Methods of treating a localized infection with locally administered antibiotics

Abstract

A method and kit for treating a periprosthetic joint infection in skeletally mature patients undergoing an exchange arthroplasty procedure is described. The method may include locally administering a combination of tobramycin sulfate at a dose of 80 mg / day and vancomycin hydrochloride at a dose of 2.6-3 g / day to the patient, where the local administration occurs daily via irrigation for 7 to 10 days.

Description

Attorney Docket No.121446-854267 METHODS OF TREATING A LOCALIZED INFECTION WITH LOCALLY ADMINISTERED ANTIBIOTICS CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority from U.S. Provisional Patent Application No.63 / 683,134, filed on August 14, 2024, the entire contents of which are incorporated by reference. TECHNICAL FIELD

[0002] The present disclosure generally relates to methods and kits for antibiotic irrigation ofbiological tissue. In particular, the description relates to methods, doses, and concentrations of irrigation of localized antibiotics in and around wounds, including surgical wounds, traumatic wounds, wounds caused by or worsened by infection and wounds containing infected tissue or medical devices. BACKGROUND

[0003] Localized infection, including septic arthritis, periprosthetic joint infection (PJI), breastimplant infection (BII), and fracture related infection (FRI), is a rare but devastating pathology associated with severe complications. Successful management of localized infection includes surgical intervention and systemic antibiotics in most cases. An important part of the surgical procedure is reduction of the bacterial bioburden. Bioburden removal is accomplished through intraoperative irrigation and surgical debridement of infected tissue. Antibiotic therapy for the treatment of the infection is commonly systemic antibiotics (administered orally or intravenously). Localized antibiotics may also be applied during the surgical procedure, but localized therapeutic concentrations are difficult to maintain post-operatively. It is the systemic antibiotic therapy that is considered the treatment of the infection.

[0004] An infected implant may be replaced or retained at the time of treatment depending onthe clinical presentation. Many pathogens commonly found in PJI, BII, FRI, or other infections involving implants are known to form a protective structure called a biofilm in the presence of an implanted medical device. Such biofilms are not susceptible to antibiotics administered systemically; therefore, the infected implant must be surgically removed as part of any treatment if the infection is to be fully eradicated with a high degree of success. In cases where the infection is well-established, implants are typically replaced in a one-stage or two-stage exchange procedure. In acute cases, cases of infection in medically compromised patients and cases of implants which are unusually difficult to remove, the most common surgical treatments retain the105228354.41Attorney Docket No.121446-854267 implants and are known as irrigation and debridement (I&D) or debridement, antibiotics and implant retention (DAIR). Replacing the implant is more invasive than retaining the implant, but it reduces bacterial bioburden, particularly biofilm, and improves outcomes compared to implant retention.

[0005] Infections of traumatic wounds are a common occurrence, as are surgical site infections(SSI) which occur post-operatively following virtually all types of surgical procedures. Such infections may be superficial and relatively easy to treat successfully, while like PJI, others involve deep tissue with or without surgically implanted devices and become very difficult to eradicate.

[0006] In view of the foregoing, there is a need for improved methods and kits for antibioticirrigation of wounds. BRIEF SUMMARY

[0007] In some aspects, provided herein is a method of treating a periprosthetic joint infectionin a skeletally mature patient undergoing an exchange arthroplasty procedure, the method comprising: locally administering a combination of tobramycin sulfate at a dose of about 80 mg / day and vancomycin hydrochloride at a dose of about 2.6 g / day to about 3 g / day to the patient.

[0008] In some aspects, the combination is only administered to the patient to treat or preventinfections that are proven or strongly suspected to be caused by bacteria.

[0009] In some aspects, the local administration occurs daily via irrigation for 7 to 10 days.

[0010] In some aspects, the locally administering comprises irrigating the periprosthetic jointinfection with the combination.

[0011] In some aspects, the irrigating the localized infection comprises soaking theperiprosthetic joint infection with the tobramycin sulfate or vancomycin hydrochloride and subsequently aspirating the tobramycin sulfate or vancomycin hydrochloride.

[0012] In some aspects, the combination is locally administered by irrigation using anirrigation system. In some aspects, the method further comprises: administering 80 mg of tobramycin sulfate in 50 mL of normal saline (1.6 mg / mL) by the irrigation system for 7-10 days (total daily exposure of 1.6 mg / day); following a 2-hour soak, removing the tobramycin sulfate using suction over 30 minutes; administering 125 mg of vancomycin hydrochloride in 50 mL of normal saline (2.5 mg / mL) with the irrigation system every hour for 10 treatments for a duration of 7-10 days (total daily exposure of 1.25 g / day); and following a 30-minute soak, removing the vancomycin hydrochloride using suction over 30 minutes after each administration. In some aspects, approximately 21-22 consecutive rounds of vancomycin irrigation cycles are administered105228354.42Attorney Docket No.121446-854267 per day. In other aspects, over a 7-day treatment, there are 7, 2-hour applications of tobramycin and approximately 147, 30-minute applications of vancomycin.

[0013] In some aspects, the method further comprises monitoring the patient duringadministration for ototoxicity and nephrotoxicity.

[0014] In some aspects, the method further comprises monitoring tobramycin serum troughlevels; maintaining tobramycin serum trough levels at less than about 2 mcg / mL; and if tobramycin serum trough levels are greater than about 2 mcg / mL or toxicity is a concern, decreasing the total dose of tobramycin based on the tobramycin serum trough levels. In some aspects, the total tobramycin administered is decreased but not total volume. In some aspects, the tobramycin serum trough levels are monitored after 2 or 3 doses, and also at 3- to 4-day intervals during administration.

[0015] In some aspects, the patient has a mean tobramycin serum concentration of about 0.5 ±0.2 mcg / mL during administration. In other aspects, the patient has a mean tobramycin serum trough level of about 0.4 ± 0.2 mcg / mL during administration.

[0016] In some aspects, the method further comprises monitoring vancomycin serum levels;maintaining vancomycin serum levels at less than about 20 mcg / mL; and if serum levels are greater than about 20 mcg / mL or if toxicity is a concern, decreasing the total dose of vancomycin based on the vancomycin serum levels. In some aspects, the total vancomycin administered is decreased but not total volume.

[0017] In some aspects, the patient has a mean vancomycin serum concentration of about 5.6± 5.4 mcg / mL during administration.

[0018] In some aspects, the dose of tobramycin sulfate is prepared by: using an approximately3 mL syringe to withdraw a 2 mL volume (80 mg) from a vial comprising tobramycin sulfate and transfer to a 50 mL 0.9% sodium chloride intravenous piggyback (IVPB) bag.

[0019] In some aspects, the dose of vancomycin hydrochloride is prepared by: reconstitutingthree 1 g vials comprising vancomycin hydrochloride using an approximately 20 mL syringe by adding 20 mL sterile water for injection to each vial; withdrawing the contents of the three 1 g vancomycin hydrochloride vials and adding all 3 g (60 mL) of vancomycin hydrochloride to a 1000 mL normal saline IVPB bag; and using an approximately 100 mL syringe, adding 100 mL of normal saline to the IVPB already containing 3 g of vancomycin hydrochloride.

[0020] In some aspects, the tobramycin sulfate is administered at a concentration of about 1.6mg / mL.

[0021] In some aspects, vancomycin hydrochloride is administered at a concentration of about2.5 mg / mL.105228354.43Attorney Docket No.121446-854267

[0022] In some aspects, the method further comprises maintaining tobramycin serum levels atless than about 2 mcg / mL. In some aspects, the method further comprises maintaining vancomycin serum levels at less than about 20 mcg / mL.

[0023] In some aspects, the combination is administered to the patient to treat or preventbacterial infections.

[0024] In some aspects, the method further comprises modifying the dose of tobramycinsulfate or vancomycin hydrochloride if nephrotoxicity or ototoxicity occurs in the patient. In some aspects, the method further comprises modifying the dose of tobramycin sulfate if a tobramycin serum trough level above about 2 mcg / mL occurs in the patient. In some aspects, modifying the dose of tobramycin sulfate comprises decreasing total drug administered but not total volume. In some aspects, the dose of tobramycin sulfate is modified to about 40 mg at a concentration of about 0.8 mg / mL.

[0025] In some aspects, the method further comprises modifying the dose of vancomycinhydrochloride if a vancomycin serum trough level above about 20 mcg / mL occurs in the patient. In some aspects, modifying the dose of vancomycin hydrochloride comprises decreasing total drug administered but not total volume. In some aspects, the dose of vancomycin hydrochloride is modified to about 1.5 g at a concentration of about 1.25 mg / mL.

[0026] In some aspects, the method further comprises maintaining systemic concentrations oftobramycin below about 15 mcg / mL, below about 14 mcg / mL, below about 13 mcg / mL, below about 12 mcg / mL, below about 11 mcg / mL, or below about 10 mcg / mL.

[0027] In some aspects, the method further comprises discontinuing administration atappearance of skin rashes, mucosal lesion, or blisters on the patient.

[0028] In some aspects, the method further comprises assessing the patient’s auditory function.In some aspects, assessing the patient’s auditory function comprises an audiometric test that evaluates hearing up to 8000 Hz.

[0029] In some aspects, the method further comprises assessing culture information orsusceptibility information of the periprosthetic infection.

[0030] In some aspects, the method further comprises monitoring toxicities associated withaminoglycosides as a class.

[0031] In some aspects, such treatment results in: an overall success rate at 90 days in apopulation of patients who have received such treatment of at least about 80%; an overall success rate at 180 days in a population of patients who have received such treatment of at least about 55%; and / or iii) an overall success rate at 360 days in a population of patients who have received such treatment of at least about 50%. In some aspects, the overall success rate is calculated as the105228354.44Attorney Docket No.121446-854267 proportion of patients in a treatment group who, at a defined timepoint satisfy the criteria for an overall success. In some aspects, the overall success is achieved when the patient has 1) received a revision prosthesis; 2) no evidence of periprosthetic joint infection following reimplantation; 3) not undergone reoperation of the affected joint prior to or following reimplantation; 4) not continued antibiotics for joint infection; and 5) not died.

[0032] In other aspects, such treatment results in an improved quality of life score in thepatient. In some aspects, the quality-of-life score is calculated from a European Quality of Life 5 Dimensions 3 Levels of Severity (EQ-5D-3L) questionnaire, a Knee Disability and Osteoarthritis Outcome Score (KOOS) questionnaire, or a Hip Disability and Osteoarthritis Outcome Score (HOOS) questionnaire.

[0033] Also provided herein, in some aspects, is Vancomycin hydrochloride and tobramycinsulfate for use according to the methods disclosed herein.

[0034] Also provided herein, in some aspects, is a method of treating or preventing a localinfection in a wound, the method comprising: locally administering to a human patient a plurality of doses of at least one antiseptic agent in solution and at least one antibiotic in solution by irrigating the wound, wherein the locally administering of each solution is performed at least once in a 24-hour period.

[0035] In some aspects, the at least one antiseptic agent comprises hypochlorous acid, sodiumhypochlorite, citric acid, acetic acid, polyhexamethylene biguanide, chlorhexidine glutonate, povidone iodine, copper sulfate / potassium iodide, taurolidine, or combinations thereof.

[0036] In some aspects, the infection comprises a bacterial pathogen, a fungal pathogen, or apolymicrobial pathogen.

[0037] In some aspects, irrigating the wound with the at least one antiseptic agent in solutionis performed prior to irrigating the wound with the at least one antibiotic solution. In some aspects, irrigating the wound with the at least one antiseptic agent comprises instillation of the at least one antiseptic agent in solution followed by a dwell period followed by aspiration of the at least one antiseptic agent in solution to remove the at least one antiseptic agent in solution. In some aspects, about 50 mL of the at least one antiseptic agent in solution is instilled with about a 5-minute dwell period followed by about a 5-minute aspiration.

[0038] In some aspects, a sterile fluid is irrigated after the at least one antiseptic agent insolution to remove or otherwise dilute the at least one antiseptic agent. In some aspects, the sterile fluid comprises normal saline.

[0039] In some aspects, irrigating the wound with the at least one antiseptic agent in solutionis accomplished by simultaneously instilling and aspirating the at least one antiseptic agent in105228354.45Attorney Docket No.121446-854267 solution. In some aspects, at least about 100 mL, at least about 250 mL, at least about 500 mL, at least about 1000 mL or at least about 2000 mL of the at least one antiseptic agent in solution is irrigated. In some aspects, the at least one antiseptic agent in solution is irrigated in less than about 15 minutes.

[0040] Also provided herein, in some aspects, is a method of treating or preventing a localinfection in a human patient at a localized site, the method comprising locally administering by irrigation to the localized site of the human patient a plurality of doses of: at least one antiseptic agent in solution; and at least one antibiotic in solution. In some aspects, the at least one antiseptic agent comprises hypochlorous acid, sodium hypochlorite, citric acid, acetic acid, polyhexamethylene biguanide, chlorhexidine glutonate, povidone iodine, copper sulfate / potassium iodide, taurolidine, or combinations thereof. In other aspects, the antiseptic agent comprises fluconazole, isavuconazole, posaconazole, voriconazole, amphotericin B, anidulafungin, caspofungin, or micafungin. In some aspects, the at least one antibiotic comprises vancomycin, daptomycin, and / or tobramycin.

[0041] In some aspects, the local infection comprises a bacterial pathogen, a fungal pathogen,or a polymicrobial pathogen.

[0042] In some aspects, irrigating the localized site with the at least one antiseptic agentcomprises instillation of the at least one antiseptic agent in solution followed by a dwell period followed by aspiration of the at least one antiseptic agent in solution to remove the at least one antiseptic agent in solution. In some aspects, about 50 mL of the at least one antiseptic agent in solution is instilled with about a 5-minute dwell period followed by about a 5-minute aspiration.

[0043] In some aspects, the least one antiseptic agent in solution is: locally administered byirrigation prior to the at least one antibiotic in solution; locally administered by irrigation following the at least one antibiotic in solution; or locally administered by irrigation concurrently with the at least one antibiotic in solution.

[0044] Also provided herein, in some aspects, is a kit for treating a periprosthetic jointinfection in skeletally mature patients undergoing an exchange arthroplasty procedure, the kit comprising: a plurality of vials, each comprising 1 g of vancomycin hydrochloride lyophilized powder intended for reconstitution / dilution with normal saline; and a second plurality of vials, each comprising 80 mg / 2 mL (40 mg / mL) of tobramycin sulfate solution intended for reconstitution / dilution with normal saline. In some aspects, the kit further comprises: a treatment delivery system and / or irrigation device configured to locally irrigate the periprosthetic joint infection with a combination of vancomycin hydrochloride and tobramycin sulfate; and instructions for administration. In some aspects, the kit comprises 21 vials of vancomycin105228354.46Attorney Docket No.121446-854267 hydrochloride and 7 vials of tobramycin sulfate. In some aspects, the kit further comprises a plurality of vials comprising an antiseptic agent. DESCRIPTION OF FIGURES

[0045] These and other aspects will now be described in detail with reference to the followingfigures.

[0046] FIG. 1 shows an example of a kit of a plurality of vials comprising vancomycinhydrochloride and a plurality of vials comprising tobramycin sulfate.

[0047] FIG. 2A shows example instruments in a spacer system.

[0048] FIG. 2B shows example spacer / irrigation devices in a spacer system.

[0049] FIG. 3A shows an example part of an irrigation kit.

[0050] FIG. 3B shows an example of an irrigation system and kit.

[0051] FIG. 3C shows a detailed view of the irrigation system and kit of FIG. 3B.

[0052] FIG. 4 shows an overview of example treatment process including Stage 1, 7-dayinterstage treatment, and Stage 2

[0053] FIGs. 5A and 5B are stacked bar graphs displaying a graphical representation ofsuccess and failure in clinical studies for the (FIG. 5A) antibiotic irrigation solution kit arm and the (FIG.5B) SOC arm per the MSIS criteria: Tier 1 success, infection control without suppressive antibiotics; Tier 2 success, infection control with suppressive antibiotics; Tier 3F failure, retained spacer; Tier 3D failure, septic revision; Tier 3C failure, aseptic revision; and Tier 4 failure, death.

[0054] FIGs. 6A and 6B are stacked bar graphs displaying a graphical representation of PJIburden in the clinical studies for the (FIG.6A) antibiotic irrigation solution kit arm and the (FIG. 6B) SOC arm. PJI burden (light grey) defined as cumulative days without a permanent prosthesis plus cumulative days spent in an AE for PJI and / or septic reoperation. PJI burden free (dark grey) defined as time spent not experiencing PJI burden.

[0055] FIGs. 7A and 7B are stacked bar graphs displaying a graphical representation ofantibiotic burden in the clinical studies for the (FIG.7A) antibiotic irrigation solution kit arm and the (FIG.7B) SOC arm. DETAILED DESCRIPTION

[0056] The disclosed subject matter relates to locally administered antibiotics that mayimprove treatment of wounds including localized infections and more specifically infections including medical devices such as joint prostheses or reconstructive implants. The dosing and method of safely administering antibiotics is disclosed herein. The method of administering doses and concentrations of antibiotics greater than previously practiced levels of systemic therapy,105228354.47Attorney Docket No.121446-854267 while maintaining systemic exposure of the patient to levels at less than or equal to safe systemic concentration limits is also disclosed. Methods of locally administering one or more antibiotics with one or more antiseptics by irrigation are also disclosed herein.

[0057] Locally administered antimicrobial therapies are not optimized for controlled delivery,partly due to a lack of medical devices to administer such therapy safely and effectively and partly due to a lack of research and development specifically intended to maximize local antimicrobial efficacy and minimize the risks associated with exposure of the wound to concentrated therapeutics and the environment during therapy. Recent advances in devices to irrigate wounds, specifically cyclic instillation and aspiration of wounds with saline, provide new opportunities for a previously unachievable method for safe and effective local delivery of therapeutic agents such as antibiotics by an irrigation route of administration.

[0058] The standard of care for the treatment of chronic PJI is the two-stage exchangearthroplasty procedure, which begins with a surgical resection of the infected implant, aggressive debridement of bone and soft tissue, placement of a temporary implant that has been formed from antibiotic impregnated polymethylmethacrylate (PMMA), followed by systemic antibiotic therapy. The antibiotics in the PMMA elute into the surrounding tissue, with concentration of the eluting antibiotics decreasing exponentially over time and with distance from the temporary implant. The objective of the surgical resection is to dramatically reduce the bioburden of the infection, such that local antibiotic elution and concurrent systemic antibiotic therapy enable the patient’s immune system to eradicate any remaining bacteria. Elution rates vary widely in clinical practice due to differences in elution properties of available PMMA materials and to substantial differences in the mixing methods and dose of antibiotics mixed into PMMA temporary implants by surgeons. Alternative materials to PMMA, such as calcium sulfate, have also been used as locally eluting antibiotic carriers. In localized biofilm infections where the structural support of a temporary implant is not required, such as BII or FRI, the two-stage exchange procedure may be performed without any intermediary implant between the two surgical procedures.

[0059] The therapeutic effectiveness of antibiotics eluting from the temporary implant islimited to only tissue in sufficient proximity to the temporary implant to achieve a therapeutic concentration of the antibiotics and only for a brief time from implantation of the temporary implant to the time at which the local tissue concentration drops below therapeutic levels. Based upon the local bioburden, nature of the biofilm that remains following surgical debridement and the minimum biofilm eradication concentration of the antibiotic selected, the locally eluted antibiotic therapy may not be sufficient. Commercial products employing this technique are cleared for sale in the United States only as adjunctive to systemic antibiotic therapy. Clinically105228354.48Attorney Docket No.121446-854267 successful treatment of PJI (replacement of the infected prosthesis without reinfection, reoperation or administration of suppressive antibiotics) following an attempted two-stage exchange arthroplasty using the local antibiotic elution method have only been reported in about 50% of cases, 1 year after the first surgical treatment. The local antibiotics are absorbed into the tissue and circulatory system where they accumulate in addition to concurrently administered systemic antibiotics. Two-stage exchange arthroplasty patients are also at risk of severe nephrotoxicity and ototoxicity, due to initially very high concentrations of toxic antibiotics in the PMMA device, which cannot be adjusted without surgical intervention to explant the device. PMMA is also structurally weakened with increasing volume of antibiotics in the mixture. These toxicologic and mechanical considerations limit the maximum local concentration that may be delivered clinically by antibiotic eluting temporary implants.

[0060] Another limitation of antibiotic impregnated carriers is that they do not allow foroptimization of pharmacodynamic target attainment. (e,g., aminoglycosides Tobramycin / Gentamicin) have a target of Pk concentration over MIC with a limited duration of exposure reaching maximum log kill after ~2h, after which adaptive resistance and toxicity risks increase. Not allowing for elimination and constantly exposing pathogens to subinhibitory concentrations increases the chance of adaptive resistance.

[0061] Local instillation of an antibiotic in solution for the treatment of PJI has been reportedusing repeated doses of antibiotics delivered via catheter to the periprosthetic tissue or joint space following aggressive debridement and one-stage exchange of the prosthesis. However, because instillation is by definition unidirectional (none of the instilled antibiotic is aspirated or flushed from the site of infection), and the unidirectional instillation doses are absorbed in the tissue and bloodstream, systemic toxicity considerations limit the local dose and concentration that may be safely administered by instillation.

[0062] Both elution from an antibiotic impregnated carrier and localized instillation ofantibiotic in solution carry a risk for localized tissue toxicity and even tissue necrosis, due to uncontrolled localized accumulation of antibiotic.

[0063] In one embodiment, the present invention is a significant improvement and departureover the prior art, because it comprises locally administering a combination of two or more antibiotics via irrigation. The two or more antibiotics may include but are not limited to tobramycin and vancomycin. For example, a method of treating a periprosthetic joint infection in a skeletally mature patient undergoing an exchange arthroplasty procedure may include locally administering a combination of tobramycin sulfate at a dose of 80 mg / day and vancomycin hydrochloride at a dose of 3 g / day to the patient.105228354.49Attorney Docket No.121446-854267 I. Methods of Treatment

[0064] The various aspects and embodiments described in this section in the context of amethod of treatment also apply to tobramycin sulfate and vancomycin hydrochloride for use according to the methods described herein unless indicated otherwise. Similarly, the various aspects and embodiments described in this section in the context of a method of treatment also apply to tobramycin sulfate and vancomycin hydrochloride for use with an irrigation system according to the methods described herein, and tobramycin sulfate and vancomycin hydrochloride for use according to the methods described herein, in combination with an irrigation system, and tobramycin sulfate and vancomycin hydrochloride for use according to the methods described herein, wherein the tobramycin sulfate and vancomycin hydrochloride are administered by an irrigation system. A. Patient Populations

[0065] The present disclosure, in some aspects, provides a method of treating a periprostheticjoint infection in a skeletally mature patient undergoing an exchange arthroplasty procedure, the method comprising: locally administering a combination of tobramycin sulfate at a dose of about 80 mg / day and vancomycin hydrochloride at a dose of about 3 g / day or about 2.6 g / day to the patient.

[0066] In some aspects, the patient is scheduled for a two-stage exchange arthroplasty due toa hip or knee periprosthetic joint infection (PJI). In other aspects, the patient is scheduled for removal of a hip or a knee prosthesis as part of an exchange arthroplasty due to hip or knee PJI. In some aspects, the hip or knee PJI meets the International Consensus Meeting of Musculoskeletal Infection (ICMMI) 2018 definition of Periprosthetic Hip and Knee Infection.

[0067] In some aspects, the patient has medical clearance for surgery.

