the antifungal agent administered topically over a 24-hour period is at least 1,200 mg.

26. 22. The method of claim 21, wherein the amount of the antifungal agent administered locally over a 24-hour period exceeds the recommended daily dose of the antifungal agent administered intravenously or systemically to an adult human patient over a 24-hour period.

27. 22. The method of claim 21, wherein the amount of the antifungal agent topically administered over a 24-hour period is between 100 mg and 3,000 mg, and wherein the administration provides a serum concentration of the antifungal agent in the human patient of less than 5 mcg / mL.

28. 22. The method of claim 21, wherein the amount of antifungal agent administered topically over a 24-hour period is at least 500 mg to 1,500 mg.

29. 22. The method of claim 21, wherein the serum concentration of the antifungal agent in the human patient is less than 2.5 mcg / mL.

30. 30. The method of claim 29, wherein the serum concentration of the antifungal agent in the human patient is less than 1.25 mcg / mL.

31. 10. The method of claim 1, wherein the antifungal agent is fluconazole or voriconazole.

32. 32. The method of claim 31, wherein the amount of fluconazole or voriconazole administered topically over a 24-hour period is at least 100 mg.

33. 33. The method of claim 32, wherein the dose of fluconazole or voriconazole administered topically is at a concentration of at least 80 mcg / mL, and said administration provides a serum concentration of fluconazole or voriconazole in the human patient of less than 5 mcg / mL.

34. 33. The method of claim 32, wherein the amount of fluconazole or voriconazole administered topically in 24 hours is at least 200 mg, 400 mg, 800 mg, 1,200 mg, or 1,600 mg.

35. 33. The method of claim 32, wherein the dose of fluconazole or voriconazole administered topically is at a concentration of at least 600 mcg / mL, and said administration provides a serum concentration of fluconazole or voriconazole in the human patient of less than 5 mcg / mL.

36. 33. The method of claim 32, wherein the amount of fluconazole or voriconazole administered topically over a 24-hour period is at least 1,200 mg.

37. 33. The method of claim 32, wherein the amount of fluconazole or voriconazole administered topically over a 24-hour period exceeds the recommended daily dose of fluconazole or voriconazole administered intravenously or systemically to an adult human patient over a 24-hour period.

38. 33. The method of claim 32, wherein the amount of fluconazole or voriconazole administered topically over a 24-hour period is between 100 mg and 3,000 mg, and said administration provides a serum concentration of fluconazole or voriconazole of less than 5 mcg / mL in the human patient.

39. 33. The method of claim 32, wherein the amount of fluconazole or voriconazole administered topically over a 24-hour period is at least 500 mg to 1,500 mg.

40. 33. The method of claim 32, wherein the serum concentration of fluconazole or voriconazole in the human patient is less than 2.5 mcg / mL.

41. 41. The method of claim 40, wherein the serum concentration of fluconazole or voriconazole in the human patient is less than 1.25 mcg / mL.

42. 10. The method of claim 1, wherein the at least one antifungal agent is amphotericin B or a lipid formulation thereof.

43. 10. The method of claim 1, wherein the at least one antifungal agent is an echinocandin.

44. 44. The method of claim 43, wherein the echinocandin is selected from the group consisting of anidulafungin, caspofungin, micafungin, and combinations thereof.

45. 45. The method of claim 44, wherein the amount of the echinocandin administered topically over a 24-hour period is at least 50 mg.

46. The method of claim 1 , wherein the wound is a superficial wound.

47. 47. The method of claim 46, wherein the superficial wound is a diabetic ulcer.

48. The method of claim 1 , wherein the wound is a traumatic wound.

49. 49. The method of claim 48, wherein the traumatic wound comprises an implantable medical device.

50. The method of claim 1 , wherein the wound is a surgical wound.

51. 51. The method of claim 50, wherein the surgical wound is a subcutaneous surgical wound.

52. 52. The method of claim 51, wherein the subcutaneous surgical wound contains an implantable medical device.

53. 53. The method of claim 52, wherein the implantable medical device is an orthopedic implant.

54. 54. The method of claim 53, wherein the orthopedic implant is a joint replacement prosthesis.

55. 53. The method of claim 52, wherein the local administration of the at least one antifungal agent reduces the treatment time of the implantable medical device.

56. 56. The method of claim 55, wherein the treatment time is reduced by at least 1 day to 10 days compared to the treatment time of the implantable medical device without the local administration of at least one antifungal agent.

57. The method of claim 1 , wherein the wound is a site of a localized fungal infection.

58. 58. The method of claim 57, wherein the topical antifungal therapy is provided to at least 15 cm from the wound.

59. The method of claim 1 , wherein the perfusion occurs within the periphery of a superficial or subcutaneous wound.

60. 10. The method of claim 1, further comprising topically administering at least one additional therapeutic agent for the treatment of a condition other than a fungal infection.

61. 61. The method of claim 60, wherein the at least one additional therapeutic agent is at least one antimicrobial agent.

62. 62. The method of claim 61, wherein the at least one antimicrobial agent is two or more antibiotics.

63. 63. The method of claim 62, wherein the two or more antibiotics comprise vancomycin and tobramycin.

64. 63. The method of claim 62, wherein the two or more antibiotics are administered sequentially.

65. 65. The method of claim 64, wherein the at least one antifungal agent is fluconazole.

66. 66. The method of claim 65, wherein the fluconazole and vancomycin are administered simultaneously and the tobramycin is administered sequentially to the simultaneously administered fluconazole and vancomycin.