[0068] In some aspects, the patient is between about 22 years to about 84 years of age, such asbetween about 25 years to about 80 years of age, about 30 years to about 75 years of age, about 35 years to about 70 years of age, or about 40 years to about 65 years of age.

[0069] In some aspects, the patient does not have a history of allergies or knownhypersensitivity to vancomycin or tobramycin. In other aspects, the patient does not have a history of allergies or known hypersensitivity to titanium, titanium alloys, or polyurethane.

[0070] In some aspects, the patient is not pregnant. In some aspects, the patient is not currentlybreastfeeding.

[0071] In some aspects, the patient does not have a skeletal defect of greater than about 150mm in length in the tibia or femur of the infected joint.105228354.410Attorney Docket No.121446-854267

[0072] In some aspects, the individual does not require long-term anticoagulation orantiplatelet therapy, wherein bridging or withholding therapy is not recommended based on the patient’s clinical condition.

[0073] In some aspects, the patient does not have advanced renal insufficiency. In someaspects, advanced renal insufficiency is defined as chronic kidney disease Stage 4 or greater, or a glomerular filtration rate less than about 30 mL / min.

[0074] In some aspects, the patient is not undergoing chemotherapy for a malignant disease.

[0075] In other aspects, the patient is not administering systemic glucocorticoid therapy, suchas for example, greater than 10 mg / day of prednisone or an equivalent thereof.

[0076] In some aspects, the patient does not have immunodeficiency. In some aspects, theimmunodeficiency comprises splenectomy, sickle cell anemia, Stage 3 human immunodeficiency virus infection, or primary immunodeficiency disease, except immunodeficiency due to immunosuppressive therapy.

[0077] In some aspects, the patient does not have a fungal PJI. In some aspects, the patientdoes not have a fungal PJI as determined by one or more positive fluid and / or tissue cultures.

[0078] In some aspects, the patient does not have a planned surgical procedure within aboutsix months of undergoing the method described herein.

[0079] In some aspects, the patient does not have bone loss or musculature, osteoporosis,neuromuscular compromise or vascular deficiency in the affected limb and in sufficient degree to render the method unjustifiable. B. Dosing Regimens

[0080] The present disclosure, in one aspect, provides a method of treating a periprostheticjoint infection in a skeletally mature patient undergoing an exchange arthroplasty procedure. The method may include locally administering a combination of tobramycin sulfate at a dose of about 80 mg / day and vancomycin hydrochloride at a dose of between about 2.6 g / day to about 3 g / day to the patient. In some aspects, the vancomycin hydrochloride is administered at a dose of about 2.6 g / day, about 2.7 g / day, about 2.8 g / day, about 2.9 g / day, or about 3.0 g / day.

[0081] In some aspects, the combination is only administered to the patient to treat or preventinfections that are proven or strongly suspected to be caused by bacteria.

[0082] In some aspects, the local administration occurs daily via irrigation for about 7 to about10 days.

[0083] In some aspects, the locally administering includes irrigating the periprosthetic jointinfection with the combination. Irrigating the localized infection comprises soaking the105228354.411Attorney Docket No.121446-854267 periprosthetic joint infection with the tobramycin sulfate or vancomycin hydrochloride and subsequently aspirating the tobramycin sulfate or vancomycin hydrochloride.

[0084] In some aspects, the combination is locally administered by irrigation using anirrigation system. For example, the method may further include administering 80 mg of tobramycin sulfate in 50 mL of normal saline (1.6 mg / mL) by the irrigation system for 7-10 days (total daily exposure of 1.6 mg / day); following a 2-hour soak, removing the tobramycin sulfate using suction over 30 minutes; administering 125 mg of vancomycin hydrochloride in 50 mL of normal saline (2.5 mg / mL) with the irrigation system every hour for 10 treatments for a duration of 7-10 days (total daily exposure of 1.25 g / day); and following a 30-minute soak, removing the vancomycin hydrochloride using suction over 30 minutes after each administration. In some examples, approximately 21-22 consecutive rounds of vancomycin irrigation cycles may be administered per day. In additional examples, over a 7-day treatment, there may be 7, 2-hour applications of tobramycin and approximately 147, 30-minute applications of vancomycin.

[0085] In some aspects, the method may further include monitoring the patient duringadministration for ototoxicity and nephrotoxicity.

[0086] In some aspects, the method may further include monitoring tobramycin serum troughlevels; maintaining tobramycin serum trough levels at less than about 2 mcg / mL; and if tobramycin serum trough levels are greater than about 2 mcg / mL or toxicity is a concern, decreasing the total dose of tobramycin based on the tobramycin serum trough levels. In an example, the total tobramycin administered is decreased but not total volume. In an example, the tobramycin serum trough levels are monitored after 2 or 3 doses, and also at 3- to 4-day intervals during administration.

[0087] In some aspects, the patient has a mean tobramycin serum concentration of 0.5 ± 0.2mcg / mL during administration. In some aspects, the patient has a mean tobramycin serum trough level of 0.4 ± 0.2 mcg / mL during administration.

[0088] In some aspects, the method may further include monitoring vancomycin serum levels;maintaining vancomycin serum levels at less than about 20 mcg / mL; and if serum levels are greater than about 20 mcg / mL or if toxicity is a concern, decreasing the total dose of vancomycin based on the vancomycin serum levels. In an aspect, the total vancomycin administered is decreased but not total volume. In some aspects, the patient has a mean vancomycin serum concentration of 5.6 ± 5.4 mcg / mL during administration.

[0089] In some aspects, the dose of tobramycin sulfate is prepared by: using an approximately3 mL syringe to withdraw a 2 mL volume (80 mg) from a vial comprising tobramycin sulfate and transfer to a 50 mL 0.9% sodium chloride intravenous piggyback (IVPB) bag.105228354.412Attorney Docket No.121446-854267

[0090] In some aspects, the dose of vancomycin hydrochloride is prepared by: reconstitutingthree 1 g vials comprising vancomycin hydrochloride using an approximately 20 mL syringe by adding 20 mL sterile water for injection to each vial; withdrawing the contents of the three 1 g vancomycin hydrochloride vials and adding all 3 g (60 mL) of vancomycin hydrochloride to a 1000 mL normal saline IVPB bag; and using an approximately 100 mL syringe, adding 100 mL of normal saline to the IVPB already containing 3 g of vancomycin hydrochloride.

[0091] In some aspects, the tobramycin sulfate is administered at a concentration of 1.6mg / mL. In some aspects, vancomycin hydrochloride is administered at a concentration of 2.5 mg / mL.

[0092] In some aspects, the method further includes maintaining tobramycin serum levels atless than about 2 mcg / mL. In some aspects, the method further includes maintaining vancomycin serum levels at less than about 20 mcg / mL.

[0093] In some aspects, the combination is administered to the patient to treat or preventbacterial infections.

[0094] In some aspects, the method further includes modifying the dose of tobramycin sulfateor vancomycin hydrochloride if nephrotoxicity or ototoxicity occurs in the patient. In some aspects, the method further includes modifying the dose of tobramycin sulfate if tobramycin serum trough level above about 2 mcg / mL occurs in the patient. In some examples, modifying the dose of tobramycin sulfate comprises decreasing total drug administered but not total volume. For example, the dose of tobramycin sulfate may be modified to 40 mg at a concentration of 0.8 mg / mL.

[0095] In some aspects, the method further includes modifying the dose of vancomycinhydrochloride if vancomycin serum trough level above about 20 mcg / mL occurs in the patient. In some examples, modifying the dose of vancomycin hydrochloride comprises decreasing total drug administered but not total volume. For example, the dose of vancomycin hydrochloride may be modified to 1.5 g at a concentration of 1.25 mg / mL.

[0096] In some aspects, the method further includes maintaining systemic concentrations oftobramycin below 15 mcg / mL, below 14 mcg / mL, below 13 mcg / mL, below 12 mcg / mL, below 11 mcg / mL, or below 10 mcg / mL.

[0097] In some aspects, the method further includes discontinuing administration atappearance of skin rashes, mucosal lesion, or blisters on the patient. In some examples, the method may further include assessing the patient’s auditory function. Assessing the patient’s auditory function may include an audiometric test that evaluates hearing up to 8000 Hz. In an example, the method may further include assessing culture information or susceptibility information of the105228354.413Attorney Docket No.121446-854267 periprosthetic infection. In other examples, the method may further include monitoring toxicities associated with aminoglycosides as a class.

[0098] Endpoints

[0099] In some aspects, provided herein is a method of treating a periprosthetic joint infectionin a skeletally mature patient undergoing an exchange arthroplasty procedure, the method comprising: locally administering a combination of tobramycin sulfate at a dose of about 80 mg / day and vancomycin hydrochloride at a dose of about 3 g / day or about 2.6 g / day to the patient, wherein such treatment results in an overall success rate in a population of patients who have received such treatment of at least about 50% .

[0100] In some aspects, such treatment results in an overall success rate at 90 days in apopulation of patients who have received such treatment of at least about 80%. In some aspects, the overall success rate at 90 days in a population of patients who have received such treatment is between about 80% and 85%, about 85% and about 90%, about 95% and about 100%. In some aspects, the overall success rate at 90 days in a population of patients who have received such treatment is about 89%. In some aspects, the overall success rate at 90 days in a population of patients who have received a standard of care treatment is about 28%. In some aspects, the overall success rate at 90 days in a population of patients who have received such treatment is at least about 60% greater than the overall success rate at 90 days in a population of patients who have received a standard of care treatment.

[0101] In some aspects, such treatment results in an overall success rate at 180 days in apopulation of patients who have received such treatment of at least about 55%. In some aspects, the overall success rate at 180 days in a population of patients who have received such treatment is between about 50% and 55%, about 55% and about 60%, about 65% and about 70%, about 70% and about 75%, about 80% and about 85%. In some aspects, the overall success rate at 180 days in a population of patients who have received such treatment is about 70%. In some aspects, the overall success rate at 180 days in a population of patients who have received such treatment is about 57%. In some aspects, the overall success rate at 180 days in a population of patients who have received a standard of care treatment is about 30% or about 33%. In some aspects, the overall success rate at 180 days in a population of patients who have received such treatment is at least about 30% greater than the overall success rate at 180 days in a population of patients who have received a standard of care treatment. In some aspects, the overall success rate at 180 days in a population of patients who have received such treatment is at least about 40% greater than the overall success rate at 180 days in a population of patients who have received a standard of care treatment.105228354.414Attorney Docket No.121446-854267

[0102] In some aspects, such treatment results in an overall success rate at 360 days in apopulation of patients who have received such treatment of at least about 50%. In some aspects, the overall success rate at 360 days in a population of patients who have received such treatment is between about 45% and 50%, about 50% and 55%, about 55% and about 60%, about 65% and about 70%, about 70% and about 75%, about 80% and about 85%. In some aspects, the overall success rate at 360 days in a population of patients who have received such treatment is about 66%. In some aspects, the overall success rate at 360 days in a population of patients who have received such treatment is about 54%. In some aspects, the overall success rate at 360 days in a population of patients who have received a standard of care treatment is about 36% or about 47%. In some aspects, the overall success rate at 360 days in a population of patients who have received such treatment is at least about 19% greater than the overall success rate at 360 days in a population of patients who have received a standard of care treatment. In some aspects, the overall success rate at 360 days in a population of patients who have received such treatment is at least about 18% greater than the overall success rate at 360 days in a population of patients who have received a standard of care treatment.

[0103] In some aspects, the overall success rate is calculated as the proportion of patients in atreatment group who, at a defined timepoint satisfy the criteria for an overall success. In some aspects, an overall success is achieved when the patient has 1) received a revision prosthesis; 2) no evidence of periprosthetic joint infection following reimplantation; 3) not undergone reoperation of the affected joint prior to or following reimplantation; 4) not continued antibiotics for joint infection; and 5) not died.

[0104] In some aspects, the methods provided herein result in significant improvements onquality of life for treated patients. In some aspects, a quality-of-life score is calculated for treated patients based on results from the European Quality of Life 5 Dimensions 3 Levels of Severity (EQ-5D-3L), the Knee Disability and Osteoarthritis Outcome Score (KOOS), and the Hip Disability and Osteoarthritis Outcome Score (HOOS) questionnaires. In some aspects, the quality- of-life score of the patient is maintained or increases following treatment by the methods provided herein. C. Combination Therapy

[0105] Also provided herein, in some aspects, is a method of treating or preventing a localinfection in a wound by locally administering to a human patient a plurality of doses of at least one antiseptic agent in solution and at least one antibiotic solution by irrigating the wound at least once with each solution in a 24-hour period. In some aspects, the infection may include105228354.415Attorney Docket No.121446-854267 a bacterial pathogen, a fungal pathogen or a polymicrobial pathogen. In some aspects, the local infection is a wound including, for example, surgical wounds, implant-associated wounds, deep incisional wounds, a hematogenous infection of a surgical site, or acute or chronic wound infections. In another example, the local infection in a wound includes a periprosthetic joint infection.

[0106] Antiseptics include but are not limited to agents with antibacterial, antiviral, orantifungal properties. Thus, non-limiting examples of antiseptics include hypochlorous acid, sodium hypochlorite, citric acid, acetic acid, polyhexamethylene biguanide, chlorhexidine glutonate, povidone iodine, copper sulfate / potassium iodide, trimethoprim, ethanol, nitroglycerin, hydrogen peroxide, PHMB preservative, taurolidine, and combinations thereof. The antiseptic agent is administered to the patient at a concentration set forth in Table 1. Table 1: Exemplary Concentration of Select Antiseptic Agents Antiseptic Agent Concentration Hypochlorous acid 0.003% - 0.057%

[0107] In other aspects, the antiseptic agent may include an antifungal agent. Severalclasses of antifungal agents may be appropriate for local irrigation of wounds, including but not limited to: azole derivatives from the group consisting of fluconazole, isavuconazole, posaconazole, voriconazole, and combinations thereof, amphotericin B or lipid formulations thereof, and echinocandins selected from the group consisting of anidulafungin, caspofungin, and micafungin. It can be seen by those skilled in the art that each of the aforementioned antifungal agents may be administered using the irrigation methods provided herein to provide safe and effective antifungal therapy of a wound by adjusting the volume, concentration, soak time, time to evacuation and cycle frequency best suited to the pharmacodynamics and pharmacokinetics of the antifungal agent to be administered.105228354.416Attorney Docket No.121446-854267

[0108] Table 2 provides example local antifungal dosage and concentration ranges. Table 2provides example local concentrations for antifungal irrigation therapy in 1200 mL solution (if administered 50 ml / hour). In additional examples, the volume administered may be less than or more than 50 cc, and the resulting concentration would be proportionally greater than or less than the concentrations listed in Table 2. Table 2 – Safe Systemic Dose and Concentration of Select Antifungal Agents Antifungal Agent Local Daily Dosage Range Local Concentration Range Fluconazole 100 mg-2400 mg 83 mcg / ml-2,000 mcg / ml, , calinfection in a human patient at a localized site, the method comprising locally administering by irrigation to the localized site of the human patient a plurality of doses of: i) at least one antiseptic agent in solution; and ii) at least one antibiotic in solution. In some aspects, the at least one antiseptic agent in solution is administered to the human patient prior to the at least one antibiotic in solution. In other aspects, the at least one antiseptic agent in solution is administered to the human patient following the at least one antibiotic in solution. In yet other aspects, the at least one antiseptic agent in solution is administered to the human patient concurrently with the at least one antibiotic in solution.

[0110] Broad spectrum antibiotic therapy for localized infections commonly includes aglycopeptide (e.g., vancomycin HCl) for coverage of gram + bacteria and an aminoglycoside (e.g., gentamicin or tobramycin sulfate) for coverage of gram – bacteria. The at least one antibiotic may be selected from amikacin, gentamicin, tobramycin, cefazolin, cefepime, ampicillin, ciprofloxacin, azithromycin, doxycycline, clindamycin, daptomycin, vancomycin or combinations thereof. In some aspects, the at least one antibiotic comprises tobramycin sulfate and / or vancomycin hydrochloride. Examples of safe dosing and systemic concentrations of these and other antibiotics are shown in Table 3. Table 3 – Safe Systemic Dose and Concentration of Select Antibiotics Antibiotic Safe Daily Dose Safe IV Concentration105228354.417Attorney Docket No.121446-854267 Tobramycin 7 mg / kg / day 5 mg / mLCefazolin 6 g / day 330 mg / mL

[0111] e antisepticagent and the at least one antibiotic administered. Because the agents are administered locally by irrigation, and they are removed locally before there is significant systemic absorption or metabolism. Therefore, there is less opportunity for either agent to interact systemically with each other or any other medications the patient may be taking. The disclosed method may provide for combinations of antiseptic agents (e.g., antifungal agents), antibiotics, anesthetics, analgesics, or other drugs to be administered that could not otherwise be combined systemically or administered at the concentration that could not otherwise be administered systemically. For example, the combined local administration of the at least one antiseptic agent and the at least one antibacterial agent may not be nephrotoxic or may not be ototoxic to the patient.

[0112] As a route of administration, irrigation is defined as administration to bathe or flushopen wounds or body cavities. By controlling irrigation dose, that is, concentration, volume, and duration of exposure (bathing or flushing) time, a novel method of treating or preventing localized fungal infections in a human patient has been developed. The irrigation concentration or the total irrigation dose of the antifungal agent may exceed manufacturer’s recommended concentration. Moreover, the dose and concentration to achieve BBC or MBEC for biofilm forming organisms varies depending upon the organism, the maturity of the biofilm, the location of the biofilm, the implant or tissue to which the biofilm has attached, the dilution and absorption rate of the antifungal agent at the site of irrigation and other factors. In one aspect, provided herein are methods of treating or preventing a localized fungal infection in a wound of a human patient in need thereof. The novel method described herein includes sustained administration of one or more antiseptic agents, by an irrigation route of administration. Optimal efficacy of this novel method is obtained when the dose and concentration of each antiseptic agent is administered based on the pharmacodynamics and pharmacokinetics of the drug to be administered. In one aspect of the105228354.418Attorney Docket No.121446-854267 invention, one or more of the drugs to be administered by irrigation is administered at a dose and / or concentration exceeding previously established safe systemic dose and / or concentrations of said drug(s), while providing safe systemic (serum) concentrations of said drug(s).

[0113] The daily dose of the at least one antiseptic agent may comprise a single administrationor a plurality of administrations during 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 during the day. In some examples, the daily dose of at least one antiseptic agent and at least one antibiotic may be administered sequentially and / or concurrently over at least 1, at least 2, at least 5, at least 10, at least 15, at least 20, or at least 24 administrations. The administrations 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.

[0114] The daily dose may also comprise a plurality of administrations such that at least oneantiseptic agent is administered in series with at least one antibiotic, and at least one dose of combined therapy for fungal and bacterial infection of the wound is considered the totality of both serial administrations. Alternatively, the daily dose may comprise a once daily administration of at least one antiseptic agent, and the daily dose of combined therapy may include a single administration or a plurality of administrations during the day. In an embodiment, at least one antiseptic agent may be administered concurrently with the at least one antibiotic, followed by administration of at least one additional antimicrobial agent in series to achieve both antifungal and broad-spectrum antibacterial coverage. Specifically, one embodiment may include concurrent administration of fluconazole and vancomycin (or daptomycin) in series with administration of tobramycin (or gentamicin). This particular irrigation regimen is tailored to the pharmacodynamic targets of each administered drug, specifically tobramycin CMax / MIC, vancomycin AUC / / MIC and fluconazole AUC / MIC. In another embodiment may include sequential administration of an antiseptic agent (e.g., amphotericin B) with at least one antibiotic (e.g. tobramycin).

[0115] Alternatively, the daily dose may include a once daily administration of at least oneantiseptic agent, followed in series by a plurality of administrations of antibiotic for the remainder of the day. In an embodiment, the once daily administration includes concurrently administering fluconazole and tobramycin, which is allowed to soak 2 hours followed by 30 minutes aspiration and the plurality of serial administrations includes sequential administration of vancomycin irrigations, which are allowed to soak for 30 minutes followed by 30 minutes aspiration and105228354.419Attorney Docket No.121446-854267 repeated for the remainder of the day, at which time, the once daily concurrent administration of fluconazole and tobramycin is repeated to start a new day of combined therapy.

[0116] Irrigating the wound may include soaking the biological tissue of the wound with theantiseptic 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, irrigating the wound may include soaking with the antibiotic for 30 minutes, 60 minutes, 90 minutes, 120 minutes, 150 minutes, or 180 minutes. In the case of fluconazole, a 30-minute soak time may be optimal. In other cases, the optimal soak time will depend upon administered concentration and may be adjusted to administer higher concentrations for effective fungal eradication, while maintaining safe levels of systemic exposure as determined by serum concentrations or other serum levels, such as creatinine.

[0117] Administration of localized antiseptic agents, with or without additional antimicrobialagents may be performed for a single day or a plurality of days as needed to provide the needed treatment or prevention. Irrigation 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. The local administration may be repeated for additional periods of up to 10 days (e.g., with a change of the irrigation apparatus between repeated administration periods).

[0118] In some aspects, the wound is irrigated with about 10 mL to about 2000 mL of theantiseptic solution, such as about 10 mL to about 1000 mL, about 20 mL to about 500 mL, about 30 mL to about 250 mL, about 40 mL to about 100 mL, about 100 mL to about 300 mL, about 200 mL to about 400 mL, about 300 mL to about 500 ml, about 500 mL to about 1,000 mL, about 1,000 mL to about 1,500 mL, or about 1,500 mL to about 2,000 mL of the antiseptic solution. In some aspects, the wound is irrigated with about 10 mL, about 20 mL, about 30 mL, about 50 mL, about 60 mL, about 70 mL, about 80 mL, about 90 mL, about 100 mL, about 200 mL, about 300 mL, about 400 mL, about 500 mL, about 600 mL, about 700 mL, about 800 mL, about 900 mL, about 1,000 mL, about 1,100 mL, about 1,200 mL, about 1,300 mL, about 1,400 mL, about 1,500 mL, about 1,600 mL, about 1,700 mL, about 1,800 mL, about 1,900 mL, or about 2,000 mL of the antiseptic solution. In some aspects, irrigating the wound comprises instillation of about 50 mL of the antiseptic solution.

[0119] In some aspects, irrigating the wound comprises instillation of the at least oneantiseptic agent in solution followed by a dwell period followed by aspiration of the at least one antiseptic agent in solution to remove the at least one antiseptic agent from the wound. In105228354.420Attorney Docket No.121446-854267 some aspects, the dwell period is about 1 minute to about 30 minutes, such as about 1 minute to about 25 minutes, about 1 minute to about 20 minutes, about 1 minute to about 15 minutes, about 1 minute to about 10 minutes, or about 1 minute to about 5 minutes. In some aspects, the dwell period is about a 5-minute dwell period. In some aspects, the aspiration is about 1 minute to about 30 minutes, for example, about 1 minute, about 2 minutes, about 3 minutes, about 4 minutes, about 5 minutes, about 6 minutes, about 7 minutes, about 8 minutes, about 9 minutes, about 10 minutes, about 11 minutes, about 12 minutes, about 13 minutes, about 14 minutes, about 15 minutes, about 16 minutes, about 17 minutes, about 18 minutes, about 19 minutes, about 20 minutes, about 21 minutes, about 22 minutes, about 23 minutes, about 24 minutes, about 25 minutes, about 26 minutes, about 27 minutes, about 28 minutes, about 29 minutes, or about 30 minutes. In some aspects, the at least one antiseptic agent in solution is instilled with about a 5-minute dwell period followed by about a 5-minute aspiration. In some aspects, about 50 mL of the at least one antiseptic agent in solution is instilled with about a 5- minute dwell period followed by about a 5-minute aspiration.

[0120] In some aspects, a sterile fluid is irrigated after the at least one antiseptic agent insolution to remove or otherwise dilute the at least one antiseptic agent. In some aspects, the sterile fluid comprises normal saline.

[0121] In other aspects, irrigating the wound with the at least one antiseptic agent insolution is accomplished by simultaneously instilling and aspirating the at least one antiseptic agent in solution. In some aspects, at least about 100 mL, at least about 250 mL, at least about 500 mL, at least about 1000 mL, or at least about 2000 mL of the at least one antiseptic agent in solution is irrigated by simultaneous instillation and aspiration.

[0122] In some aspects, the at least one antiseptic agent in solution is irrigated in less thanabout 30 minutes, less than about 25 minutes, less than about 20 minutes, less than about 15 minutes, less than about 10 minutes, or less than about 5 minutes. In some aspects, the at least one antiseptic agent in solution is irrigated in less than about 15 minutes.

[0123] When administered in combination with the at least one antiseptic agent, the at leastone antibiotic may be administered according to any dosing and administration protocol disclosed herein. II. Kits

[0124] Further provided herein is a kit for treating a periprosthetic joint infection in skeletallymature patients undergoing an exchange arthroplasty procedure. In some aspects, the kit may include: a plurality of vials, each comprising 1 g of vancomycin hydrochloride lyophilized powder105228354.421Attorney Docket No.121446-854267 intended for reconstitution / dilution with normal saline; and a second plurality of vials, each comprising 80 mg / 2 mL (40 mg / mL) of tobramycin sulfate solution intended for reconstitution / dilution with normal saline. In some aspects, the kit may further include a plurality of vials comprising an antiseptic agent.

[0125] In some aspects, the kit may further include: a treatment delivery system and / orirrigation device configured to locally irrigate the periprosthetic joint infection with a combination of vancomycin hydrochloride and tobramycin sulfate; and instructions for administration.

[0126] In some aspects, the kit may include but is not limited to 21 vials of vancomycinhydrochloride and 7 vials of tobramycin sulfate.

[0127] In one example, FIG. 1 shows a kit of a plurality of vials comprising vancomycinhydrochloride and a plurality of vials comprising tobramycin sulfate.

[0128] FIGs. 2A-2B and 3A -3 show an example of portions of a kit for delivery of acombination of vancomycin hydrochloride and tobramycin sulfate. For example, FIGs.2A-2B and 3A -3C show a treatment delivery system 100 and irrigation device 107 that can provide controlled delivery of two or more antibiotics into a treatment site 102 (e.g., infection in a periprosthetic space, bone segment, or wound area). All or portions of the treatment delivery system 100 and the irrigation device 107 can be included in the kit. In general, the treatment delivery system 100 can include a (portable) disposable device for enabling adjustment of a distance between the treatment delivery system 100 and a treated site 102 of a patient, such as a patient suffering from an infection treatable with fluid irrigation. In the example illustrated in FIG.3B, the treatment delivery system 100 provides irrigation to a treatment site 102 including an irrigable volume (e.g., joint space or bone segment). The system 100 can include a fluid delivery system 104A, a fluid collection system 104B, and a control system 106. The fluid delivery system 104A can include one or more fluid reservoirs 108A,B. In some examples, the one or more fluid reservoirs 108A,B can contain the one or more antibiotics provided by the kit. For example, fluid reservoir 108A can contain a first antibiotic such as tobramycin in a saline solution and fluid reservoir 108B can contain a second antibiotic such as vancomycin in a saline solution. The fluid collection system 104B can include one or more collection fluid canisters 109.

[0129] In some examples, the control system 106 can control fluid flow from the fluidreservoirs 108A,B towards the treatment site 102 and / or draw fluid away from the treatment site 102 toward the fluid collection system 104B. For example, the control system 106 can include one or more of a vacuum pressure source, pump, or any other means for moving fluid through the system 100. In some examples, one means for moving the fluid may be used for both instilling and aspirating fluid from the treatment site 102. In other examples, one means may be used for105228354.422Attorney Docket No.121446-854267 instillation and another means may be used for aspiration. The system can be configured to deliver the fluid transcutaneously to irrigation devices deployed within treated area (e.g., infected tissue and / or infected joints, such as hip, knee, shoulder, wrist, ankle). Although not shown, one or more other medical devices may be assisting and working in coordination and / or parallel with the treatment delivery system 100 to provide treatment for the patient (including the treatment site 102).

[0130] In an example, the irrigation device 107 can be configured to be fluidly coupled to thetreatment delivery system 100 as shown in FIG. 3B. The treatment delivery system 100 can also be coupled to a syringe or another manual component for delivery and withdrawal of fluid from the treatment site. In some aspects, the irrigation device 107 may have a porous component 103. The porous component 103 of the irrigation device 107 may be configured to fill the space and / or opening of the treatment site and allow for fluid exiting the tubing to flow through the porous component 103 into the treatment site 102.

[0131] The treatment system 100 can be configured to fluidly couple with the irrigation device107 that can provide controlled delivery of fluids (e.g., antibiotics, saline, local anesthetics) into the treatment site 102 (e.g., an infected articulating joint, such as knee or hip) during, for example, I&D, DAIR, Double DAIR, or another procedure as described elsewhere herein or other type of healing including wound and perioperative healing.

[0132] Within a context example, the treatment delivery system 100 can be used for deliveringone or more antibiotics to infected joints (e.g., hip, knee, shoulder, wrist, ankle) or any type of biological tissue that can be treated using controlled fluid irrigation. Examples of treatments include periprosthetic joint infection treatment protocols, such as debridement, antibiotics and implant retention (DAIR) and exchange arthroplasty, irrigation of surgical incisions and traumatic wounds or irrigation for osteomyelitis and septic arthritis. Although the application may be described in the context of a particular treatment site (e.g., infected joints) and connection with that site, it should be appreciated that other treatment sites are considered and the way in which the system connects with those various sites may vary.

[0133] Again, with respect to FIGs. 3B-3C, the fluid delivery system 104A includes two ormore fluid reservoir(s) 108A, 108B.

[0134] Each of the fluid reservoirs 108A, 108B can have a particular volume and store aparticular fluid type that is delivered during a respective treatment phase. The contents of the fluid reservoirs may be switched such that a first antibiotic may be stored in a first fluid reservoir 108B or a second fluid reservoir 108A and a second antibiotic may be stored in a second fluid reservoir 108A or a first fluid reservoir 108B. The fluid reservoirs may also contain combinations of105228354.423Attorney Docket No.121446-854267 antibiotics in some instances. The fluid reservoirs may be provided as part of the kit or may be provided separately and combined with the one or more antibiotics of the kit prior to use.

[0135] For example, the first fluid reservoir 108A can contain or store a first fluid that caninclude an antibiotic (e.g., a first antibiotic), such as tobramycin, or a first antibiotic combination. The first fluid can be delivered from first fluid reservoir 108A to the treatment site 102 according to a respective fluid delivery protocol. The fluid delivery protocol can be included within the instructions of a kit. The protocol can define a concentration of a first antibiotic, a volume of the first antibiotic fluid to be delivered, a duration of antibiotic fluid delivery, and pre-delivery vacuum that can be performed for a set vacuum time period (e.g., approximately 30 minutes) at a set pressure (e.g., -125 mmHg). The volume of first antibiotic fluid to be delivered to the treatment site 102 can be set in a range between 6 mL and 500 mL, such as, 50 mL. In some implementations, approximately 80 mg of tobramycin sulfate in 50 mL of 0.9% sodium chloride are delivered in about 30 to 60 seconds and allowed to soak for a total of 2 hours in a single 24-hour period. The delivery of the first fluid volume can be controlled with an accuracy of ± approximately 5 mL to 10 mL. In some implementations, the delivery of first antibiotic fluid is followed by a soaking protocol to enable the treatment site 102 to soak the delivered fluid. The duration of the first antibiotic fluid soaking protocol can be between 1 and 3 hours, such as approximately 2 hours. The first antibiotic fluid can be removed from the treatment site 102, by the fluid collection system 104B, before a second fluid is delivered to the treatment site 102. The duration of the first antibiotic fluid removal from the treatment site 102 can be approximately 30 minutes.

[0136] The second fluid reservoir 108B can store a second fluid that can include an antibiotic(e.g., a second antibiotic), such as vancomycin or daptomycin, or a second antibiotic combination. The volume of second fluid to be delivered to the treatment site 102 over at time period can be set in a range between 500 mL and 1500 mL, such as 1200 mL. The total volume of the second antibiotic fluid delivered can vary depending on the length of the time period as well as the total time for first fluid delivery, soak, and removal. For example, in a 24-hour time period where the first fluid delivery, soak, and removal was 2 hours, the time period of delivery of the second fluid can be approximately 22 hours. The delivery of the second antibiotic fluid volume can be controlled with an accuracy of ± approximately 5mL. The delivery of second antibiotic fluid is followed by a soaking protocol to enable the treatment site 102 to soak the delivered fluid. The duration of the second antibiotic fluid soaking protocol can be between 15 and 45 minutes, such as approximately 30 minutes. The second fluid can be removed from the treatment site 102, by the fluid collection system 104B. The duration of the second fluid removal from the treatment site 102 can be approximately 30 minutes. In some implementations, multiple cycles of second antibiotic105228354.424Attorney Docket No.121446-854267 fluid delivery, soaking, and removal are repeated before the first fluid is subsequently delivered to the treatment site 102. For example, the treatment protocol can be repeated over multiple (e.g., 5, 6, 7) days and during each day, the first antibiotic fluid can be delivered once to soak the treatment area 102 and after the removal of the first fluid, multiple cycles of second antibiotic fluid delivery, soaking, and removal can be repeated to complete a 24 hour treatment protocol. On Day 1, for example, the treatment site 102 and system can be prepped and a vacuum within the system established such as by a pump. Following seal checks and confirmations within the system, the first fluid can be delivered and allowed to soak as described above. After removal of the first fluid, the second fluid can be delivered, allowed to soak, and subsequently removed a plurality of times (e.g., 20-23 times) the remainder of day 1. At the start of day 2 (e.g., 24 hours after initiation of treatment), the canister and / or one or more reservoir bags can be changed and seal confirmed. A pre-treatment vacuum cycle can commence prior to initiation of the first fluid delivery and soak. After removal of the first fluid, the second fluid can be delivered, allowed to soak, and subsequently removed a plurality of times (e.g., 20-23 times) the remainder of day 2. This daily protocol can be repeated for a period of up to about 7 days, up to about 10 days, up to about 14 days, or however long the treatment is desired.

[0137] The fluid collection system 104B can direct fluid from the treatment site 102 to acollection fluid canister 109. In some examples, the control system 106 can generate a vacuum in the collection fluid canister 109 to remove the fluid from the treatment site 102 into the collection fluid canister 109. For example, a pump can be activated by the control system 106 to create a vacuum within at least the collection fluid canister 109. In other examples, vacuum pressure sources, syringes, gravity, pumps, or any other mechanism for moving fluid in and out of the treatment site 102 are contemplated. The collection fluid canister 109 can include a single-use canister with a known volume (e.g., 2000 mL). The collection fluid canister 109 collects antibiotic solution or other fluids (e.g., wound exudate) accumulated during vacuum-induced drainage of fluid from the treatment site 102. The material of the canister 109 is preferably translucent or transparent in order for a user to assess the level of the contents within the canister 109 during use. The material of the canister 109 is also preferably capable of retaining a vacuum without deforming or restricting flow at maximum vacuum level. EXAMPLES Example 1: Tobramycin sulfate and vancomycin hydrochloride for irrigation / irrigation system

[0138] The antibiotic irrigation solution (tobramycin sulfate and vancomycin hydrochloridefor irrigation) is administered using the Irrigation System.105228354.425Attorney Docket No.121446-854267

[0139] WARNING: NEPHROTOXICITY, OTOTOXICTY, CONCOMINANT USE WITHSYSTEMIC AMINOGLYCOSIDES, and EMBRYO-FETAL TOXICITY See full prescribing information for complete boxed warning.

[0140] Patients treated with the antibiotic irrigation solution (tobramycin sulfate) and otheraminoglycosides should be under close clinical observation, because these drugs have an inherent potential for causing:

[0141] Nephrotoxicity: Renal function should be closely monitored in patients with known orsuspected renal impairment. (5.2)

[0142] Ototoxicity: Neurotoxicity manifested as both auditory and vestibular ototoxicity canoccur. (5.3)

[0143] Concomitant Use with Systemic Aminoglycosides could increase the occurrence ofnephrotoxicity and ototoxicity. (5.6)

[0144] Embryo-Fetal Toxicity: Aminoglycosides can cause fetal harm when administered topregnant women. (5.5) INDICATIONS AND USAGE

[0145] The antibiotic irrigation solution kit (tobramycin sulfate and vancomycinhydrochloride for irrigation / irrigation system) is indicated for the treatment of periprosthetic joint infection in skeletally mature patients undergoing an exchange arthroplasty procedure, where vancomycin hydrochloride and tobramycin sulfate are appropriate antibiotics for treatment of the infection. (1)

[0146] To reduce the development of drug‑resistant bacteria and maintain the effectiveness oftobramycin sulfate and vancomycin hydrochloride and other antibacterial drugs, tobramycin sulfate and vancomycin hydrochloride should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria. (1) DOSAGE AND ADMINISTRATION

[0147] The antibiotic irrigation solution comprising tobramycin sulfate and vancomycinhydrochloride are components of the the antibiotic irrigation solution kit and are administered by irrigation using the Irrigation System. The recommended dose is 80 mg / day of tobramycin sulfate and 3 g / day of vancomycin hydrochloride administered daily via irrigation for 7-10 days. (2.1)

[0148] Dose modification may be required for the development of nephrotoxicity orototoxicity. (2.2) DOSAGE FORMS AND STRENGTHS

[0149] For irrigation: The Antibiotic Irrigation Solution Kit Drug Pack intended forreconstitution / dilution with normal saline includes:105228354.426Attorney Docket No.121446-854267

[0150] 21 vials, each with 1 g of vancomycin hydrochloride.

[0151] 7 vials, each with 80 mg of tobramycin sulfate (3).CONTRAINDICATIONS

[0152] Patients with a history of allergies or known hypersensitivity to vancomycin ortobramycin or a component or material utilized within the antibiotic irrigation solution kit including: titanium, titanium alloys, or polyurethane.

[0153] Patients who require long-term anticoagulation or antiplatelet therapy, and for whombridging or withholding therapy is not recommended based on the individual’s clinical condition.

[0154] Patients who are pregnant.

[0155] Patients who have a skeletal defect of greater than 150 mm in length in the tibia orfemur of the infected joint.

[0156] Patients who have bone loss or musculature, osteoporosis, neuromuscular compromiseor vascular deficiency in the affected limb and in sufficient degree to render the procedure unjustifiable. (4) WARNINGS AND PRECAUTIONS

[0157] Allergic reactions: Discontinue the antibiotic irrigation solution at first appearance ofskin rashes, mucosal lesions, or blisters. (5.1)

[0158] Nephrotoxicity has occurred with aminoglycoside during or after completion oftreatment. (5.2, 5.8)

[0159] Ototoxicity has occurred in patients receiving vancomycin and tobramycin.Assessment of auditory function may be appropriate in some instances. (5.3, 5.8)

[0160] Clostridium Difficile Associated Diarrhea has been reported with use of nearly allantibacterial agents, including intravenously delivered vancomycin hydrochloride and tobramycin sulfate. (5.4)

[0161] Embryo-Fetal Toxicity: Aminoglycosides (tobramycin) can cause fetal harm whenadministered to pregnant women. Apprise women of the potential hazard to the fetus. (5.5, 8.1)

[0162] Aminoglycoside (tobramycin) may aggravate muscle weakness because of a potentialcurare-like effect on neuromuscular function. (5.7) ADVERSE REACTIONS

[0163] The most common adverse reactions include anemia and post-operative pain. (6.1)DRUG INTERACTIONS

[0164] Concurrent and / or sequential use of the antibiotic irrigation solution kit with otherdrugs with neurotoxic, nephrotoxic, or ototoxic potential should be avoided. (7) USE IN SPECIFIC POPULATIONS105228354.427Attorney Docket No.121446-854267

[0165] Aminoglycosides can cause fetal harm. (8.1)

[0166] Because elderly patients are more likely to have decreased renal function, it may beuseful to monitor renal function. (8.5)

[0167] The risk of adverse reactions to tobramycin and vancomycin may be greater in patientswith renal impairment. (8.6)

[0168] See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patientlabeling. WARNINGS: OTOTOXICITY, NEPHROTOXICITY, CONCOMITANT USE WITH SYSTEMIC AMINOGLYCOSIDES, and EMBRYO-FETAL TOXICITY

[0169] Patients treated with tobramycin sulfate, an aminoglycoside antibiotic in the antibioticirrigation solution kit and other aminoglycosides should be under close clinical observation, because aminoglycosides have an inherent potential for causing ototoxicity and nephrotoxicity.

[0170] Ototoxicity: Neurotoxicity, manifested as both auditory and vestibular ototoxicity, canoccur [see Warnings and Precautions (5.3)]. The auditory changes are irreversible, are usually bilateral, and may be partial or total. Eighth-nerve impairment may develop, primarily in patients having pre-existing renal damage and in those with normal renal function to whom aminoglycosides are administered for longer periods or in higher doses than those recommended. The risk of aminoglycoside-induced hearing loss increases with the degree of exposure to either high peak or high trough serum concentrations. Patients who develop cochlear damage may not have symptoms during therapy to warn them of eighth-nerve toxicity, and partial or total irreversible bilateral deafness may continue to develop after the drug has been discontinued. When feasible, it is recommended that serial audiograms be obtained in patients old enough to be tested, particularly high-risk patients [see Warnings and Precautions (5.8)]. Evidence of impairment of vestibular or auditory function requires discontinuation of the drug or dosage adjustment [Dosage and Administration (2.2)]. Other manifestations of neurotoxicity besides ototoxicity may include numbness, skin tingling, muscle twitching, and convulsions.

[0171] Nephrotoxicity: Renal function should be closely monitored in patients with known orsuspected renal impairment and also in those whose renal function is initially normal but who develop signs of renal dysfunction during therapy [see Warnings and Precautions (5.2)]. Rarely, nephrotoxicity may not become apparent until the first few days after cessation of therapy. Aminoglycoside-induced nephrotoxicity usually is reversible. Peak and trough serum concentrations of aminoglycosides should be monitored periodically during therapy to assure adequate levels and to avoid potentially toxic levels. Prolonged serum concentrations above 12 mcg / mL should be avoided. Rising trough levels (above 2 mcg / mL) may indicate tissue105228354.428Attorney Docket No.121446-854267 accumulation. Such accumulation, excessive peak concentrations, advanced age, and cumulative dose may contribute to nephrotoxicity. Urine should be examined for decreased specific gravity and increased excretion of protein, cells, and casts. Blood urea nitrogen, serum creatinine, and creatinine clearance should be measured periodically [see Warnings and Precautions (5.8)]. Evidence of impairment of renal function requires discontinuation of the drug or dosage adjustment [Dosage and Administration (2.2)].

[0172] • Concomitant Use with Systemic Aminoglycosides: Concurrent use of otherneurotoxic and / or nephrotoxic antibiotics, particularly other aminoglycosides (e.g., amikacin, streptomycin, neomycin, kanamycin, gentamicin, and paromomycin), cephaloridine, viomycin, polymyxin B, colistin, cisplatin, and vancomycin, should be avoided [see Warnings and Precautions (5.6)]. Other factors that may increase patient risk are advanced age and dehydration. Aminoglycosides should not be given concurrently with potent diuretics, such as ethacrynic acid and furosemide. Some diuretics themselves cause ototoxicity, and intravenously administered diuretics enhance aminoglycoside toxicity by altering antibiotic concentrations in serum and tissue.

[0173] • Embryo-Fetal Toxicity: Aminoglycosides can cause fetal harm when administeredto a pregnant woman [see Warnings and Precautions (5.5) and Use in Specific Populations (8.1)]. 1 INDICATIONS AND USAGE

[0174] The antibiotic irrigation solution kit containing the aminoglycoside antibiotictobramycin sulfate and tricyclic glycopeptide antibiotic vancomycin hydrochloride for irrigation administration using the antibiotic irrigation solution kit Irrigation System is indicated for the treatment of periprosthetic joint infection in skeletally mature adult patients undergoing an exchange arthroplasty procedure, where vancomycin hydrochloride and tobramycin sulfate are appropriate antibiotics for treatment of the infection. Limitations of Use

[0175] Prescribing the antibiotic irrigation solution kit in the absence of a proven or stronglysuspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria. The decision to use or continue therapy with the antibiotic irrigation solution kit should be based on the results of susceptibility studies, the severity of the infection, and the important additional concepts discussed in the BOXED WARNING.