67. 66. The method of claim 65, wherein the serum concentrations of each of the fluconazole, the vancomycin, and the tobramycin remain below the recommended safe serum concentrations of each of the fluconazole, the vancomycin, and the tobramycin throughout the administration period.

68. 62. The method of claim 61, wherein the at least one antifungal agent is amphotericin B.

69. 69. The method of claim 68, wherein the amphotericin B is administered sequentially with the at least one antimicrobial agent.

70. 70. The method of claim 69, wherein the at least one antimicrobial agent is tobramycin.

71. 62. The method of claim 61, wherein the at least one antifungal agent is administered sequentially with the at least one antimicrobial agent.

72. 62. The method of claim 61, wherein the at least one antifungal agent is administered simultaneously with the at least one antimicrobial agent.

73. 62. The method of claim 61, wherein there is no drug-drug interaction between the at least one antifungal agent and the at least one antimicrobial agent.

74. 10. The method of claim 1, wherein the topical administration is provided for 1 to 10 days.

75. 10. The method of claim 1, wherein the at least one antifungal agent is in a solution comprising saline.

76. 76. The method of claim 75, wherein the solution further comprises dextrose.

77. 10. The method of claim 1, wherein the concentration of the at least one antifungal agent exceeds a maximum recommended concentration of the at least one antifungal agent.

78. 78. The method of claim 77, wherein the local administration comprises irrigating the local wound by soaking with the at least one antifungal agent and aspirating the at least one antifungal agent after a period of time.

79. 10. The method of claim 1, wherein the patient experiences reduced side effects following topical administration compared to topical administration of the at least one antifungal agent.

80. 80. The method of claim 79, wherein the patient experiences reduced irritation, itching, or a systemic inflammatory response.

81. 10. The method of claim 1, wherein the patient has immunosuppression, cancer, renal failure, or a combination thereof.

82. 82. The method of claim 81, wherein the immunosuppression in the human patient results from an autoimmune disease in the human patient or from an immunosuppressant drug administered to the human patient.

83. 10. The method of claim 1, wherein the patient is prevented from becoming persistently or recurrently infected with a fungal infection.

84. 10. The method of claim 1, wherein there is no or substantially no risk of ototoxicity to the human patient.

85. 10. The method of claim 1, wherein there is no or substantially no risk of nephrotoxicity to the human patient.

86. 1. A kit for administering topical antifungal therapy in a human patient, comprising: at least one antifungal agent; a therapeutic delivery system and / or perfusion device configured to locally perfuse a localized fungal infection site with at least one dose of said at least one antifungal agent in solution; instructions for administering at least one dose of said at least one antifungal agent to provide continuous topical antifungal therapy to said patient for at least 24 hours; Includes a kit.

87. 87. The kit of claim 86, wherein the at least one antifungal agent is fluconazole.

88. 88. The kit of claim 87, wherein the perfusion device is configured to locally administer a total amount of fluconazole of 100 mg or more in 24 hours.

89. 87. The kit of claim 86, wherein the kit further comprises at least one antimicrobial agent.

90. 90. The kit of claim 89, wherein the at least one antifungal agent is provided as a solution in a first independent source and the first antimicrobial agent is provided in a second independent source.

91. 90. The kit of claim 89, wherein a second antimicrobial agent is provided in a first, independent source along with the at least one antifungal agent.

92. 90. The kit of claim 89, wherein an anesthetic or analgesic is provided in a second, independent source along with the first antimicrobial agent.

93. 87. The kit of claim 86, wherein the perfusion device is configured so that it is not removed from the patient until administration is complete.

94. 94. The kit of claim 93, wherein the perfusion device is configured to be applied to a localized fungal infection site for greater than 48 hours.

95. 94. The kit of claim 93, wherein the perfusion device is configured to be applied to a localized fungal infection site for at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, or at least 10 days.

96. 87. The kit of claim 86, wherein the at least one antifungal agent is in a solution comprising saline.

97. 87. The kit of claim 86, wherein the perfusion device comprises a local perfusion component that remains in place for up to 10 days.

98. 1. A method for treating or preventing a localized fungal infection in a wound of a human patient, said method comprising locally administering to said human patient by perfusion, without interruption to change sources, repeated doses of at least two therapeutic agents from separate sources, one of said two or more therapeutic agents being at least one antifungal agent.

99. 99. The method of claim 98, wherein the two or more therapeutic agents are administered sequentially.

100. 99. The method of claim 98, wherein the two or more therapeutic agents are administered simultaneously.

101. 1. A method of treating or preventing a localized fungal infection in a human patient in need thereof, said method comprising locally administering to said human patient by perfusion, without interruption to change sources, repeated doses of two therapeutic agents from separate sources, wherein one of said two or more therapeutic agents is at least one antifungal agent and at least one antimicrobial agent.

102. 102. The method of claim 101, wherein the at least one antimicrobial agent is at least one antibiotic.

103. 103. The method of claim 102, wherein the at least one antimicrobial agent is at least two antibiotics.

104. 104. The method of claim 103, wherein the at least one antifungal agent is fluconazole and the at least two antibiotics are vancomycin and tobramycin.

105. 105. The method of claim 104, wherein the fluconazole and vancomycin are administered simultaneously and the tobramycin is administered sequentially to the simultaneously administered fluconazole and vancomycin.

106. 106. The method of claim 105, wherein the fluconazole and vancomycin are administered from a common source.

107. 1. A method for treating or preventing a localized fungal infection in a human patient in need thereof, said method comprising locally administering at least one antifungal agent and at least two antimicrobial agents to said human patient by perfusion.

108. 108. The method of claim 107, wherein the at least one antifungal agent is fluconazole and the at least two antimicrobial agents are vancomycin and tobramycin.

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