[0176] To reduce the development of drug‑resistant bacteria and maintain the effectiveness ofthe antibiotic irrigation solution kit and other antibacterial drugs, the antibiotic irrigation solution kit should be used only to treat or prevent infections that are proven or strongly suspected to be105228354.429Attorney Docket No.121446-854267 caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy. 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosage

[0177] The antibiotic irrigation solution kit consists of tobramycin sulfate for irrigation andvancomycin hydrochloride for irrigation as individual antibiotics administered separately with the antibiotic irrigation solution kit Irrigation System. The Irrigation System sequentially and separately delivers the antibiotic solutions to either the knee or hip space, allows the antibiotics to soak for a predetermined time and then removes fluid from the joint space using suction. See below the specific treatment cycle for each antibiotic. Tobramycin Sulfate Dosage and Administration

[0178] The recommended dose is irrigation of the joint space with 80 mg / day of tobramycinsulfate daily for 7-10 days using the Irrigation System. Each day of a 7- to 10-day treatment with the antibiotic irrigation solution kit begins with the administration of 80 mg of tobramycin sulfate for irrigation in 50 mL of normal saline (1.6 mg / mL) delivered with Irrigation System. Following a 2-hour soak of tobramycin antibiotic in the infected joint, liquid is removed from the wound space is removed using suction over 30 minutes with the Irrigation System. Vancomycin Hydrochloride Dosage and Administration

[0179] Following the daily tobramycin sulfate irrigation, the joint space is irrigated withapproximately 3 g / day of vancomycin hydrochloride for the 7- to 10-day treatment. The vancomycin dose is divided into approximately 22 hourly doses which consist of hourly administration of 125 mg of vancomycin hydrochloride in a 50 mL saline solution which is followed by a 30-minute soak in the joint space. Following the 30-minute soak of vancomycin in the infected joint, liquid is removed from the joint space is removed using suction over 30 minutes with the Irrigation System. The vancomycin hydrochloride administration step is repeated hourly for approximately 22 cycles a day. The dual tobramycin / vancomycin cyclic process is repeated each day for 7-10 days. 2.2 Dosing Modifications for Adverse Reactions Tobramycin sulfate for Irrigation

[0180] Maintain tobramycin serum trough levels at <2 mcg / mL [see Warnings andPrecautions (5.8)]. If serum trough levels are >2 mcg / mL or toxicity is a concern [see Warnings and Precautions (5.2, 5.3)], decrease total dose based on observed serum concentration. Decrease105228354.430Attorney Docket No.121446-854267 total drug administered but not total volume (e.g., 40 mg of tobramycin sulfate in 50 mL 0.9% sodium chloride, 0.8 mg / mL). Vancomycin Hydrochloride for Irrigation

[0181] Maintain vancomycin serum levels at <20 mcg / mL [see Warnings and Precautions(5.8)]. If serum levels are >20 mcg / mL or if toxicity is a concern [see Warnings and Precautions (5.2, 5.3)], decrease total dose based on observed serum concentration. Decrease total drug administered but not total volume (e.g., 1.5 g vancomycin hydrochloride in 1,200 mL 0.9% sodium chloride, 1.25 mg / mL). 2.3 Preparation and Administration

[0182] Refer to the Irrigation System Instructions for Use and Surgical Treatment Guide formore instructions.^ Following reconstitution and dilution detailed below, visually inspect the diluted drugproducts for particulate matter and discoloration prior to administration, whenever solution and container permit.^ If particulates and discolorations are noted, the product should not be used. Administerreconstituted and diluted tobramycin sulfate and vancomycin hydrochloride via irrigation as described in the antibiotic irrigation solution kit irrigation system Instructions for Use. Tobramycin Sulfate Dilution Instructions

[0183] Sterile compounding is conducted in the pharmacy under sterile compoundingguidelines.^ Using an appropriate syringe (approximately 3 mL), withdraw the entire 2 mL volume (80mg) from the tobramycin sulfate for irrigation vial and transfer to a 50 mL 0.9% sodium chloride intravenous piggyback (IVPB) bag.^ Seal port with Secur‐Seal or equivalent.^ Affix auxiliary “For Irrigation ONLY” labels.^ Write Beyond Use Date (BUD) on label (24 hours at room temperature or 48 hoursrefrigerated) [see How Supplied / Storage and Handling (16.2)].^ This is repeated daily for 7-10 days.Vancomycin Hydrochloride Reconstitution and Dilution Instructions

[0184] Sterile compounding is conducted in the pharmacy under sterile compoundingguidelines.^ Reconstitute 3 vancomycin hydrochloride 1 g vials using an appropriate syringe(approximately 20 mL) by adding 20 mL sterile water for injection to each vial.105228354.431Attorney Docket No.121446-854267^ Once in solution withdraw the contents of the 3 vancomycin hydrochloride 1 g vials andadd all 3 g (60 mL) of vancomycin hydrochloride to a 1000 mL normal saline IVPB bag.^ Use an appropriate syringe (approximately 100 mL) add 100 mL of normal saline to the1000 mL 0.9% Sodium Chloride IVPB already containing 3 g of vancomycin hydrochloride (Total volume is now approximately 1200 mL).^ Seal port with Secur‐Seal.^ Affix auxiliary “For Irrigation Only” labels.^ Write BUD on label (24 hours at room temperature or 7 days at refrigerated) [see HowSupplied / Storage and Handling (16.2)].^ This is repeated daily for 7-10 days.3 DOSAGE FORMS AND STRENGTHS

[0185] The Antibiotic Irrigation Solution Drug Pack includes:^ 7 vials each containing 80 mg / 2 mL (40 mg / mL) tobramycin sulfate solution for irrigationintended for reconstitution / dilution with normal saline.^ 21 vials each containing 1 g vancomycin hydrochloride lyophilized powder for irrigationintended for reconstitution / dilution with normal saline. 4 CONTRAINDICATIONS

[0186] Tobramycin sulfate for irrigation, vancomycin hydrochloride for irrigation and theantibiotic irrigation solution kit Irrigation System are contraindicated in patients:^ Patients with a history of allergies or known hypersensitivity to vancomycin or tobramycin[see Warnings and Precautions (5.1) and Description (11)] or a component or material utilized within the antibiotic irrigation solution kit including: titanium, titanium alloys, or polyurethane. [see Instructions for Use].^ Patients who require long-term anticoagulation or antiplatelet therapy, and for whombridging or withholding therapy is not recommended based on the individual’s clinical condition.^ Patients who are pregnant^ Patients who have a skeletal defect of greater than 150 mm in length in the tibia or femurof the infected joint

[0187] Patients who have bone loss or musculature, osteoporosis, neuromuscular compromiseor vascular deficiency in the affected limb and in sufficient degree to render the procedure unjustifiable.

[0188] Use of tobramycin sulfate and vancomycin hydrochloride for irrigation, arecontraindicated in patients with a history of allergies or known hypersensitivity to the drug105228354.432Attorney Docket No.121446-854267 components vancomycin or tobramycin [see Warnings and Precautions (5.1) and Description (11)]. Cross-allergenicity among aminoglycosides has been demonstrated.

[0189] The Irrigation System is contraindicated in patients with a history of allergies or knownhypersensitivity to device components or materials utilized within the antibiotic irrigation solution kit Irrigation System including titanium, titanium alloys, polymethylmethacrylate, or polyurethane [see Instructions for Use]. 5 WARNINGS AND PRECAUTIONS 5.1 Allergic and Dermatologic Reactions

[0190] No allergic or dermatologic reactions occurred during the antibiotic irrigation solutionkit clinical trials.

[0191] tobramycin sulfate contains sodium metabisulfite, a sulfite that may cause allergic-typereactions, including anaphylactic symptoms and life-threatening or less severe asthmatic episodes, in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people.

[0192] Serious allergic reactions including anaphylaxis and dermatologic reactions includingexfoliative dermatitis, toxic epidermal necrolysis, erythema multiforme, and Stevens-Johnson Syndrome have been reported rarely in patients on tobramycin therapy. Although rare, fatalities have been reported [see Contraindications (4)].

[0193] If an allergic reaction occurs, the drug should be discontinued, and appropriate therapyinstituted. 5.2 Nephrotoxicity

[0194] In the clinical trials results described herein, 4 cases of acute kidney injury (AKI) werereported with 2 being considered serious adverse reactions with 1 death which AKI contributed to the death. This was attributed to receiving either oral or intravenous (IV) antibiotics in addition to the antibiotic irrigation solution kit by the irrigation route. High serum creatine and blood urea nitrogen (BUN) were observed in 1 patient receiving THE ANTIBIOTIC IRRIGATION SOLUTION KIT [see Adverse Reactions (6.1)].

[0195] Caution should be exercised when prescribing the antibiotic irrigation solution kit topatients with known or suspected renal dysfunction and should be monitored closely. Rarely, nephrotoxicity may not become apparent until the first few days after cessation of therapy. Aminoglycoside-induced nephrotoxicity usually is reversible.

[0196] Nephrotoxicity has been associated with aminoglycosides as a class, which includestobramycin. Aminoglycosides may be absorbed in significant quantities from body surfaces after105228354.433Attorney Docket No.121446-854267 local irrigation and may cause nephrotoxicity. Patients with known or suspected renal dysfunction or taking concomitant nephrotoxic drugs along with tobramycin via the irrigation route should have serum concentrations of tobramycin and laboratory measurements of renal function obtained at the discretion of the treating physician. Peak and trough serum concentrations of aminoglycosides should be monitored periodically during therapy to assure adequate levels and to avoid potentially toxic levels. Prolonged serum concentrations above 12 mcg / mL should be avoided. Rising trough levels (above 2 mcg / mL) may indicate tissue accumulation. Such accumulation, excessive peak concentrations, advanced age, and cumulative dose may contribute to nephrotoxicity. Urine should be examined for decreased specific gravity and increased excretion of protein, cells, and casts. BUN, serum creatinine, and creatinine clearance should be measured periodically [see Warnings and Precautions (5.8)]. If nephrotoxicity develops, the patient should be managed as medically appropriate, including potentially discontinuing tobramycin administered by the irrigation route in the infected hip or knee joint until serum concentrations fall below 2 mcg / mL. Evidence of impairment of renal function requires discontinuation of or dosage adjustment of the antibiotic irrigation solution kit [Dosage and Administration (2.2)].

[0197] Vancomycin exposure may result in AKI. The risk of AKI increases as systemicexposure / serum levels increase; however, during clinical trials the systemic vancomycin levels were low based on the irrigation route of administration. It is recommended to monitor renal function in all patients, especially patients with underlying renal impairment, patients with co- morbidities that predispose to renal impairment, and patients receiving concomitant therapy with a drug known to be nephrotoxic.

[0198] Concurrent use of the antibiotic irrigation solution kit with potent diuretics andconcurrent and sequential use with other nephrotoxic drugs increases the risk of nephrotoxicity. 5.3 Ototoxicity

[0199] One case each of mild hearing loss and acute encephalopathy was observed in patientsreceiving the antibiotic irrigation solution kit in clinical trials [see Adverse Reactions (6.1)]. This was attributed to receiving either oral or IV antibiotics in addition to the antibiotic irrigation solution kit by the irrigation route. Neurotoxicity, manifested as both auditory and vestibular ototoxicity, has been reported with parenteral aminoglycosides. The auditory changes are irreversible, are usually bilateral, and may be partial or total. Other manifestations of neurotoxicity besides ototoxicity may include numbness, skin tingling, muscle twitching, and convulsions.

[0200] Ototoxicity has occurred in patients receiving IV vancomycin hydrochloride ortobramycin. It may be transient or permanent. It has been reported mostly in patients who have been given excessive doses, who have an underlying hearing loss, or who are receiving105228354.434Attorney Docket No.121446-854267 concomitant therapy with another ototoxic agent, such as an aminoglycoside. Vancomycin and tobramycin should be used with caution in patients with renal insufficiency because the risk of toxicity is appreciably increased by high, prolonged blood concentrations. The risk of aminoglycoside-induced hearing loss increases with the degree of exposure to either high peak or high trough serum concentrations.

[0201] Tinnitus may be a sentinel symptom of ototoxicity, and therefore the onset of thissymptom warrants further clinical investigation. Vestibular toxicity may be manifested by vertigo, ataxia or dizziness. Patients with known or suspected auditory or vestibular dysfunction should be closely monitored when taking tobramycin for irrigation. Monitoring might include obtaining audiometric evaluations and serum tobramycin levels [see Warnings and Precautions (5.8)]. If ototoxicity is noted, the patient should be managed as medically appropriate, including potentially discontinuing or requiring dosage adjustment of the antibiotic irrigation solution kit [Dosage and Administration (2.2)].

[0202] Aminoglycosides may be absorbed in significant quantities from body surfaces afterlocal irrigation and may cause ototoxicity and neurotoxicity. Concurrent use of potent diuretics and concurrent and sequential use of other neurotoxic drugs with VT-X& KIT should be use with caution in patients. Risk of Ototoxicity Due to Mitochondrial DNA Variants

[0203] Cases of ototoxicity with aminoglycosides have been observed in patients with certainvariants in the mitochondrially encoded 12S rRNA gene (MT-RNR1), particularly the m.1555A>G variant. Ototoxicity occurred in some patients even when their aminoglycoside serum levels were within the recommended range. Mitochondrial DNA variants are present in less than 1% of the general US population, and the proportion of the variant carriers who may develop ototoxicity as well as the severity of ototoxicity is unknown. In case of known maternal history of ototoxicity due to aminoglycoside use or a known mitochondrial DNA variant in the patient, consider alternative treatments other than aminoglycosides unless the increased risk of permanent hearing loss is outweighed by the severity of infection and lack of safe and effective alternative therapies. 5.4 Clostridium Difficile Associated Diarrhea (CDAD)

[0204] One case of chronic diarrhea was observed in the antibiotic irrigation solution kitclinical trials. Clostridium difficile associated diarrhea (CDAD) was not observed with the antibiotic irrigation solution kit for irrigation administration to the infected hip or knee joint by the Irrigation System in clinical studies.

[0205] CDAD has been reported with use of nearly all antibacterial agents, includingintravenously delivered vancomycin hydrochloride and tobramycin sulfate, and may range in105228354.435Attorney Docket No.121446-854267 severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

[0206] C. difficile produces toxins A and B which contribute to the development of CDAD.Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after administration of antibacterial agents.

[0207] If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C.difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

[0208] Therapy with tobramycin and vancomycin may result in overgrowth of nonsusceptibleorganisms. If overgrowth of nonsusceptible organisms occurs, appropriate therapy should be initiated. Careful observation of the patient is essential. If superinfection occurs during therapy, appropriate measures should be taken. In rare instances, there have been reports of pseudomembranous colitis due to C. difficile developing in patients who received IV vancomycin hydrochloride for injection. 5.5 Embryo-Fetal Toxicity

[0209] Aminoglycosides can cause fetal harm when administered to a pregnant woman.Aminoglycosides cross the placenta, and streptomycin has been associated with several reports of total, irreversible, bilateral congenital deafness in pediatric patients exposed in utero. However, systemic absorption of tobramycin following irrigation administration is expected to be minimal [see Clinical Pharmacology (12.3)]. Patients who use the antibiotic irrigation solution kit during pregnancy or become pregnant during the use of the antibiotic irrigation solution kit should be apprised of the potential hazard to the fetus [see Use in Specific Populations (8.1)]. 5.6 Concomitant Use with Systemic Aminoglycosides and Other Antibiotics

[0210] Patients receiving concomitant tobramycin for irrigation and parenteralaminoglycoside therapy should be monitored as clinically appropriate for toxicities associated with aminoglycosides as a class [see Warnings and Precautions (5.2, 5.3)]. Serum tobramycin levels should be monitored if symptoms develop associated with ototoxicity and nephrotoxicity [Warnings and Precautions (5.8)].

[0211] The inactivation of tobramycin and other aminoglycosides by β-lactam-type antibiotics(penicillins or cephalosporins) has been demonstrated in vitro and in patients with severe renal105228354.436Attorney Docket No.121446-854267 impairment. Such inactivation has not been found in patients with normal renal function who have been given the drugs by separate routes of administration. 5.7 Neuromuscular Disorders

[0212] The antibiotic irrigation solution kit should be used cautiously in patients with musculardisorders. Aminoglycosides, including tobramycin, may aggravate muscle weakness because of a potential curare-like effect on neuromuscular function. Neuromuscular blockade, respiratory failure, and prolonged respiratory paralysis may occur more commonly in patients with underlying neuromuscular disorders, such as myasthenia gravis or Parkinson’s disease. The possibility of prolonged respiratory paralysis or secondary apnea should be considered if tobramycin is administered to anesthetized patients who are also receiving concomitant neuromuscular blocking agents, such as succinylcholine, tubocurarine, or decamethonium, or to patients receiving massive transfusions of citrated blood. If neuromuscular blockade occurs, it may be reversed by the administration of calcium salts but mechanical assistance may be necessary. 5.8 Laboratory Tests Audiograms

[0213] Clinical studies of the antibiotic irrigation solution kit did not identify hearing lossusing audiometric tests which evaluated hearing up to 8000 Hz. Physicians should consider an audiogram for patients who show any evidence of auditory dysfunction, or who are at increased risk for auditory dysfunction. Tinnitus may be a sentinel symptom of ototoxicity, and therefore the onset of this symptom warrants caution. When feasible, it is recommended that serial audiograms be obtained in high-risk patients to minimize the risk of ototoxicity [see Warnings and Precautions (5.3)]. Serum Concentrations of Tobramycin

[0214] Tobramycin: peak and trough serum levels of tobramycin should be measuredperiodically during therapy. A useful guideline would be to perform serum level assays after 2 or 3 doses, so that the dosage could be adjusted if necessary, and also at 3- to 4-day intervals during therapy. In the event of changing renal function, more frequent serum levels should be obtained and the dosage or dosage interval adjusted according to the guidelines [see Dosage and Administration (2.2)].

[0215] In order to measure the peak level, a serum sample should be drawn about 120 minutesfollowing irrigation administration in the infected joint. Trough levels are measured by obtaining serum samples at 8 hours or just prior to the next dose of tobramycin. These suggested time intervals are intended only as guidelines and may vary according to institutional practices. It is important, however, that there be consistency within the individual patient program unless105228354.437Attorney Docket No.121446-854267 computerized pharmacokinetic dosing programs are available in the institution. These serum-level assays may be especially useful for monitoring the treatment of severely ill patients with changing renal function or of those infected with less sensitive organisms or those receiving maximum dosage.

[0216] Prolonged systemic concentrations of tobramycin above 12 mcg / mL should beavoided. Rising trough levels (above 2 mcg / mL) may indicate tissue accumulation. Such accumulation, advanced age, and cumulative dosage may contribute to ototoxicity and nephrotoxicity [see Warnings and Precautions (5.2, 5.3)]. It is particularly important to monitor serum levels closely in patients with known renal impairment.

[0217] In patients with normal renal function treated with the antibiotic irrigation solution kit,serum tobramycin concentrations do not require routine monitoring. Serum concentrations of tobramycin in patients with renal dysfunction or patients treated with concomitant parenteral tobramycin should be monitored at the discretion of the treating physician [see Use in Specific Population (8.6)].

[0218] The serum concentration of tobramycin should only be monitored throughvenipuncture and not finger prick blood sampling. Contamination of the skin of the fingers with tobramycin may lead to falsely increased measurements of serum levels of the drug. This contamination cannot be completely avoided by hand washing before testing.

[0219] In patients with extensive burns or cystic fibrosis, altered pharmacokinetics may resultin reduced serum concentrations of aminoglycosides. In such patients treated with tobramycin, measurement of serum concentration is especially important as a basis for determination of appropriate dosage. Serum Concentrations of Vancomycin

[0220] Vancomycin: peak serum levels of vancomycin should be measured periodicallyduring therapy. A useful guideline would be to perform serum level assays after the first day of dosing, so that the dosage could be adjusted if necessary, and also at 3- to 4-day intervals during therapy. In the event of changing renal function, more frequent serum levels should be obtained and the dosage or dosage interval adjusted according to the guidelines [see Dosage and Administration (2.2)].

[0221] In order to measure the peak level, a serum sample should be drawn about 120minutes following irrigation administration in the infected joint. The suggested time interval is intended only as guideline and may vary according to institutional practices. It is important, however, that there be consistency within the individual patient program unless computerized pharmacokinetic dosing programs are available in the institution. These serum-level assays may105228354.438Attorney Docket No.121446-854267 be especially useful for monitoring the treatment of severely ill patients with changing renal function or of those infected with less sensitive organisms or those receiving maximum dosage. Renal Function

[0222] The clinical studies of the antibiotic irrigation solution kit did not reveal any imbalancein the percentage of patients who experienced at least a 50% rise in serum creatinine from baseline in either the antibiotic irrigation solution group (n=76) or the standard of care group (n=76). Laboratory tests of urine and renal function should be conducted at the discretion of the treating physician. Urine should be examined for decreased specific gravity and increased excretion of protein, cells, and casts. BUN, serum creatinine, and creatinine clearance should be measured periodically. Serum and urine specimens for examination should be collected during therapy. Serum calcium, magnesium, and sodium should be monitored. Leukocyte Count

[0223] Reversible neutropenia has been reported in patients receiving vancomycinhydrochloride for injection. Patients who will undergo prolonged therapy with vancomycin hydrochloride for injection or those who are receiving concomitant drugs which may cause neutropenia should have periodic monitoring of the leukocyte count. 6 ADVERSE REACTIONS

[0224] Below are adverse reactions associated with the antibiotic irrigation solution kit.Additional adverse reactions related to the procedure and / or medical device are described in further detail in the antibiotic irrigation solution kit Irrigation System Instructions for Use. Additionally, the following clinically significant adverse reactions associated with the use of antibiotics are described elsewhere in the labeling:^ Allergic and Dermatologic Reactions [see Warnings and Precautions (5.1)].^ Nephrotoxicity [see Warnings and Precautions (5.2)].^ Ototoxicity [see Warnings and Precautions (5.3)].^ Clostridium Difficile Associated Diarrhea [see Warnings and Precautions (5.4)].^ Embryo-Fetal Toxicity [see Warnings and Precautions (5.5)].^ Concomitant Use with Systemic Aminoglycosides and Other Antibiotics [see Warningsand Precautions (5.6)].^ Neuromuscular Disorders [see Warnings and Precautions (5.7)].6.1 Clinical Trial Experience

[0225] Because clinical trials are conducted under widely varying conditions, adverse reactionrates observed in the clinical trials of drugs-devices combination cannot be directly compared to105228354.439Attorney Docket No.121446-854267 rates in the clinical trials of another drug or device and may not reflect the rates observed in practice.

[0226] The data described were identified from the “Abbreviated Protocol for Two-StageExchange” (APEX) and the APEX-2 clinical trials that reflect the exposure of 80 mg of tobramycin sulfate in 50 mL of normal saline (1.6 mg / mL) delivered by Irrigation System for 7-10 days (total daily exposure of 1.6 mg / day). Following a 2-hour soak, the liquid in the wound space is removed using suction over 30 minutes. This is followed by each subsequent hour, 125 mg of vancomycin hydrochloride in 50 mL of normal saline (2.5 mg / mL) is administered with the antibiotic irrigation solution kit every hour for 10 treatments for duration of 7-10 days (total daily exposure of 1.25 g / day). Following a 30-minute soak, the liquid in the wound space is removed using suction over 30 minutes [Dosages and Administrations (2.1)]. The patients were followed for 1 year after the antibiotic irrigation solution kit treatment. The APEX and APEX 2 trials were randomized, active- controlled (standard of care) clinical studies where 75 patients received treatment with the antibiotic irrigation solution kit (tobramycin and vancomycin) and # with standard of care. The overall pooled safety data was # (%) female, # (%) male, # (%) White # (%) Black, # (%) Asian, and # (%) patients classified as Other. Of these patients, the age range was #-# with #(%) were 65 years of age or older. Of these patients # (%) had a hip infection and # (%) had a knee infection. Patients with advanced renal insufficiency (chronic kidney disease Stage 4 or greater or globular filtration rate < 30 mL / min) were excluded from the clinical studies [Warnings and Precautions (5.2)].

[0227] There were no serious adverse reactions found in the APEX and APEX-2 clinical trialswhich were determined to be related to treatment with tobramycin sulfate or vancomycin hydrochloride for irrigation. There were 5 adverse reactions in 3 subjects (8.1%, 3 / 75) which were determined to be possibly related to tobramycin sulfate and vancomycin hydrochloride for irrigation. Two (2) events were reported in 1 subject which included mild hearing loss and chronic diarrhea. These events occurred approximately 6 weeks after completion of Stage 2 surgery and while the subject was on IV vancomycin. The other three 3 adverse reactions were: (1) worsening of post-operative pain; (2) high serum creatinine, and (3) high BUN.

[0228] There were 2 additional adverse reactions in 2 subjects treated with the antibioticirrigation solution kit (5.4%, 2 / 75) determined to be related or likely related to the antibiotic irrigation solution kit spacer device / study procedure. These 2 events were related to an irrigation line blockage. Each event was due to an investigator surgical technique error resulting in impingement of the irrigation line. There was 1 additional adverse reaction (2.7%, 1 / 75) as related105228354.440Attorney Docket No.121446-854267or possibly related to the fluid management system which was a Candida auris infection of theleft knee.

[0229] There were 9 additional adverse reactions (9 / 75, 24.3%) in antibiotic irrigation solutiontreatment arm considered as related, or possibly related: six (6 / 75, 16.2%) anemia, 2 (5.4%) post- operative pain, and 1 (2.7%) leukocytosis. Again, while these events are untoward medical events, they are expected in subjects with PJI undergoing a surgical procedure. Two of these events were reported as serious and were the same events described above related to the irrigation line blockage.

[0230] No patient discontinued the antibiotic irrigation solution kit due to an adverse reaction.

[0231] Table 4 summarizes all adverse reactions related to the surgical procedure observed ata frequency of ≥10% in patients treated with the antibiotic irrigation solution kit. Table 4. All Adverse Reactions Related to the Surgical Procedure Observed at a Frequency of ≥10% in Patients Treated with the Antibiotic Irri ation Solution Kit )7.1 Concurrent and / or Sequential Use of the Antibiotic Irrigation Solution Kit with Other Drugs with Neurotoxic, Nephrotoxic, or Ototoxic Potential

[0232] No drug interaction studies have been conducted using the antibiotic irrigation solutionkit (vancomycin hydrochloride or tobramycin sulfate) delivered by the irrigation route of administration.

[0233] Concurrent and / or sequential use of the antibiotic irrigation solution kit with otherdrugs with neurotoxic, nephrotoxic, or ototoxic potential should be avoided. Some diuretics can enhance aminoglycoside toxicity by altering antibiotic concentrations in serum and tissue. the105228354.441Attorney Docket No.121446-854267 antibiotic irrigation solution kit should not be administered concomitantly with ethacrynic acid, furosemide, urea, or IV mannitol.

[0234] Monitor renal function in patients receiving vancomycin or tobramycin and concurrentand / or sequential systemic or topical use of other potentially neurotoxic and / or nephrotoxic drugs, such as amphotericin B, aminoglycosides, bacitracin, polymixin B, colistin, viomycin, or cisplatin [see Warnings and Precautions (5.8)].

[0235] There have been reports that the frequency of infusion-related events (includinghypotension, histamine-like flushing, erythema, urticaria, and pruritus) and anaphylactoid reactions [see Warnings and Precautions (5.1)] which increases with the concomitant administration of anesthetic agents. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary

[0236] There are no adequate and well-controlled studies of the antibiotic irrigation solutionkit for irrigation route of administration in pregnant women to evaluate for drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. If the antibiotic irrigation solution kit is used during pregnancy, advise pregnant women of the potential risk to a fetus.

[0237] No reproductive and developmental toxicity studies with the combination oftobramycin and vancomycin were conducted.

[0238] The estimated background risks of major birth defects and miscarriage for the indicatedpopulation are unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Individual Components of the Antibiotic Irrigation Solution Kit Vancomycin:

[0239] There are no available data on for the irrigation route of administration of vancomycinin pregnant women to inform a drug associated risk of major birth defects or miscarriage. Available published data on vancomycin use in pregnancy during the second and third trimesters have not shown an association with adverse pregnancy-related outcomes (see Data). Vancomycin did not show adverse developmental effects when administered intravenously to pregnant rats and rabbits during organogenesis at doses less than or equal to the recommended maximum human dose based on body surface area (see Data).105228354.442Attorney Docket No.121446-854267 Tobramycin:

[0240] Aminoglycosides can cause fetal harm. Published literature reports that use ofstreptomycin, an aminoglycoside, can cause total, irreversible, bilateral congenital deafness when administered to a pregnant woman [see BOXED WARNINGS and Warnings and Precautions (5.3)]. Although there are no available data on tobramycin for irrigation use in pregnant women to inform a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes, systemic absorption of tobramycin following local irrigation administration is expected to be minimal [see Clinical Pharmacology (12.3)]. There are risks to the mother associated with cystic fibrosis in pregnancy (see Clinical Considerations). In animal reproduction studies with subcutaneous administration of tobramycin in pregnant rats and rabbits during organogenesis, there were no adverse developmental outcomes; however, ototoxicity was not evaluated in the offspring from these studies (see Data: Tobramycin). Advise pregnant women of the potential risk to a fetus.

[0241] Clinical Considerations

[0242] Disease-Associated Maternal and / or Embryo / Fetal Risk with tobramycinadministration. Cystic fibrosis may increase the risk for preterm delivery with tobramycin administration. Data Human Data Vancomycin:

[0243] A published study evaluated hearing loss and nephrotoxicity in infants of pregnant IVdrug users treated with vancomycin for suspected or documented methicillin‑resistant S. aureus in the second or third trimester. The comparison groups were 10 non‑IV drug‑dependent patients who received no treatment, and 10 untreated IV drug‑dependent patients served as substance abuse controls. No infant in the vancomycin-exposed group had abnormal sensorineural hearing at 3 months of age or nephrotoxicity.

[0244] A published prospective study assessed outcomes in 55 pregnant women with a positiveGroup B Streptococcus culture and a high‑risk penicillin allergy with resistance to clindamycin or unknown sensitivity who were administered vancomycin at the time of delivery. Vancomycin dosing ranged from the standard 1 g intravenously every 12 hours to 20 mg / kg IV every 8 hours (maximum individual dose 2 g). No major adverse reactions were recorded either in the mothers or their newborns. None of the newborns had sensorineural hearing loss. Neonatal renal function was not examined, but all the newborns were discharged in good condition. Animal Data105228354.443Attorney Docket No.121446-854267 Vancomycin:

[0245] Vancomycin did not cause fetal malformations when administered duringorganogenesis to pregnant rats (gestation days 6 to 15) and rabbits (gestation days 6 to 18) at the equivalent recommended maximum human dose (based on body surface area comparisons) of 200 mg / kg / day IV to rats or 120 mg / kg / day IV to rabbits. No effects on fetal weight or development were seen in rats at the highest dose tested or in rabbits given 80 mg / kg / day (approximately 1 and 0.8 times the recommended maximum human dose based on body surface area, respectively). Maternal toxicity was observed in rats (at doses 120 mg / kg and above) and rabbits (at 80 mg / kg and above). Tobramycin:

[0246] No reproduction toxicology studies have been conducted with tobramycin sulfate usingthe irrigation route of administration. However, subcutaneous administration of tobramycin at doses of up to 100 (rat) or 20 (rabbit) mg / kg / day during organogenesis was not associated with adverse developmental outcomes. Doses of tobramycin ≥40 mg / kg / day were severely maternally toxic to rabbits and precluded the evaluation of adverse developmental outcomes. Ototoxicity was not evaluated in offspring during nonclinical reproductive toxicity studies with tobramycin. 8.2 Lactation Risk Summary

[0247] There are insufficient data to inform the levels of vancomycin and tobramycin in humanmilk following use of the antibiotic irrigation solution kit for irrigation route of administration. However, systemic absorption of vancomycin and tobramycin following the irrigation route of administration is expected to be minimal [see Clinical Pharmacology (12.3)].

[0248] There are no data on the effects of the antibiotic irrigation solution kit for irrigation onthe breastfed infant or milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for the antibiotic irrigation solution kit for irrigation and any potential adverse effects on the breastfed infant from the antibiotic irrigation solution kit for irrigation or from the underlying maternal condition. Vancomycin

[0249] It is noteworthy that vancomycin is excreted in human milk. Caution should beexercised when using a systemically absorbed vancomycin product. Because of the potential for adverse events, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Tobramycin105228354.444Attorney Docket No.121446-854267

[0250] Limited published data on other formulations of tobramycin in lactating womenindicate that tobramycin is present in human milk. Tobramycin may cause alteration in the intestinal flora of the breastfeeding infant. Clinical Considerations

[0251] Tobramycin may cause intestinal flora alteration. Advise a woman to monitor thebreastfed infant for loose or bloody stools and candidiasis (thrush, diaper rash). 8.4 Pediatric Use

[0252] Safety and effectiveness of tobramycin sulfate and vancomycin hydrochloride forirrigation / irrigation system in pediatric patients have not been established. 8.5 Geriatric Use

[0253] In clinical trials with the antibiotic irrigation solution kit, 44 patients (57.9%) were >65years of age. Of these, 32 were between the ages of >65 and 75 (42.1%), and 12 were >75 years of age (15.8%).

[0254] Clinical studies with vancomycin hydrochloride and tobramycin sulfate havedemonstrated that geriatric subjects are at increased risks of developing nephrotoxicity and ototoxicity following treatment with these antibiotics, which may occur during or after completion of therapy [see Warnings and Precautions (5.2, 5.3)]. In patients over 65 years of age, including those with normal renal function prior to treatment, renal function should be monitored during and following treatment with vancomycin hydrochloride and tobramycin sulfate to detect potential antibiotic induced nephrotoxicity. Elderly patients may have reduced renal function that may not be evident in the results of routine screening tests, such as BUN or serum creatinine. A creatinine clearance determination may be more useful. Monitoring of renal function during treatment with aminoglycosides is particularly important in the elderly [see Warnings and Precautions (5.8)]. Other factors that may contribute to nephrotoxicity and ototoxicity are rising trough levels, excessive peak concentrations, dehydration, concomitant use of other neurotoxic or nephrotoxic drugs, and cumulative dose. Peak and trough serum levels of tobramycin should be measured periodically during therapy to assure adequate levels and to avoid potentially toxic levels [see Warnings and Precautions (5.8)].

[0255] Patients over 65 years of age may take longer to respond to therapy compared topatients 65 years of age and younger [see Clinical Studies ( 14.1)]. Clinicians should be aware of the importance of appropriate duration of vancomycin hydrochloride and tobramycin sulfate treatment in patients over 65 years of age. 8.6 Renal Impairment105228354.445Attorney Docket No.121446-854267

[0256] Tobramycin is primarily excreted unchanged in the urine and renal function is expectedto affect the exposure to tobramycin. Parenteral vancomycin is primarily eliminated by glomerular filtration in the kidneys as unchanged drug. The risk of adverse reactions to the antibiotic irrigation solution kit may be greater in patients with impaired renal function [Clinical Pharmacology (12.3)]. Patients with advanced renal insufficiency (chronic kidney disease Stage 4 or greater or globular filtration rate < 30 mL / min) were excluded from the antibiotic irrigation solution kit clinical studies. No dosage adjustment of the antibiotic irrigation solution kit is recommended in patients with mild to moderate renal impairment (eGFR 30 to 89 mL / min). If signs of nephrotoxicity develop, patients should be monitored and the dose of the antibiotic irrigation solution kit may need to be modified or treatment discontinue [see Boxed Warning, Dosage and Administration (2.2), and Warnings and Precautions (5.2, 5.8)]. Avoid the use of the antibiotic irrigation solution kit in patients with severe renal impairment (eGFR < 30 mL / min). 8.7 Hepatic Impairment

[0257] No studies with the antibiotic irrigation solution kit have been performed in patientswith hepatic impairment. As tobramycin and vancomycin are not metabolized and excreted renally with parenteral administration, an effect of hepatic impairment on the exposure of the antibiotics is not expected. 10 OVERDOSAGE

[0258] No information is available on accidental overdosage of the antibiotic irrigationsolution kit in humans.

[0259] In all cases of suspected overdosage, call your Regional Poison Control Center toobtain the most up-to-date information about the treatment of overdose. Telephone numbers of certified poison control centers are listed in the Physicians' Desk Reference (PDR). This recommendation is made because, in general, information regarding the treatment of overdose may change more rapidly than the package insert. In managing overdosage, consider the possibility of multiple drug overdoses, interaction among drugs, and unusual drug kinetics in your patient.

[0260] The available overdosage information for each of the individual drug components inNEXCHANGE are summarized below: Vancomycin

[0261] Supportive care is advised, with maintenance of glomerular filtration. Vancomycin ispoorly removed by dialysis. Hemofiltration and hemoperfusion with polysulfone resin have been reported to result in increased vancomycin clearance. The median lethal IV dose is 319 mg / kg in rats and 400 mg / kg in mice. Tobramycin105228354.446Attorney Docket No.121446-854267 Signs and Symptoms

[0262] The severity of the signs and symptoms following a tobramycin overdose are dependenton the dose administered, the patient's renal function, state of hydration, and age and whether or not other medications with similar toxicities are being administered concurrently. Toxicity may occur in patients treated more than 10 days, in adults given more than 5 mg / kg / day or patients with reduced renal function whose dose has not been appropriately adjusted.

[0263] Nephrotoxicity following the parenteral administration of an aminoglycoside is mostclosely related to the area under the curve (AUC) of the serum concentration versus time graph. Nephrotoxicity is more likely if trough blood concentrations fail to fall below 2 mcg / mL and is also proportional to the average blood concentration [see Warnings and Precautions (5.2, 5.8)]. Patients who are elderly, have abnormal renal function, are receiving other nephrotoxic drugs, or are volume depleted are at greater risk for developing acute tubular necrosis [see Drug Interactions (7.1) and Use in Specific Populations [8.5, 8.6)]. Auditory and vestibular toxicity has been associated with aminoglycoside overdose; these toxicities occur in patients treated longer than 10 days, in patients with abnormal renal function, in dehydrated patients, or in patients receiving medications with additive auditory toxicities. These patients may not have signs or symptoms or may experience dizziness, tinnitus, vertigo, and a loss of high-tone acuity, as ototoxicity progresses. Ototoxicity signs and symptoms may not begin to occur until long after the drug has been discontinued [see Warnings and Precautions (5.3)].

[0264] Neuromuscular blockade or respiratory paralysis may occur following administrationof many aminoglycosides. Neuromuscular blockade, respiratory failure, and prolonged respiratory paralysis may occur more commonly in patients with myasthenia gravis or Parkinson's disease [see Warnings and Precautions (5.7)]. Prolonged respiratory paralysis may also occur in patients receiving decamethonium, tubocurarine, or succinylcholine. If neuromuscular blockade occurs, it may be reversed by the administration of calcium salts but mechanical assistance may be necessary.

[0265] If tobramycin were ingested, toxicity would be less likely because aminoglycosides arepoorly absorbed from an intact gastrointestinal tract. Treatment

[0266] The initial intervention in a tobramycin overdose is to establish an airway and ensureoxygenation and ventilation. Resuscitative measures should be initiated promptly if respiratory paralysis occurs.

[0267] Patients that have received an overdose of tobramycin and have normal renal functionshould be adequately hydrated to maintain a urine output of 3 to 5 mL / kg / hr. Fluid balance,105228354.447Attorney Docket No.121446-854267 creatinine clearance, and tobramycin plasma levels should be carefully monitored until the serum tobramycin level falls below 2 mcg / mL.

[0268] Patients in whom the elimination half-life (t1 / 2) is greater than 2 hours or whose renalfunction is abnormal may require more aggressive therapy. In such patients, hemodialysis may be beneficial. 11 DESCRIPTION The antibiotic irrigation solution kit contains both tobramycin sulfate for irrigation and vancomycin hydrochloride for irrigation. Tobramycin Sulfate for Irrigation

[0269] Tobramycin Sulfate, a water-soluble antibiotic of the aminoglycoside group, is derivedfrom the actinomycete Streptomyces tenebrarius. Tobramycin Injection, USP is a clear and colorless sterile aqueous solution for irrigation administration.

[0270] Each mL contains tobramycin sulfate equivalent to 40 mg tobramycin; sodiummetabisulfite added as an antioxidant 3 mg; and edetate disodium added as a stabilizer, 0.1 mg. Contains sulfuric acid and may contain sodium hydroxide for pH adjustment. pH 4.0 (3.0 to 6.5).

[0271] Tobramycin sulfate is O-3-amino-3-deoxy-α-D-glucopyranosyl-(1→4)-O-[2,6-diamino-2,3,6-trideoxy-α-D-ribo-hexopyranosyl-(1→6)]-2-deoxy-L-streptamine sulfate (2:5)(salt) and has the chemical formula (C18H37N5O9)2• 5H2SO4. The molecular weight is 1,425.45. The tobramycin has the following structure:for Irrigation

[0272] Vancomycin is a tricyclic glycopeptide antibiotic derived from Amycolatopsisorientalis (formerly Nocardia orientalis). The chemical name for vancomycin hydrochloride is 3S- [3R*,6S*(S*),7S*,22S*,23R*,26R*,36S*,38aS*]]-3-(2-Amino-2-oxoethyl)-44-[[2-O-(3- amino-2,3,6-trideoxy-3-C-methyl-α-L-lyxo-hexopyranosyl)-β-D-glucopyranosyl]oxy]-10,19- dichloro-2,3,4,5,6,7,23,24,25,26,36,37,38,38a-tetradecahydro-7,22,28,30,32-pentahydroxy-6-[[4- methyl-2-(methylamino)-1-oxopentyl]amino]-2,5,24,38,39-pentaoxo-22H-8,11:18,21-dietheno- 23,36- (iminomethano)-13,16:31,35-dimetheno-1H,16H-[1,6,9]oxadiazacyclohexadecino[4,5- m][10,2,16]-benzoxadiazacyclotetracosine-26-carboxylic acid, monohydrochloride. The105228354.448Attorney Docket No.121446-854267 molecular formula is C66H75Cl2N9O24 HCl and the molecular weight is 1,485.74. Vancomycin hydrochloride has the following structure: 1212.1

[0273] Tobramycin sulfate for irrigation is an aminoglycoside antibiotic with activity againstGram-positive and Gram-negative bacteria [see Microbiology (12.4)].

[0274] Vancomycin hydrochloride for irrigation is a glycopeptide antibiotic with activityagainst Gram-positive bacteria [see Microbiology (12.4)]. 12.3 Pharmacokinetics

[0275] vancomycin hydrochloridefor irrigation and tobramycin sulfate for irrigation aredelivered using Irrigation System which provides the full concentration of the dose delivered in the infected joint space with minimal systemic adsorption. Absorption

[0276] There is only minimal systemic absorption of tobramycin when administered via theirrigation route of administration with the antibiotic irrigation solution kit. Vancomycin is poorly systemically absorbed when administered via the irrigation route of administration with the antibiotic irrigation solution kit.

[0277] During the APEX clinical study, tobramycin plasma concentrations were assessedapproximately 30 minutes before tobramycin start (approximate trough concentration) and 3-4 hours after tobramycin therapy start (approximate peak concentration) on days 1, 3, 5, and 7 of therapy. Vancomycin serum concentration was assessed daily at any time during that day on all interstage days (i.e., days 1-7).

[0278] In total, 35 patients had 226 measured serum vancomycin levels during the interstageperiod. Of these 226 values, 62 (27.4%) were below the lower limit of quantitation (LLOQ) of 0.4 mcg / mL. Only two patients had a single value above 30 mcg / mL and only two additional patients had values above 20 mcg / mL. Both patients with vancomycin levels above the 30 mcg / mL were receiving IV vancomycin in addition to local irrigation with vancomycin during the interstage105228354.449Attorney Docket No.121446-854267 period. The remainder of patients (31 / 35) had all measured serum vancomycin levels below the typical trough values of 5-15 mcg / mL from IV administration.

[0279] During the interstage period 256 serum samples from 35 patients were tested fortobramycin concentrations. A total of 139 samples were obtained for peak tobramycin testing and 117 samples for trough tobramycin testing. Tobramycin was below the LLOQ in 83 peak samples (59.7%) and 98 trough samples (83.8%). Of the samples with concentrations above the LLOQ, all were less than 2 mcg / mL in both the peak and trough testing with the majority less than 1 mcg / mL.

[0280] A summary of the observed vancomycin and tobramycin concentrations during theantibiotic irrigation solution kit treatment is presented in Table . Table 5. Vancomycin and Tobramycin Serum Concentrations During Antibiotic Irrigation Solution Treatment L) nd s a nts ge

[0281] Tobramycin is rapidly absorbed following intramuscular administration. Peak serumconcentrations of tobramycin occur between 30 and 90 minutes after intramuscular administration. Following an intramuscular dose of 1 mg / kg tobramycin of body weight, maximum serum concentrations reach about 4 mcg / mL, and measurable levels persist for as long as 8 hours. Therapeutic serum levels of tobramycin are generally considered to range from 4 to 6 mcg / mL. When tobramycin injection is administered by IV infusion over a 1-hour period, the serum concentrations are similar to those obtained by intramuscular administration. Tobramycin is poorly absorbed from the gastrointestinal tract after oral administration.105228354.450Attorney Docket No.121446-854267

[0282] For other routes of administration, in subjects with normal kidney function, multipleIV dosing of 1 g of vancomycin (15 mg / kg) infused over 60 minutes produces mean plasma concentrations of approximately 63 mcg / mL immediately after the completion of infusion, mean plasma concentrations of approximately 23 mcg / mL 2 hours after infusion, and mean plasma concentrations of approximately 8 mcg / mL 11 hours after the end of the infusion. Multiple dosing of 500 mg infused over 30 minutes produces mean plasma concentrations of about 49 mcg / mL at the completion of infusion, mean plasma concentrations of about 19 mcg / mL 2 hours after infusion, and mean plasma concentrations of about 10 mcg / mL 6 hours after infusion. The plasma concentrations during multiple dosing are similar to those after a single dose. About 60% of an intraperitoneal (IP) dose of vancomycin administered during peritoneal dialysis is absorbed systemically in 6 hours. Serum concentrations of about 10 mcg / mL are achieved by intraperitoneal injection of 30 mg / kg of vancomycin. However, the safety and efficacy of the intraperitoneal use of vancomycin hydrochloride has not been established in adequate and well-controlled trials. Distribution

[0283] Tobramycin can be detected in tissues and body fluids after parenteral administration.Tobramycin has appeared in low concentration in the cerebrospinal fluid following parenteral administration, and concentrations are dependent on dose, rate of penetration, and degree of meningeal inflammation. It has also been found in sputum, peritoneal fluid, synovial fluid, and abscess fluids, and it crosses the placental membranes. Concentrations in the renal cortex are several times higher than the usual serum levels.

[0284] The distribution coefficient of vancomycin is from 0.3 to 0.43 L / kg. Vancomycin isapproximately 55% serum protein bound as measured by ultrafiltration at vancomycin serum concentrations of 10 to 100 mcg / mL. After IV administration of vancomycin, inhibitory concentrations are present in pleural, pericardial, ascitic, and synovial fluids; in urine; in peritoneal dialysis fluid; and in atrial appendage tissue. Vancomycin does not readily diffuse across normal meninges into the spinal fluid; but, when the meninges are inflamed, penetration into the spinal fluid occurs. Elimination

[0285] Tobramycin and vancomycin are not metabolized and are excreted unchanged in theurine. Metabolism:

[0286] Following parenteral administration of tobramycin, little, if any, metabolictransformation occurs, and tobramycin is eliminated almost exclusively by glomerular filtration.105228354.451Attorney Docket No.121446-854267 Renal clearance is similar to that of endogenous creatinine. Ultrafiltration studies demonstrate that practically no serum protein binding occurs.

[0287] There is no apparent metabolism of vancomycin.Excretion:

[0288] In patients with normal renal function, up to 84% of the tobramycin dose is recoverablefrom the urine in 8 hours and up to 93% in 24 hours. Peak urine concentrations ranging from 75 to 100 mcg / mL have been observed following the intramuscular injection of a single dose of 1 mg / kg tobramycin. After several days of treatment, the amount of tobramycin excreted in the urine approaches the daily dose administered. After parenteral administration of tobramycin, concentrations in bile and stools ordinarily have been low, which suggests minimum biliary excretion.

[0289] Vancomycin is primarily eliminated by glomerular filtration in the kidneys asunchanged drug. The mean elimination t1 / 2of vancomycin from plasma is 4 to 6 hours in subjects with normal renal function. In the first 24 hours, about 75% of an administered dose of vancomycin is excreted in urine by glomerular filtration. Mean plasma clearance is about 0.058 L / kg / h, and mean renal clearance is about 0.048 L / kg / h. Specific Populations Geriatric Patients:

[0290] Total systemic and renal clearance of vancomycin may be reduced in the elderly.Patients with Renal Impairment:

[0291] In adult patients with normal renal function, tobramycin administered every 8 hoursdoes not accumulate in the serum. However, in those patients with reduced renal function, the serum concentration of the antibiotic is usually higher and can be measured for longer periods of time than in normal adults. Dosage for such patients must, therefore, be adjusted accordingly [see Dosage and Administration (2.1)]. The serum t1 / 2 of tobramycin in normal individuals is 2 hours. An inverse relationship exists between serum t1 / 2and creatinine clearance, and the dosage schedule should be adjusted according to the degree of renal impairment. In patients undergoing dialysis, 25% to 70% of the administered dose may be removed, depending on the duration and type of dialysis. When renal function is impaired, excretion of tobramycin is slowed, and accumulation of the drug may cause toxic blood levels [BOXED Warning, Warning and Precautions (5.2, 5.3) and Use in Specific Populations (8.6)].

[0292] Renal dysfunction slows excretion of vancomycin. In anephric patients, the averageelimination t1 / 2is 7.5 days.

[0293] Drug Interaction Studies105228354.452Attorney Docket No.121446-854267

[0294] Probenecid does not affect the renal tubular transport of tobramycin.12.4 Microbiology Mechanism of Action

[0295] Tobramycin is an aminoglycoside antibiotic with activity against Gram-positive andGram-negative bacteria. Tobramycin acts by inhibiting synthesis of protein in bacterial cells. In vitro tests demonstrate that tobramycin is bactericidal.

[0296] The bactericidal action of vancomycin results primarily from inhibition of cell-wallbiosynthesis. In addition, vancomycin alters bacterial-cell-membrane permeability and RNA synthesis. There is no cross-resistance between vancomycin and other antibiotics. Vancomycin is not active in vitro against gram-negative bacilli, mycobacteria, or fungi.

[0297] The combination of vancomycin and an aminoglycoside (i.e., tobramycin) actssynergistically in vitro against many strains of Staphylococcus aureus, Streptococcus bovis, enterococci, and the viridans group Streptococci. Resistance

[0298] Cross-resistance between aminoglycosides may occur. Although most strains ofenterococci demonstrate in vitro resistance, some strains in this group are susceptible. Interactions With Other Antimicrobials

[0299] In vitro studies have shown that an aminoglycoside combined with an antibiotic thatinterferes with cell-wall synthesis affects some enterococcal strains synergistically. The combination of penicillin G and tobramycin results in a synergistic bactericidal effect in vitro against certain strains of Enterococcus faecalis. However, this combination is not synergistic against other closely related organisms, e.g. Enterococcus faecium. Speciation of enterococci alone cannot be used to predict susceptibility. Susceptibility testing and tests for antibiotic synergism are emphasized. Antimicrobial Activity

[0300] Tobramycin

[0301] Tobramycin has been shown to be active against most strains of the followingorganisms both in vitro and in clinical infections (see Indications and Usage [2.1]):

[0302] Aerobic and facultative Gram-positive microorganisms

[0303] Staphylococcus aureus

[0304] Aerobic and facultative Gram-negative microorganisms

[0305] Citrobacter sp Pseudomonas aeruginosa

[0306] Enterobacter sp Proteus mirabilis

[0307] Escherichia coli Proteus vulgaris105228354.453Attorney Docket No.121446-854267

[0308] Klebsiella sp Providencia sp

[0309] Morganella morganii Serratia sp

[0310] Aminoglycosides have a low order of activity against most Gram-positive organisms,including Streptococcus pyogenes, Streptococcus pneumoniae, and enterococci.

[0311] Vancomycin

[0312] NVancomycin has been shown to be active against most strains of the followingmicroorganisms, both in vitro and in clinical infections (see Indications and Usage [2.1]).

[0313] Aerobic gram-positive microorganisms:

[0314] DiphtheroidsEnterococci (e.g., Enterococcus faecalis) Staphylococci, including Staphylococcus aureus and Staphylococcus epidermidis (including heterogeneous methicillin-resistant strains) Streptococcus bovis Viridans group streptococci

[0315] The following in vitro data are available, but their clinical significance is unknown.

[0316] Vancomycin exhibits in vitro maximum inhibitory concentration (MIC) of 1 mcg / mLor less against most (≥ 90%) strains of streptococci listed below and MIC of 4 mcg / mL or less against most (≥ 90%) strains of other listed microorganisms; however, the safety and effectiveness of vancomycin in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials.

[0317] Aerobic gram-positive microorganisms:

[0318] Listeria monocytogenesStreptococcus pyogenes Streptococcus pneumoniae (including penicillin-resistant strains) Streptococcus agalactiae

[0319] Anaerobic gram-positive microorganisms:

[0320] Actinomyces speciesLactobacillus species Susceptibility Testing

[0321] For specific information regarding susceptibility test interpretive criteria and associatedtest methods and quality control standards recognized by FDA for this drug, please see: https: / / www.fda.gov / STIC. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility105228354.454Attorney Docket No.121446-854267

[0322] No adequate and well-controlled long-term studies have been performed to evaluatethe effect of the antibiotic irrigation solution kit on carcinogenesis, mutagenesis, or impairment of fertility. Vancomycin Carcinogenicity

[0323] Long-term studies in animals have not been performed to evaluate carcinogenicpotential. Mutagenesis

[0324] At concentrations up to 1000 mcg / mL, vancomycin had no mutagenic effect in vitro inthe mouse lymphoma forward mutation assay or the primary rat hepatocyte unscheduled DNAsynthesis assay. The concentrations tested in vitro were above the peak plasma vancomycinconcentrations of 20 to 40 mcg / mL usually achieved in humans after slow infusion of themaximum recommended dose of 1 g. Vancomycin had no mutagenic effect in vivo in the Chinesehamster sister chromatid exchange assay (400 mg / kg IP) or the mouse micronucleus assay (800mg / kg IP). Tobramycin Carcinogenicity

[0325] Long-term studies in animals have not been performed to evaluate carcinogenicpotential. Mutagenesis

[0326] Additionally, tobramycin has been evaluated for genotoxicity in a battery of in vitroand in vivo tests. The Ames bacterial reversion test, conducted with 5 tester strains, failed to show a significant increase in revertants with or without metabolic activation in all strains. Tobramycin was negative in the mouse lymphoma forward mutation assay, did not induce chromosomal aberrations in Chinese hamster ovary cells, and was negative in the mouse micronucleus test. Impairment of Fertility

[0327] Subcutaneous administration of up to 100 mg / kg of tobramycin did not affect matingbehavior or cause impairment of fertility in male or female rats. 13.2 Animal Toxicology and / or Pharmacology

[0328] In animal studies, hypotension and bradycardia occurred in dogs receiving an IVinfusion of vancomycin hydrochloride 25 mg / kg, at a concentration of 25 mg / mL and an infusion rate of 13.3 mL / min. 14 CLINICAL STUDIES 14.1 Treatment of Periprosthetic Joint Infection105228354.455Attorney Docket No.121446-854267

[0329] Two randomized, well-controlled, open-label clinical studies, the “AbbreviatedProtocol for Two-Stage Exchange” (APEX) study (NCT03721328) and the APEX-2 study (NCT05607030) were conducted comparing the antibiotic irrigation solution kit to standard two- stage exchange arthroplasty (standard of care [SOC]). For the antibiotic irrigation solution kit (tobramycin sulfate and vancomycin hydrochloride for irrigation / irrigation system), each day of a 7- to 10-day treatment cycle, 80 mg of tobramycin sulfate in 50 mL of normal saline was administered by the irrigation route with the antibiotic irrigation solution kit irrigation system. Following a 2-hour soak, the liquid in the wound space is removed using vacuum over 30 minutes. Each subsequent hour, 125 mg of vancomycin in 50 mL of normal saline is administered by the irrigation route with the antibiotic irrigation solution kit irrigation system. Following a 30-minute soak, the liquid in the wound space is removed using vacuum over 30 minutes. There were approximately 21-22 consecutive rounds of vancomycin irrigation cycles per day. Over a 7-day treatment, there are 7, 2-hour applications of tobramycin and approximately 147, 30-minute applications of vancomycin. The SOC treatment arm consisted of following 4-step process; (1) resection arthroplasty; (2) debridement and insertion of an antibiotic impregnated temporary spacer in a Stage 1 surgical procedure; (3) 6 (or more) weeks of systemic antibiotics (i.e., also called the interstage period); (4) a stage-2 surgery to remove the temporary spacer, debride and implant a permanent prosthesis after a median of 16 weeks. Patients were followed for one year after treatment in both APEX and APEX-2 trials.

[0330] APEX trial included 39 patients in the SOC arm (control) and 37 patients in theantibiotic irrigation solution kit arm with 35 completing the study with 4 patients discontinuing from the study due to death. The mean age was 66 years of age with range of 44-80 years in the antibiotic irrigation solution kit treatment arm with mean age of 63 years of age with range of 41- 79 years in the SOC group. For the NEXCHANGE treatment arm there were 21 (57%) males with 25 (64%) males in the SOC group and mean body mass index (BMI) of 31.5 kg / m2(range: 18-44) for VT-X7 KIT versus 34.5 kg / m2(range: 20-50) for SOC. For periprosthetic joint infection location, the antibiotic irrigation solution kit group consisted of 27 (69.2%) knee and 12 (30.8%) hip joints versus 23 (62.2%) knee and 14 (37.8%) hip joints in SOC group. The database was not large enough to assess where there were differences in effects in age, gender, or race subgroups.

[0331] The APEX trial evaluated the efficacy of the antibiotic irrigation solution kit ascompared to SOC with the primary efficacy composite endpoint of Overall Success at 90 days composed of the following 4 elements: (1) Stage 2 revision prosthesis implanted; (2) absence of PJI post-stage-2 surgery; (3) absence of reoperation of the affected joint pre- or post-stage 2; and (4) absence of mortality. The secondary composite endpoints of Overall Success at 180 and 365105228354.456Attorney Docket No.121446-854267 days was composed of the following 5 elements: (1) Stage 2 revision prosthesis implanted; (2) absence of PJI post-stage-2 surgery; (3) absence of reoperation of the affected joint pre- or post- stage 2; (4) absence of mortality; and (5) absence of continued antibiotic therapy for treatment or prophylaxis of PJI [no antibiotic use >12 weeks post-stage 2 surgery and not on antibiotics on day 180 or day 365].

[0332] Overall Success for the SOC vs the antibiotic irrigation solution kit arms at 90, 180 and365 days in the Intent-to-Treat (ITT) population is presented Table . The primary endpoint for APEX study, proportion of subjects classified as an Overall Success at 90 days, was significantly larger in the antibiotic irrigation solution kit arm compared to the SOC arm (89.2% vs 28.2%, p<0.001) with a difference in treatment effect of 61%. The first key secondary endpoint, proportion of subjects classified as an Overall Success at 180 days, was also significantly larger in the Narm compared to the SOC arm (56.8% vs 33.3%, p=0.04) with a difference in treatment effect of 23.4%. At 365-days, a strong, clinically relevant and persistent difference in treatment effect of 18.2% was found when comparing the antibiotic irrigation solution kit and SOC arms (54.1% vs 35.9%, p=0.11). Overall Success at 90 days, 180 days, and 365 days with VT-X& KIT compared to SOC was observed regardless if the periprosthetic joint infection was in the knee or hip (see Table 6). Table 6. APEX Study: Overall Success at 90, 180 and 365 Days (ITT) t c

[0333] The antibiotic irrigation solution kit treated patients (100%, 36 of 36) were reimplantedwith their permanent prothesis compared to 87% (34 of 39) of the SOC patients at 365 days post Stage-1 surgery. The average time to implantation for the antibiotic irrigation solution kit patients105228354.457Attorney Docket No.121446-854267 was 7.1 days (36 / 36 patients) compared to 119.9 days in the SOC patients (considering only control patients who had a Stage-2 surgery, 34 / 39 SOC patients). The assessment of Quality of Life with the Knee Disability and Osteoarthritis Outcome Score (KOOS) and the Hip Disability and Osteoarthritis Outcome Score (HOOS) at 90, 180, and 365 days the VT_X& KIT treatment arm observing improvement in pain, other symptoms, daily living function, sport and recreation function, and overall quality of life (QOL) scores between baseline and all timepoints compared to the SOC. Patients in the antibiotic irrigation solution group demonstrated a larger mean change in the EQ-5D-3L index value from baseline to 90 day demonstrating a greater improvement in QOL over the SOC (0.16 versus 0.04, respectively, with higher number indicating an improvement in overall health). 16 HOW SUPPLIED / STORAGE AND HANDLING 16.1 How Supplied

[0334] The antibiotic irrigation solution kit (NDC 83138-118-07 [knee] and NDC 83138-218-07 [hip]) includes the Antibiotic Irrigation SolutionDrug Pack and Irrigation System. The Antibiotic Irrigation Solution Drug Pack is co-package containing 21 vials of vancomycin hydrochloride for irrigation and 7 vials of tobramycin sulfate for irrigation intended for reconstitution / dilution with normal saline:^ Each vial of vancomycin hydrochloride for irrigation contains 1 g of vancomycinhydrochloride supplied as a sterile, lyophilized powder which is supplied as part of a day pack carton which contains 3 single-dose, glass vials of vancomycin hydrochloride for irrigation and 1 single-dose, glass vials of tobramycin sulfate for irrigation.^ Each vial of tobramycin sulfate for irrigation contains 80 mg / 2 mL (40 mg / mL) of tobramycinsulfate which is supplied as part of a day pack carton which contains 3 single-dose, glass vials of vancomycin hydrochloride for irrigation and 1 single-dose, glass vials of tobramycin sulfate for irrigation.

[0335] Vancomycin hydrochloride for irrigation and vancomycin hydrochloride for irrigationmust only be administered with the antibiotic irrigation solution kit Irrigation System device supplied with the antibiotic irrigation solution kit and components specified by OstealTherapeutics, Inc, in the Instructions of Use [see Dosage and Administration (2.1)].16.2 Storage and Handling

[0336] The Antibiotic Irrigation Solution Drug Pack containing vials of vancomycinhydrochloride for irrigation and vancomycin hydrochloride for irrigation must be stored at controlled room temperature 20 to 25 °C (68 to 77 °F). Temperature excursions are permitted between 15 to 30 °C (59 to 86 °F) [see USP Controlled Room Temperature].105228354.458Attorney Docket No.121446-854267

[0337] Following reconstitution with normal saline, tobramycin sulfate for irrigation is stablefor 24 hours at controlled room temperature 20 to 25 °C (68 to 77 °F) or 48 hours at refrigerated temperature 2 to 8 °C (36 to 46 °F) [see Dosage and Administration (2.3)].

[0338] Following reconstitution with normal saline, vancomycin hydrochloride for irrigationis stable for 24 hours at controlled room temperature 20 to 25 °C (68 to 77 °F) or 7 days at refrigerated temperature 2 to 8 °C (36 to 46 °F) [see Dosage and Administration (2.3)].

[0339] The Irrigation System may be stored at room temperature 20 to 25 °C (68 to 77 °F).

[0340] Vancomycin hydrochloride for Irrigation (NDC 83138-010-01) is made in either US orChina and tobramycin sulfate for Irrigation (NDC 83138-080-01) is made in US and are Manufactured for: Osteal Therapeutics, Inc. Dallas, TX 75244. The antibiotic irrigation solution kit (tobramycin sulfate and vancomycin hydrochloride for irrigation / irrigation system) (NDC 83138-118-07 [knee] and NDC 83138-218-07 [hip]) are Packaged for and Distributed by: Osteal Therapeutics, Inc. Dallas, TX 75244. 17 PATIENT COUNSELING INFORMATION 17.1 Severe Dermatologic Reactions

[0341] Advise patients about the signs and symptoms of serious skin manifestations. Instructpatients to stop taking the antibiotic irrigation solution kit immediately and promptly seek medical attention at the first signs or symptoms of skin rash, mucosal lesions, or blisters [see Warnings and Precautions (5.1)]. 17.2 Kidney Damage

[0342] Advise patients to inform their physician if they have any history of kidney problemsbecause tobramycin is in a class of drugs that have caused kidney damage [see Warnings and Precautions (5.2, 5.8)]. 17.3 Hearing Loss

[0343] Advise patients to inform their physician if they experience ringing in the ears,dizziness, or any changes in hearing because tobramycin has been associated with hearing loss[see Warnings and Precautions (5.3, 5.8)].17.4 Severe Diarrhea

[0344] Diarrhea is a common problem caused by antibiotics, which usually ends when theantibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible [see Warnings and Precautions (5.4)]. 17.5 Pregnancy and Lactation105228354.459Attorney Docket No.121446-854267

[0345] Advise pregnant women that aminoglycosides can cause irreversible congenitaldeafness when administered to a pregnant woman [see Warnings and Precautions (5.5) and Usein Specific Populations (8.1)]. Advise them to inform their doctor if they are pregnant, become pregnant, or plan to become pregnant.

[0346] Advise a woman to monitor their breastfed infants for diarrhea and / or bloody stools[see Use in Specific Populations (8.2)]. 17.6 Antibacterial Resistance

[0347] Patients should be counseled that antibacterial drugs including tobramycin sulfate forirrigation and vancomycin hydrochloride for irrigation should only be used to treat bacterial infections. tobramycin sulfate for irrigation and vancomycin HCl for irrigation do not treat viral or fungal infections. When the antibiotic irrigation solution kit is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by tobramycin sulfate for irrigation and vancomycin hydrochloride for irrigation or other antibacterial drugs in the future. Example 2: Irrigation System System Description

[0348] The antibiotic irrigation solution kit is composed of the Antibiotic Irrigation SolutionKit Drug Pack and Irrigation System, each of which is labeled for exclusive use with the other. See Figure 1.

[0349] The Antibiotic Irrigation Solution Drug Pack contains a 10-day supply of vancomycinhydrochloride for irrigation and tobramycin sulfate for irrigation.

[0350] The Irrigation System contains the Fluid Management System and Spacer System. TheFluid Management System contains the Control Unit, Irrigation Pole, Instillation Line, Patient Suction Line, wound dressing kit and canisters. The Spacer System contains Spacer Device components and surgical instruments.

[0351] The Irrigation System delivers the intended therapy in three steps: (1) irrigate the siteof infection with the Antibiotic Irrigation Solution Drug Pack antibiotics through the Spacer Device, (2) allow the antibiotics to soak the site of infection for a predetermined time, and (3) remove fluid from the site of infection. These three steps are repeated continuously until therapy is paused or completed.105228354.460Attorney Docket No.121446-854267 NEXCHANGE KIT Treatment Overview

[0352] FIG. 4 shows an overview of example treatment process including Stage 1, 7-dayinterstage treatment, and Stage 2, which are more fully described below.

[0353] Stage 1

[0354] Treatment begins during Stage 1 of a two-stage exchange arthroplasty. The infectedprothesis is removed and debridement & irrigation is performed per standard of care. To apply Irrigation System, a Spacer Device is placed, wound dressing is applied and Instillation and Patient Suction Lines are connected per the antibiotic irrigation solution kit Surgical Technique Guide and Fluid Management System User Manual.

[0355] Interstage

[0356] Each day of therapy with Antibiotic Irrigation Solution Kitstarts with delivery of theantibiotics and their administration per the Fluid Management System User Manual. Upon hanging of the antibiotics and replacement of the canister, daily administration of the antibiotics is automated by the Control Unit per the Treatment Overview of the Interstage Period in Figure 2. There is one tobramycin cycle followed by approximately 21 consecutive vancomycin irrigation cycles per day. Over a 7-day treatment, there are 7, 2-hour applications of tobramycin and approximately 147, 30-minute applications of vancomycin.

[0357] Stage 2

[0358] Upon completion of the interstage period, Stage 2 of a two-stage exchange arthroplastyis completed. The wound dressing and Spacer System are first removed, followed by debridement, irrigation, and placement of a revision prosthesis per standard of care. Use

[0359] Osteal Therapeutics Inc.’s Antibiotic Irrigation Solution Kit(tobramycin sulfate andvancomycin hydrochloride for irrigation / irrigation System) is comprised of the following components and should not be used with any other device or treatment: the Antibiotic Irrigation Solution Drug Pack and Irrigation System, which includes: Fluid Management System and Spacer System. The Antibiotic Irrigation Solution treatment is intended for use for no more than 10 days, after which treatment must be terminated prior to the revision arthroplasty procedure. Indications

[0360] The Antibiotic Irrigation Solution Kit(tobramycin sulfate and vancomycinhydrochloride for irrigation / irrigation system) is indicated for the treatment of periprosthetic joint infection in skeletally mature patients undergoing an exchange arthroplasty procedure, where vancomycin hydrochloride and tobramycin sulfate are appropriate antibiotics for treatment of the infection.105228354.461Attorney Docket No.121446-854267 Contraindications

[0361] Patients who require long-term anticoagulation or antiplatelet therapy, and for whombridging or withholding therapy is not recommended based on the individual’s clinical condition;

[0362] Patients who are pregnant;

[0363] Patients who have a skeletal defect of greater than 150 mm in length in the tibia orfemur of the infected joint;

[0364] Patients who have bone loss or musculature, osteoporosis, neuromuscular compromiseor vascular deficiency in the affected limb and in sufficient degree to render the procedure unjustifiable;

[0365] Patients who have a history of allergies or known hypersensitivity to vancomycin ortobramycin or a component or material utilized within the antibiotic irrigation solution kit including: titanium, titanium alloys, or polyurethane. Warnings and Precautions

[0366] Read and understand all warnings, precautions, and directions completely and carefullybefore use. Failure to do so may result in serious injury.

[0367] Do not use if any part of the antibiotic irrigation solution kit is damaged. Carefullyinspect devices for damage or defects prior to use.

[0368] Do not reuse or reprocess this device. This device is single use only. Reuse orreprocessing may damage the device and may result in injury, infection, or death.

[0369] Disposal of used product should follow facility policies or local ordinances relating tothe handling of potentially infected or bio-hazardous materials.

[0370] Bleeding: Monitor patients with an increased risk of bleeding, which, if not controlled,could be potentially fatal. Examples include:

[0371] Patients with weakened, irradiated or sutured blood vessels or organs, in or around thewound.

[0372] Patients with difficult wound hemostasis.

[0373] Patients on anticoagulants or platelet aggregation inhibitors.

[0374] Patients that do not have overlying fascia, tissue or other protective barriers overvascular structures.

[0375] If active bleeding or bright red blood is seen in the tubing or canister, immediately stopantibiotic irrigation solution kittreatment, take measures to stop the bleeding and seek medical assistance. The Fluid Management System should not be used to prevent, minimize, or stop vascular bleeding.105228354.462Attorney Docket No.121446-854267

[0376] Bone Fragments: Bone fragments may puncture dressing protective barriers, ordamage tissue causing injury. Any injury could cause bleeding, which, if uncontrolled, could be potentially fatal. Care should be taken to cover or eliminate bone fragments from the infection area when placing dressing components, as well as when removing dressing components from the site of infection so that the infection site tissue is not damaged by unprotected sharp edges.

[0377] Circumferential Dressing Application: Avoid use of circumferential dressingapplication except in the presence of anasarca or excessively weeping extremities, where a circumferential dressing technique may be necessary to establish and maintain a seal. Use of circumferential dressing applications may pose a risk of decreased distal circulation. Consider using multiple small wound dressing kit ‘drapes’ or when using circumferential drape applications, it is crucial to systematically and recurrently assess distal circulatory status. If circulatory compromise is suspected, discontinue antibiotic irrigation solution kittreatment, remove dressing, and contact a physician.

[0378] Compatible Accessories Only: The Control Unit hangers are designed to be used withcompatible commercially available accessories. Do not hang or mount accessories that do not meet the specifications provided in the Fluid Management System User Manual and Instructions for Use (OTX-8000010). Failure to comply may compromise patient or user safety or the effectiveness of treatment.

[0379] Damaged Power Cord: Do not operate the Fluid Management System if the powercord, supply, or plug is damaged, as the damaged components are risks for electrical shock. Contact Osteal Therapeutics for a replacement if components are worn or damaged.

[0380] Defibrillation: Discontinue use of the Fluid Management System and remove alldressing kit items if defibrillation is required. Failure to do so may inhibit electrical current transmission and / or proper patient resuscitation.

[0381] Electrical Installation: Ensure the electrical installation of the room complies with theappropriate national electrical wiring standards. To avoid the risk of electrical shock, this product must be connected to a grounded power receptacle.

[0382] Electrical Interference: This product conforms to the intent of IEC 60601-1-2 as itrelates to Electromagnetic Compatibility. However, electrical equipment may produce interference and inhibit effective delivery of treatment. Contact Osteal Therapeutics if interference is suspected.

[0383] Heated Surfaces: Refrain from positioning the Fluid Management System near anyheated surfaces. Operating near heated surfaces is considered a fire hazard and may cause burns.105228354.463Attorney Docket No.121446-854267

[0384] Hyperbaric Oxygen Therapy (HBO): Do not take the Fluid Management System – ONor OFF – into a hyperbaric chamber. The System is not designed for use in an oxygen enriched environment and should be considered a fire hazard. Disconnect the system prior to HBO therapy.

[0385] Irrigation Cycle Selection: The Day 0 Irrigation Cycle shall be used following surgery.Selecting Day 1-6 Irrigation Cycle immediately after surgery may result in excessive bleeding.

[0386] Keep System Turned ON: The Fluid Management System shall remain powered andin use for the duration of treatment. Never leave the System connected without active treatment for more than 2 hours. If treatment is OFF for more than 2 hours, continue treatment only at the direction of the physician.

[0387] Magnetic Resonance Imaging (MRI): The Fluid Management System is not MagneticResonance Imaging (MRI)-compatible and cannot be used in the presence of strong magnetic fields. The System contains metal components that could cause unintended movement or pose a projectile risk resulting in harm due to falling objects or collisions.

[0388] Modification: The Fluid Management System has no serviceable components.Modification of the System may lead to safety risks and is not allowed. Do not connect this device or its components to devices or accessories not recommended by Osteal Therapeutics.

[0389] Patient Size & Weight: Patients with high exudating wounds or large wounds inrelation to the patient size and weight should be closely monitored, as they have a risk of excessive fluid loss and dehydration. When monitoring fluid output, consider the volume of fluid in both the tubing and canister.

[0390] 7-Day Treatment: Interstage treatment is administered over a 7-day period, up to 10-days. Treatment is not intended to be used for more than 10 days.

[0391] Spilled Fluids: Avoid spilling fluids on any part of the Fluid Management System.Fluid remaining on the Control Unit or Irrigation Pole may cause corrosion and electronic component failure. If spill occurs, unplug the system immediately, clean with an absorbent cloth, and ensure there is no moisture in or near the power connection and power supply components before reconnecting to power.

[0392] Wireless Communication Devices: Wireless communications equipment such asmobile phones, hand-held tablets, cordless telephones and their base stations, and walkie-talkies should be kept at least 3.3m away to prevent electrical interference and interruption to treatment.

[0393] Wound Filler Placement: Observe Cork Medical’s wound dressing kit Instructions forUse. Always use dressings from sterile packages that have not been opened or damaged. Do not place wound filler (foam) into blind / unexplored tunnels. To account for the total number of wound filler pieces used in the site of infection, always count and document on the patient chart.105228354.464Attorney Docket No.121446-854267

[0394] Wound Filler Removal: Observe Cork Medical’s wound dressing kit Instructions forUse. Always count the pieces of wound filler (foam) removed from the wound and ensure the same number of pieces are removed as were initially placed. The wound filler is not bioabsorbable, so wound filler left in the site of infection for greater than the recommended time period may lead to infection or other adverse events. Regardless of treatment, disruption of the new granulation tissue during any dressing change may result in bleeding at the wound site.

[0395] The NEXCHANGE Spacer System is only compatible with Irrigation System.

[0396] Use only Knee or Hip Surgical Instruments specifically designed for use with the Kneeor Hip Spacer respectively to help ensure accurate surgical implantation and soft tissue tensioning. Do not alter or modify the Spacers in any way. Spacer devices have not been designed to undergo or withstand any form of alteration, cleaning or re-sterilization. Reuse can potentially compromise device performance and patient safety.

[0397] Improper Spacer selection or alignment, inadequate fixation, use where contraindicatedor in patients whose medical, physical, or mental conditions will likely result in extreme stresses to the implant, may result in premature failure due to loosening or fracture.

[0398] A Spacer should never be reused. Any Spacer, once used, should be discarded. Eventhough it appears undamaged, it may have small defects and / or internal stress patterns that may lead to failure. Likewise, a new Spacer should be handled carefully to avoid damage that could compromise the integrity of the device and cause early failure or loosening.

[0399] CAUTION: The following conditions, singularly or concurrently, tend to imposesevere loading on the affected extremity thereby placing the patient at higher risk of failure of the NEXCHANGE Spacer:

[0400] 1. Obesity or excessive patient weight

[0401] 2. Likelihood of falls

[0402] 3. Alcohol or drug addiction

[0403] 4. Other disabilities, as appropriate

[0404] The following physical conditions, singularly or concurrently, tend to adversely affectthe fixation of the Spacer:

[0405] 1. Marked osteoporosis or poor bone stock

[0406] 2. Severe deformities leading to impaired fixation or improper positioning of theimplant

[0407] 3. Tumors of the supporting bone structures

[0408] 4. Allergic reactions to implant materials (e.g., titanium, aluminum, vanadium,polyurethane).105228354.465Attorney Docket No.121446-854267

[0409] The surgical and postoperative management of the patient must be carried out with dueconsideration for all existing conditions. Mental attitudes or disorders resulting in a patient’s failure to adhere to the surgeon’s orders may delay postoperative recovery and / or increase the risk of adverse effects including device or fixation failure.

[0410] Excessive physical activity or trauma to the joint may contribute to premature failureof the Spacer by causing a change in position and / or fracture of the implants.

[0411] In addition to those risks commonly associated with surgery, the following adversereactions are associated with using the antibiotic irrigation solution kit. Additional information related to these adverse reactions are described in further detail in the antibiotic irrigation solution kit Package Insert (OTX-8000301)

[0412] Anemia

[0413] Post-Operative Pain

[0414] Additional adverse events related to two-stage exchange arthroplasty surgery are asfollows:

[0415] Bending, cracking, fracture, deformation, wear, loosening, or subluxation / dislocationof the spacer, often related to factors listed under warnings and precautions

[0416] Cardiovascular disorders and thromboembolic disease, including venous thrombosis,pulmonary embolus, and heart attack

[0417] Deformity of the leg

[0418] Delayed wound healing or wound dehiscence

[0419] Hematoma

[0420] Pain, flexion contracture, decreased range of motion, or lengthening or shortening ofthe leg caused by improper positioning of the spacer

[0421] Persistent or recurring periprosthetic joint infection

[0422] Possible loss of limb or death if complications occur

[0423] Surgical site infection

[0424] The incidence and severity of complications in two-stage exchange arthroplasty areusually greater than in primary or aseptic operations. Increased operative time and increased incidence of infection, pulmonary embolism and wound hematoma can be expected. Example 3: Spacer System DEVICE DESCRIPTION

[0425] The Spacer System consists of a titanium Knee Spacer or Hip Spacer with attachedpolyurethane instillation line and associated surgical instruments. The Spacer is a short-term105228354.466Attorney Docket No.121446-854267 implantable device for local irrigation of the antibiotics during a two-stage exchange arthroplasty for periprosthetic joint infection of the knee or hip. The Spacer System is provided for exclusive use with, and provides the means for local delivery of, Vancomycin, Irrigation and Tobramycin, Irrigation in the intramedullary canal and joint space, while providing stability to the joint when exclusively used in conjunction with the Irrigation System. The Knee Spacer consists of knee stems and connectors of various sizes. The Hip Spacer consists of femoral stems and femoral heads of various sizes. INDICATIONS

[0426] The Spacer System is indicated for the treatment of periprosthetic joint infection (PJI)in skeletally mature patients undergoing an exchange arthroplasty procedure, where vancomycin hydrochloride and tobramycin sulfate are appropriate antibiotics for treatment of the infection. CONTRAINDICATIONS

[0427] Loss of bone or musculature, osteoporosis, neuromuscular compromise or vasculardeficiency in the affected limb and in sufficient degree to render the procedure unjustifiable.

[0428] Known allergy to implant materials, including titanium, aluminum, vanadium andpolyurethane. WARNINGS AND PRECAUTIONS

[0429] The Spacer System is only compatible with the Irrigation System.

[0430] Use only Knee or Hip Surgical Instruments specifically designed for use with the Kneeor Hip Spacer respectively to help ensure accurate surgical implantation and soft tissue tensioning. Do not alter or modify Spacers in any way. Spacer devices have not been designed to undergo or withstand any form of alteration, cleaning or re-sterilization. Reuse can potentially compromise device performance and patient safety.

[0431] Improper Spacer selection or alignment, inadequate fixation, use where contraindicatedor in patients whose medical, physical, or mental conditions will likely result in extreme stresses to the implant, may result in premature failure due to loosening or fracture.

[0432] A Spacer should never be reused. Any Spacer, once used, should be discarded. Eventhough it appears undamaged, it may have small defects and / or internal stress patterns that may lead to failure. Likewise, a new Spacer should be handled carefully to avoid damage that could compromise the integrity of the device and cause early failure or loosening.

[0433] CAUTION: The following conditions, singularly or concurrently, tend to imposesevere loading on the affected extremity thereby placing the patient at higher risk of failure of the Spacer:105228354.467Attorney Docket No.121446-854267 Example 4: Tobramycin sulfate and vancomycin hydrochloride for irrigation / irrigation system update INDICATIONS AND USAGE

[0434] The antibiotic irrigation solution kit is indicated for the treatment of periprosthetic jointinfection (PJI) in skeletally mature adult patients undergoing an exchange arthroplasty procedure, where vancomycin hydrochloride and tobramycin sulfate for irrigation are appropriate antibiotics for treatment of infection.

[0435] To reduce the development of drug‑resistant bacteria and maintain the effectiveness ofthe Antibiotic Irrigation Solution Drug Pack (tobramycin sulfate for irrigation; vancomycin hydrochloride for irrigation) and other antibacterial drugs, the Antibiotic Irrigation Solution Drug Pack should be used only to treat infections that are proven or strongly suspected to be caused by bacteria. DOSAGE AND ADMINISTRATION

[0436] The Antibiotic Irrigation Solution Drug Pack (tobramycin sulfate for irrigation;vancomycin hydrochloride for irrigation) is a component of the antibiotic irrigation solution kit and is administered by irrigation using the Irrigation System. The recommended dosages are 80 mg / day of tobramycin sulfate and approximately 2.6 g / day of vancomycin hydrochloride administered by irrigation daily for 7 days. Treatment may continue up to 10 days.

[0437] Dose modification may be required to manage risk for nephrotoxicity or ototoxicity.DOSAGE FORMS AND STRENGTHS

[0438] For irrigation: The Antibiotic Irrigation Solution Drug Pack intended forreconstitution / dilution with normal saline includes:

[0439] 21 vials, each with 1 g of vancomycin hydrochloride for irrigation.

[0440] 7 vials, each with 80 mg of tobramycin sulfate for irrigation.CONTRAINDICATIONS

[0441] Patients with a history of allergies or known hypersensitivity to vancomycin ortobramycin or a component or material utilized within the antibiotic irrigation solution kit including titanium alloys or polyurethane.

[0442] Patients who require long-term anticoagulation or antiplatelet therapy.

[0443] Patients who are pregnant.

[0444] • Patients with a skeletal defect greater than 150 mm in length adjacent to the infectedjoint. WARNINGS AND PRECAUTIONS105228354.468Attorney Docket No.121446-854267

[0445] Allergic reactions: Discontinue use of the antibiotic irrigation solution kit at firstappearance of allergic response such as skin rashes, mucosal lesions, or blisters.

[0446] Clostridium Difficile associated diarrhea has been reported with the use of nearly allantibacterial agents, including vancomycin hydrochloride and tobramycin sulfate.

[0447] Tobramycin may aggravate muscle weakness because of a potential curare-like effecton neuromuscular function.

[0448] Specific laboratory tests are recommended to monitor for ototoxicity andnephrotoxicity.

[0449] Monitor patients with an increased risk of bleeding, which, if not controlled, could bepotentially fatal.

[0450] Patients should be tested during the reimplant surgery for the presence of Candidaisolates. ADVERSE REACTIONS

[0451] The most common adverse reactions include post-procedural pain and postoperativeanemia. DRUG INTERACTIONS

[0452] Use of the antibiotic irrigation solution kit with other drugs with neurotoxic,nephrotoxic, or ototoxic potential should be avoided.

[0453] Anesthetic Agents: Concomitant administration of vancomycin and anesthetic agentshave been associated with erythema and histamine-like flushing.

[0454] Piperacillin / Tazobactam: Increased incidence of acute kidney injury in patientsreceiving concomitant piperacillin / tazobactam and vancomycin. Kidney function monitoring is recommended. USE IN SPECIFIC POPULATIONS

[0455] Because elderly patients are more likely to have decreased renal function, it may beuseful to monitor renal function.

[0456] The risk of adverse reactions to tobramycin and vancomycin may be greater in patientswith renal impairment. DOSAGE AND ADMINISTRATION Recommended Dosage

[0457] The antibiotic irrigation solution kit consists of tobramycin sulfate for irrigation andvancomycin hydrochloride for irrigation as individual antibiotics administered sequentially and separately with the Irrigation System. The Irrigation System allows the antibiotics to soak for a105228354.469Attorney Docket No.121446-854267 predetermined times and then removes fluid from the joint space using vacuum. See below the specific treatment cycle for each antibiotic. Tobramycin Sulfate Dosage and Administration

[0458] The recommended dose is irrigation of the joint space with 80 mg / day of tobramycinsulfate daily for 7 days using the Irrigation System. Treatment using the antibiotic irrigation solution kit can be extended for up to 10 days for scheduling purposes. Each day of treatment with the antibiotic irrigation solution kit begins with the administration of an 80 mg solution of tobramycin sulfate for irrigation in 50 mL of normal saline (1.6 mg / mL) delivered with the Irrigation System. Following a 2-hour soak of tobramycin antibiotic in the infected joint, fluid is removed from the joint space using vacuum over 30 minutes with the Irrigation System. Vancomycin Hydrochloride Dosage and Administration

[0459] Following the daily tobramycin sulfate irrigation, the joint space is irrigated withapproximately 2.6 g / day of vancomycin hydrochloride for the 7-day treatment. Treatment using the antibiotic irrigation solution kit can be extended for up to 10 days for scheduling purposes. The vancomycin dose is divided into approximately 21 hourly doses consisting of hourly administration of 125 mg of vancomycin hydrochloride in a 50 mL saline solution followed by a 30-minute soak in the joint space. Following the 30-minute vancomycin soak, liquid is removed from the joint space using vacuum over 30 minutes with the Irrigation System.

[0460] The dual tobramycin / vancomycin irrigation process is repeated each day for 7 to 10days. Dosing Modifications for Adverse Reactions Tobramycin Sulfate for Irrigation

[0461] Maintain tobramycin serum trough levels at <2 mcg / mL. If serum trough levels are >2mcg / mL or toxicity is a concern, decrease total dose based on observed serum concentration. Decrease total drug administered but not total volume (e.g., 40 mg of tobramycin sulfate in 50 mL 0.9% sodium chloride, 0.8 mg / mL). Vancomycin Hydrochloride for Irrigation

[0462] Maintain vancomycin serum levels at <20 mcg / mL. If serum levels are >20 mcg / mLor if toxicity is a concern, decrease total dose based on observed serum concentration. Decrease total drug administered but not total volume (e.g., 1.5 g vancomycin hydrochloride in 1,200 mL 0.9% sodium chloride, 1.25 mg / mL). DOSAGE FORMS AND STRENGTHS^ The Antibiotic Irrigation Solution Drug Pack includes: 7 vials each containing 80 mg / 2 mL(40 mg / mL) tobramycin sulfate solution for irrigation intended for reconstitution / dilution with105228354.470Attorney Docket No.121446-854267 normal saline, and 21 vials each containing 1 g vancomycin hydrochloride lyophilized powder for irrigation intended for reconstitution / dilution with normal saline. ADVERSE REACTIONS

[0463] This section describes adverse reactions observed during clinical trials with theantibiotic irrigation solution kit. Additional adverse reactions related to the procedure and / or medical device are described in further detail in the Irrigation System Instructions for Use. Additionally, the following clinically significant adverse reactions associated with the use of antibiotics are described elsewhere in the labeling: Allergic and Dermatologic Reactions, Nephrotoxicity, Ototoxicity, Clostridium Difficile Associated Diarrhea, Embryo-Fetal Toxicity, Concomitant Use with Systemic Aminoglycosides and Other Antibiotics, and Neuromuscular Disorders. Clinical Trial Experience

[0464] Clinical trials for drug-device combination products occur in diverse settings.Therefore, the rates of adverse reactions observed in these trials cannot be directly compared to those of individual drugs or devices. Furthermore, these trial rates may not accurately reflect the real-world occurrence of adverse reactions. The data presented originates from the APEX Clinical Trial Program, specifically the APEX (Study JPS-0301) and APEX-2 (Study OTX-0302) clinical trials [see Clinical Studies (14.1)]. Each day of antibiotic irrigation solution kit treatment started with 80 mg of tobramycin sulfate in 50 mL of normal saline (1.6 mg / mL) delivered to the infected joint (total daily exposure of 1.6 mg / day). Following a 2-hour soak with the tobramycin solution, liquid was removed from the joint space using vacuum over 30 minutes. Next, 125 mg of vancomycin hydrochloride in 50 mL of normal saline (2.5 mg / mL) was administered to the joint space every hour with a 30-minute soak for approximately 21 daily treatments (total daily exposure of approximately 2.625 g / day). Following each 30-minute soak with the vancomycin solution, liquid was removed from the joint space using vacuum over 30 minutes [see Dosages and Administrations (2.1)]. Patients were followed for 1 year after treatment with the antibiotic irrigation solution kit.

[0465] The APEX and APEX-2 trials were both randomized, active-controlled (vs. standardof care) clinical studies where 75 patients received the antibiotic irrigation solution kit in the safety population. The overall pooled safety data was 31 (41.3%) female, 44 (58.7%) male, 67 (89.3%) White, 6 (8.0%) Black, 1 (1.3%) patient classified as Other, and 1 (1.3%) patient who did not report. Of these patients, the age range was 44-83 years with 44 (58.7%) being 65 years of age or older. Thirty-three (33, 44.0%) patients had a hip infection and 42 (56.0%) had a knee infection.105228354.471Attorney Docket No.121446-854267 Patients with advanced renal insufficiency (chronic kidney disease Stage 4 or greater or globular filtration rate < 30 mL / min) were excluded from the clinical studies.

[0466] No serious adverse events were determined to be related to the antibiotics used in theantibiotic irrigation solution kit. There were 2 serious adverse events of device occlusion that were both determined to be related to the Irrigation System (device) and treatment procedure (surgery). There were 2 additional events related to the treatment procedure (surgery), including postoperative anemia (1) and hemorrhage.

[0467] The most common adverse reactions considered related to antibiotics in subjects treatedin APEX clinical studies (n = 75) that were ≥ 2% were diarrhea and identification of Candida isolates observed in 2 subjects each. Other adverse reactions considered related to drugs observed in 1 subject each were nausea, catheter site pain, pyrexia, procedural pain, tendon rupture, antibiotic level above therapeutic, blood creatinine increase, blood urea increase, erythema, pruritus, deafness, and hypokalaemia. In the APEX studies the observed adverse events are primarily procedural related and were observed at a frequency similar to that of the standard of care 2-stage exchange arthroplasty. Table 7 summarizes all adverse events observed in the APEX and APEX-2 clinical program at a frequency of ≥10% in patients treated with the antibiotic irrigation solution kit. Table 7. All Adverse Events Observed at a Frequency of ≥10% in Patients Treated with the Antibiotic Irrigation Solution Kit

[0468] The antibiotic irrigation solution kit contains tobramycin sulfate for irrigation andvancomycin hydrochloride for irrigation as separate co-packaged vials. Tobramycin Sulfate for Irrigation105228354.472Attorney Docket No.121446-854267

[0469] Tobramycin sulfate, a water-soluble antibiotic of the aminoglycoside group, is derivedfrom the actinomycete Streptomyces tenebrarius. Tobramycin sulfate for irrigation is a clear and colorless sterile aqueous solution for irrigation administration.

[0470] Each mL contains tobramycin sulfate equivalent to 40 mg tobramycin; 3 mg sodiummetabisulfite added as an antioxidant; and 0.1 mg edetate disodium added as a stabilizer. Tobramycin sulfate for irrigation contains sulfuric acid and may contain sodium hydroxide for pH adjustment: pH 4.0 (3.0 to 6.5).

[0471] Tobramycin sulfate is O-3-amino-3-deoxy-α-D-glucopyranosyl-(1→4)-O-[2,6-diamino-2,3,6-trideoxy-α-D-ribo-hexopyranosyl-(1→6)]-2-deoxy-L-streptamine sulfate (2:5)(salt) and has the chemical formula (C18H37N5O9)2 • 5H2SO4. The molecular weight is 1,425.45. Tobramycin has the following structure: for Irrigation

[0472] Vancomycin is a tricyclic glycopeptide antibiotic derived from Amycolatopsisorientalis (formerly Nocardia orientalis). Vancomycin hydrochloride for irrigation may contain hydrochloric acid and / or sodium hydroxide for pH adjustment. The chemical name for vancomycin hydrochloride is 3S- [3R*,6S*(S*),7S*,22S*,23R*,26R*,36S*,38aS*]]-3-(2-Amino- 2-oxoethyl)-44-[[2-O-(3-amino-2,3,6-trideoxy-3-C-methyl-α-L-lyxo-hexopyranosyl)-β-D- glucopyranosyl]oxy]-10,19-dichloro-2,3,4,5,6,7,23,24,25,26,36,37,38,38a-tetradecahydro- 7,22,28,30,32-pentahydroxy-6-[[4-methyl-2-(methylamino)-1-oxopentyl]amino]-2,5,24,38,39- pentaoxo-22H-8,11:18,21-dietheno-23,36- (iminomethano)-13,16:31,35-dimetheno-1H,16H- [1,6,9]oxadiazacyclohexadecino[4,5- m][10,2,16]-benzoxadiazacyclotetracosine-26-carboxylic acid, monohydrochloride. The molecular formula is C66H75Cl2N9O24 HCl and the molecular weight is 1,485.74. Vancomycin hydrochloride has the following structure:105228354.473Attorney Docket No.121446-854267 CLINICAL PHARMACOLOGY Mechanism of Action

[0473] Tobramycin sulfate for irrigation is an aminoglycoside antibiotic with activity againstGram-positive and Gram-negative bacteria.

[0474] Vancomycin hydrochloride is a tricyclic glycopeptide antibacterial with activityagainst Gram-positive bacteria. Pharmacokinetics

[0475] The Antibiotic Irrigation Solution Kit Drug Pack (tobramycin sulfate for irrigation;vancomycin hydrochloride for irrigation) is delivered using the Irrigation System which provides the full concentration of the dose delivered to the infected joint space with minimal systemic adsorption. Absorption

[0476] There is minimal systemic absorption of tobramycin or vancomycin when administeredvia the irrigation route of administration with the antibiotic irrigation solution.

[0477] During the APEX study, tobramycin serum concentrations were assessedapproximately 30 minutes before tobramycin administration (approximate trough concentration) and 3-4 hours after tobramycin administration (approximate peak concentration) on days 1, 3, 5, and 7 of therapy. Vancomycin serum concentration was assessed daily at any time during that day on all local irrigation treatment days (i.e., days 1-9). During the APEX-2 study tobramycin and vancomycin serum concentrations were obtained daily.

[0478] The tobramycin serum concentrations by day of local irrigation treatment are presentedin Table 8. Table 8. Tobramycin Serum Concentrations (mcg / mL) During Local Irrigation Treatment with th Antibi ti Irri ti n S l ti n Kit i th APEX d APEX 2 Cli i l St dia9105228354.474Attorney Docket No.121446-854267

[0479] Most frequently, the observed serum concentrations of tobramycin during treatmentwere near the lower limit of detection of the analytical method and did not demonstrate any accumulation.

[0480] The vancomycin serum concentrations by day of location irrigation treatment arepresented in Table 9. Table 9. Vancomycin Serum Concentrations (mcg / mL) During Local Irrigation Treatment with the Antibiotic Irrigation Solution Kit in the APEX and APEX-2 Clinical Studies 9

[0481] On average, the observed serum concentrations of vancomycin during treatment were4-7 mcg / mL with only a slight accumulation over time. Two (2) patients had a single value above 30 mcg / mL. Both patients with vancomycin levels above 30 mcg / mL received IV vancomycin concurrent to local irrigation with vancomycin.

[0482] If tobramycin plasma concentrations are > 2 mcg / mL and vancomycin plasmaconcentrations are > 20 mcg / mL or signs of toxicity develop, the dose of the antibiotic irrigation solution kit antibiotics should be modified.

[0483] Tobramycin delivered by other routes of administration: Tobramycin is rapidlyabsorbed following intramuscular administration. Peak serum concentrations of tobramycin occur between 30 and 90 minutes after intramuscular administration. Following an intramuscular dose of 1 mg / kg tobramycin of body weight, maximum serum concentrations reach about 4 mcg / mL, and measurable levels persist for as long as 8 hours. Therapeutic serum levels of tobramycin are generally considered to range from 4 to 6 mcg / mL. When tobramycin injection is administered by IV infusion over a 1-hour period, the serum concentrations are similar to those obtained by intramuscular administration. Tobramycin is poorly absorbed from the gastrointestinal tract after oral administration.

[0484] Vancomycin delivered by other routes of administration: For other routes ofadministration, in subjects with normal kidney function, multiple IV dosing of 1 g of vancomycin (15 mg / kg) infused over 60 minutes produces mean plasma concentrations of approximately 63105228354.475Attorney Docket No.121446-854267 mcg / mL immediately after the completion of infusion, mean plasma concentrations of approximately 23 mcg / mL 2 hours after infusion, and mean plasma concentrations of approximately 8 mcg / mL 11 hours after the end of the infusion. Multiple dosing of 500 mg infused over 30 minutes produces mean plasma concentrations of about 49 mcg / mL at the completion of infusion, mean plasma concentrations of about 19 mcg / mL 2 hours after infusion, and mean plasma concentrations of about 10 mcg / mL 6 hours after infusion. The plasma concentrations during multiple dosing are similar to those after a single dose. About 60% of an intraperitoneal (IP) dose of vancomycin administered during peritoneal dialysis is absorbed systemically in 6 hours. Serum concentrations of about 10 mcg / mL are achieved by IP injection of 30 mg / kg of vancomycin. However, the safety and efficacy of the IP use of vancomycin hydrochloride has not been established in adequate and well-controlled trials. 14 CLINICAL STUDIES 14.1 Treatment of Periprosthetic Joint Infection

[0485] Two randomized, well-controlled, open-label clinical studies, the APEX study (StudyJPS-0301, NCT03721328) and the APEX-2 study (Study OTX-0302, NCT05607030) were conducted comparing exchange arthroplasty with the antibiotic irrigation solution kit to standard- of-care (SOC) two-stage exchange arthroplasty. The antibiotic irrigation solution kit arm consisted of implant resection and debridement, followed by a 7-day local antibiotic irrigation with the antibiotic irrigation solution kit, a second debridement, and revision prosthesis reimplantation which all occurred during one hospital admission. Each day of the 7-day local irrigation treatment, 80 mg of tobramycin sulfate in 50 mL of normal saline was administered by the irrigation route delivered by a fluid management system. The Irrigation System is substantially equivalent in both safety and efficacy to that used in the APEX Clinical Trial Program; therefore, any mention of the antibiotic irrigation solution treatment or the antibiotic irrigation solution kit in APEX or APEX-2 should be read as reflecting this additional detail. Following the 2-hour tobramycin soak, fluid was removed from the joint space using vacuum for 30 minutes. Each subsequent hour, 125 mg of vancomycin in 50 mL of normal saline was administered by irrigation. Following a 30-minute soak, fluid was removed from the joint space using vacuum for 30 minutes. There were approximately 21 consecutive rounds of vancomycin irrigation cycles per day. Over a 7-day treatment, there are 7, 2-hour applications of tobramycin and approximately 147, 30-minute applications of vancomycin. The SOC arm consisted of the following 4-step process; (1) resection arthroplasty; (2) debridement and insertion of an antibiotic-impregnated temporary spacer in a Stage 1 surgical procedure; (3) 6 or more weeks of systemic antibiotics (i.e., also called the interstage period); (4) a stage-2 surgery to remove the temporary spacer, debride, and implant a105228354.476Attorney Docket No.121446-854267 permanent prosthesis. Patients were followed for one year after treatment in both the APEX and APEX-2 trials.

[0486] The APEX trial program (APEX and APEX-2) included two arms of 76 patients each:a SOC arm and an antibiotic irrigation solution kit arm. The mean age of patients in the antibiotic irrigation solution kit arm was 67 years (ranging from 44 to 83 years), while the mean age in the SOC arm was 65 years (ranging from 39 to 82 years). The antibiotic irrigation solution kit arm comprised 44 males (57.9%), whereas the SOC arm included 51 males (67.1%). The mean Body Mass Index (BMI) was 31.8 kg / m2 (ranging from 17.7 to 45.9) in the antibiotic irrigation solution kit arm and 34.0 kg / m2 (ranging from 19.9 to 50.9) in the SOC arm. Regarding the location of the Periprosthetic Joint Infection (PJI), 43 patients (56.6%) in the antibiotic irrigation solution kit arm had knee PJI, and 33 patients (43.4%) had hip PJI. In the SOC arm, 48 patients (63.2%) had knee PJI, and 28 patients (36.8%) had hip PJI.

[0487] The APEX trial program (APEX and APEX-2) evaluated the efficacy of the antibioticirrigation solution kit as compared to SOC using a composite endpoint of Overall Success. The composite endpoint was composed of the following five elements in line with the Musculoskeletal Infection Society (MSIS) Guidelines for Reporting of Outcomes After Surgical Treatment of PJI: (1) revision prosthesis implanted; (2) absence of PJI post-reimplant surgery; (3) absence of reoperation of the affected joint pre- or post-reimplant; (4) absence of continued antibiotics; and (5) absence of mortality.

[0488] Overall Success for the antibiotic irrigation solution kit and SOC arms at 180 and 365days in the Intent-to-Treat (ITT) population is presented in Table 10. The proportion of patients classified as an Overall Success at 180 days was statistically significantly larger in the antibiotic irrigation solution kit arm compared to the SOC arm (69.7% vs 30.3%, p<0.0001) with a difference in treatment effect of 39.4%. The proportion of patients classified as an Overall Success at 365 days was also significantly larger in the antibiotic irrigation solution kit arm compared to the SOC arm (65.8% vs 47.4%, p=0.0275) with a difference in treatment effect of 18.4% (Table 10). Table 10. APEX Clinical Studies: Overall Success at 180 and 365 Days (ITT Population) 180 D End int 365 D End int105228354.477Attorney Docket No.121446-854267

[0489] Osteal also analyzed the 365-day Overall Success according to the MSIS evaluationcriteria. MSIS Tier 1 success is defined as infection control (revision prosthesis implanted, no recurrent PJI or reoperation on the affected joint, and no mortality) without suppressive antibiotics. MSIS Tier 2 success is defined as infection control with suppressive antibiotics. Given the MSIS criteria requires patient assessment to evaluate success, Osteal completed an ITT analysis using the evaluable population (i.e., removed patients without a 365-day visit who were not already failures due to a recurrent PJI or reoperation on the affected joint or due to death). The proportion of patients classified as an Overall Success at 365 days using the MSIS Tier 1 criteria was statistically significantly larger in the antibiotic irrigation solution kit arm compared to the SOC arm (71.2 % [52 / 73] vs 52.1% [38 / 73], p=0.0172). When considering both MSIS Tier 1 & 2 (infection control with or without suppressive antibiotics), the proportion of patients classified as an Overall Success remained statistically significantly larger in the antibiotic irrigation solution kit arm compared to the SOC arm (80.8% [59 / 73] vs 65.8% [48 / 73], p=0.0396). Table 11 summarizes the 365-day outcomes based on the MSIS evaluation criteria. Table 11. Outcomes Based on MSIS Evaluation Criteria (First Mode of Failure) Antibiotic Irrigation SOC Statistical .

[0490] A superior difference in treatment effect for the antibiotic irrigation solution kit versusSOC was observed at 180 and 365 days regardless of whether the PJI was in the knee or hip (Table 12).105228354.478Attorney Docket No.121446-854267 Table 12. APEX Clinical Studies: Overall Success at 180 and 365 Days (ITT Population) Stratified by Knee and Hip 180-Day Endpoint 365-Day Endpointcalstudies for the (a) antibiotic irrigation solution kit arm and the (b) SOC arm per the MSIS evaluation criteria is presented in FIG. 5A and FIG. 5B. To fully understand the impact of the treatment received in each patient, the graphs represent a per-treatment analysis (i.e., patients analyzed according to treatment received) for each patient who completed the study follow-up or who failed for reinfection, reoperation, and / or death (evaluable population). The analysis was performed by documenting the treatment status and success status for each patient every day between their Stage 1 / Explant surgery and Day 365 post-Stage 1 / Explant surgery. Each row represents an individual patient and each column an individual day with the associated success / failure outcome for that day. Patients were counted as failures for reinfection, reoperation, and / or death, and were counted as in treatment during the interstage period and during the time of active antibiotic use post-Stage 2 / Reimplant surgery.

[0492] The MSIS Tier 1 area (green) highlights the patients having infection control withoutsuppressive antibiotics; Tier 2 area (yellow) highlights the patients having infection control with suppressive antibiotics; Tier 3F area (orange) highlights the patients with a retained spacer; Tier^3C / 3D (red) area highlights the patients with a septic or aseptic reoperation; and Tier 4 (black) highlights the patients who died prior to Day 365. Patients treated with the antibiotic irrigation solution kit spent on average 120 days in treatment (interstage period + active antibiotic use) compared to 237 days for patients treated with SOC. On the other hand, antibiotic irrigation solution kit patients who completed the 365-day study period had on average over 100 more opportunity days to fail for a post-Stage 2 reinfection in Study JPS-0301 and OTX-0302, given the longer follow-up period after Stage 2 surgery in the antibiotic irrigation solution kit arm. Despite having fewer treatment days and more opportunity days for post Stage 2 reinfection, patients treated with the antibiotic irrigation solution kit spent on average 117 more days as a MSIS Tier 1 success (or 2.5x) than patients treated with SOC (195.3 vs 77.9 days).105228354.479Attorney Docket No.121446-854267

[0493] FIG. 6A and FIG. 6B provide a graphical analysis documenting the PJI burden foreach patient in the (a) antibiotic irrigation solution kit arm and the (b) SOC arm of the APEX clinical program. The graphs represent a per-treatment analysis of all patients to determine the cumulative time spent experiencing the negative effects ofPJI during the study period, defined as days without a permanent prosthesis plus days spent in an AE for PJI and / or septic reoperation. Each row represents an individual patient and each column an individual day with the associated PJI status for that day. Patients treated with SOC spent 43% of the 365-day study period burdened by PJI (or 11,599 of the 26,971 study days; n=77) compared to 7% for patients treated with the antibiotic irrigation solution kit (1,798 of the 26,613 study days; n=75), an 84% reduction in PJI burden.

[0494] FIG. 7A and FIG. 7B are a graphical analysis of the PJI antibiotic burden for eachpatient in the (a) antibiotic irrigation solution kit arm and the (b) SOC arm of the APEX clinical program. The graphs represent a per-treatment analysis of patients who received a permanent implant at Stage 2 / Reimplant surgery and who received post-Stage 2 antibiotics for PJI treatment to determine the cumulative number of days of prescribed PJI antibiotics during the study period. Each row represents an individual patient and each column an individual day with the PJI antibiotic status for that day. The graphs include parenteral and enteral antibiotics, along with ‘other’ antibiotics prescribed for PJI. PJI antibiotics were only counted once on any given day (i.e. if a patient was prescribed both parenteral and enteral PJI antibiotics, the specific day was included as parenteral antibiotics). Patients treated with the antibiotic irrigation solution kit (n=75) had on average 37 fewer days of prescribed PJI antibiotics than patients treated with SOC (n=60) during the 365-day study period. Antibiotic irrigation solution kit patients also had on average 6 fewer days of parenteral PJI antibiotics prescribed during the study period.

[0495] All patients treated with the antibiotic irrigation solution kit (76 of 76, 100%) werereimplanted with their permanent prosthesis compared to 82.9% (63 of 76) of SOC patients by Day 365 post-resection arthroplasty surgery (Table 13). There were 2 deaths experienced in the antibiotic irrigation solution kit arm and 5 deaths in the SOC arm. The median time to reimplantation for antibiotic irrigation solution kit patients was 7 days compared to 98 days in the SOC patients (considering only SOC patients who had a Stage 2 surgery). In patients who completed both the Stage 1 / Explant and Stage 2 / Reimplant surgeries, the total surgery time for antibiotic irrigation solution kit patients was significantly shorter than SOC patients (293 vs 355 minutes).105228354.480Attorney Docket No.121446-854267 Table 13. APEX Clinical Studies – Clinical Observations at 365 days (ITT Population) Antibiotic Irrigation Solution SOCdexscore of the European Quality of Life 5 Dimensions 3 Levels of Severity (EQ-5D-3L), the Knee Disability and Osteoarthritis Outcome Score (KOOS), and the Hip Disability and Osteoarthritis Outcome Score (HOOS) questionnaires.

[0497] At 90 days, antibiotic irrigation solution kit patients had a significantly greater qualityof life improvement than SOC patients, demonstrated by a larger change from baseline in EQ-5D- 3L index score. Antibiotic irrigation solution kit patients with knee PJI also showed a significantly greater improvement in all KOOS dimension scales (Pain, Other Symptoms, Function in Activities of Daily Living, Function in Sport and Recreation, Quality of Life) than SOC patients at 90 days, demonstrated by a larger change from baseline in each dimension score. At 180 days, antibiotic irrigation solution kit patients with knee PJI showed a significantly greater improvement in the KOOS Quality of Life dimension and at 365 days in the KOOS Function in Sport and Recreation dimension than SOC patients.

[0498] Antibiotic irrigation solution kit patients reported consistently higher EQ-5D-3L scores(Quality of Life) across all time points, including baseline. Differences were most pronounced at 90 days, where antibiotic irrigation solution kit patient’s mean and median scores were >10% higher than SOC. This difference was not only statistically significant but also clinically meaningful, surpassing the established minimally important difference (8.5%) for patients undergoing primary knee arthroplasty. DEFINITIONS

[0499] In various implementations, description is made with reference to the figures.However, certain implementations may be practiced without one or more of these specific details, or in combination with other known methods and configurations. In the description, numerous specific details are set forth, such as specific doses, fixed dose combinations and concentrations, in order to provide a thorough understanding of the invention. In other instances, specific doses,105228354.481Attorney Docket No.121446-854267 fixed dose combinations and concentrations have not been described in particular detail in order to not unnecessarily obscure the description. Reference throughout this specification to “dose,” “fixed dose ratio,” “concentration” or the like, means that a particular method, or characteristic described is included in at least one novel method of treatment. Thus, the appearance of the phrase “one method of treatment,” or the like, in various places throughout this specification is not necessarily referring to the same method of treatment. Furthermore, the particular antibiotics, doses, fixed dose combinations, ratios and concentrations may be combined in any suitable manner in one or more novel method of treatment.

[0500] As used herein, the term “antiseptic” refers to an agent capable of inhibiting the growthof or destroying microorganisms on living tissue or wounds, thereby reducing or preventing infection. Antiseptics include but are not limited to agents with antibacterial, antiviral, or antifungal properties. In particular, antibacterial agents, as discussed throughout the present disclosure, are a species of antiseptics specifically effective against bacterial pathogens. The methods, formulations, and dosing described herein for antibacterial agents are thus equally applicable to other classes of antiseptics unless otherwise specified.

[0501] Antiseptics may comprise, by way of non-limiting example, antifungal agents,antibacterial agents, and antiviral agents. Where the specification refers to the administration of antibacterial agents, it is to be understood that such references also contemplate the use of antiseptics more broadly, including but not limited to antifungal agents.

[0502] Where a range of values is provided, each value between the upper and lower ends ofthe range are specifically contemplated and described herein.

[0503] As used herein, the term “about” means a range of values including the specified value,which a person of ordinary skill in the art would consider reasonably similar to the specified value. In aspects, about means within a standard deviation using measurements generally acceptable in the art. In aspects, about means a range extending to + / - 10% of the specified value and may include the specified value. For example, the endpoint may be within 10%, 8%, 5%, 3%, 2%, or 1% of the listed value. Further, for the sake of 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 of “50 mg / mL to 80 mg / mL” The endpoint may also be based on the variability allowed by an appropriate regulatory body, such as the FDA, USP, etc.

[0504] As used herein, the term “substantially” means a value a person of ordinary skill in theart would consider significantly more than a specified value. In some aspects, substantially means at least 25% more than the specified value, or at least 125% of the specified value.105228354.482Attorney Docket No.121446-854267

[0505] As used herein, the terms “safe” and “recommended” means recommended by amedical authority, such as a manufacturer, the FDA or other similar regulatory body. In some examples, the maximum dose or serum level may be based on peer reviewed medical literature, for example 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, p. 685-700, 2009, or recommended by a professional medical organization or association. In additional examples, a maximum recommended daily systemic dose and / or a maximum safe serum concentration may be provided in the label or instructions for use of the particular antibiotic.

[0506] As used herein, the terms “maximum recommended daily dose”, “maximumrecommended daily systemic dose” and “maximum recommended systemic daily dose” may be used interchangeably. In some examples, the systemic daily dose may be a daily dose administered by IV.

[0507] As used herein, the terms “combination”, “antibiotics”, “NEXCHANGE Kit”,“Antibiotic Irrigation Solution”, “NEXCHANGE KIT Drug Pack”, and “Antibiotic Irrigation Solution Drug Pack” may be used interchangeably. In some examples, the kit includes a combination of vancomycin hydrochloride and tobramycin sulfate for irrigation.

[0508] As used herein, the terms “NEXCHANGE Spacer System” and “irrigation device” maybe used interchangeably. In some examples, the NEXCHANGE Spacer System includes instruments (e.g., FIG.2A) and a spacer device (e.g., FIG.2B).

[0509] As used herein, the terms “NEXCHANGE Fluid Management System”,“NEXCHANGE Irrigation system”, and “irrigation system” may be used interchangeably. In some examples, “NEXCHANGE KIT Irrigation System” includes the NEXCHANGE spacer system (e.g., FIGS.2A-2B) and the NEXCHANGE Fluid Management System (e.g., FIGS.3A-3C).

[0510] While this specification contains many specifics, these should not be construed aslimitations on the scope of what is claimed or of what may be claimed, but rather as descriptions of features specific to particular methods. Certain methods that are described in this specification may also be implemented in combination in a single method. Conversely, various features that are described in the context of a single method may also be implemented individually, in multiple methods separately or in any suitable sub-combination of novel methods. Moreover, although methods may be described herein as including certain combinations of antibiotics, doses or concentrations and even initially claimed as such, one or more features from such a claimed combination may in some cases be excised from the combination, and the claimed combination105228354.483Attorney Docket No.121446-854267 may be directed to a sub-combination or a variation of a sub-combination. Similarly, while administration of more than one antibiotic sequentially is described in the specification in a particular order or for particular durations, this should not be understood as requiring that such methods be performed in the particular sequential order or for the particular durations, or that all elements of the sequence be performed, to achieve desirable results. Only a few examples and methods are disclosed. Variations, modifications and enhancements to the described methods and other methods may be made based on what is disclosed.

[0511] In the descriptions above and in the claims, phrases such as “at least one” or “one ormore” may occur followed by one or a conjunctive list of elements, antibiotics, combinations, doses or concentrations. The term “and / or” may also occur in a list of two or more such elements. Unless otherwise implicitly or explicitly contradicted by the context in which it is used, such a phrase is intended to mean any of the listed elements individually or any of the recited elements in combination with any of the other recited 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 each intended to mean “A alone, B alone, or A and B together.” A similar interpretation is also intended for lists including three or more 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 each intended to mean “A alone, B alone, C alone, A and B together, A and C together, B and C together, or A and B and C together.”

[0512] Use of the term “based on” above and in the claims is intended to mean, “based at leastin part on,” such that an unrecited feature or element is also permissible.

[0513] As used herein, “comprises,” “comprising,” “containing,” and “having” and the likemay have the meaning ascribed to them in U.S. Patent Law and may mean “includes,” “including,” and the like, and are generally interpreted to be open ended terms. The terms “consisting of” or “consists of” are closed terms, and include only the components, structures, steps, or the like specifically listed in conjunction with such terms, as well as that which is in accordance with U.S. Patent law. “Consisting essentially of” or “consists essentially of” have the meaning generally ascribed to them by U.S. Patent law. In particular, such terms are generally closed terms, with the exception of allowing 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) used in connection therewith. For example, trace elements present in a composition, but not affecting the composition’s nature or characteristics would be permissible if present under the “consisting essentially of” language, even though not expressly recited in a list of items following such terminology. In this specification when using an open-ended term, like “comprising” or105228354.484Attorney Docket No.121446-854267 “including,” it is understood that direct support should be afforded also to “consisting essentially of” language as well as “consisting of” language as if stated explicitly and vice versa.

[0514] As used herein, first, second, third, etc. are used to characterize and distinguish variousantibiotics. Use of numerical terms may be used to distinguish one antibiotic from another antibiotic. Use of such numerical terms does not imply a sequence or order unless clearly indicated by the context. Such numerical references may be used interchangeably without departing from the teaching of the embodiments and variations herein.

[0515] The inventions disclosed herein may be packaged together in a single package ofmultiple antibiotics or in multiple packages of individual or combinations of antibiotics for use together, and such use may be administered concurrently, serially, cyclically or sequentially (in a particular sequence which may include repeat use of one or more individual or combination of antibiotics) per specific instructions.

[0516] All methods described herein may be performed in any suitable order unless otherwiseindicated herein or otherwise 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 illuminate the invention and does not pose 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. EMBODIMENTS

[0517] Embodiment 1. A method of treating a periprosthetic joint infection in a skeletallymature patient undergoing an exchange arthroplasty procedure, the method comprising: locally administering a combination of tobramycin sulfate at a dose of 80 mg / day and vancomycin hydrochloride at a dose of 2.6 to 3 g / day to the patient.

[0518] Embodiment 2. The method of embodiment 1, wherein the combination is onlyadministered to the patient to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.

[0519] Embodiment 3. The method of embodiment 1, wherein the local administration occursdaily via irrigation for 7 to 10 days.

[0520] Embodiment 4. The method of embodiment 1, wherein the locally administeringcomprises irrigating the periprosthetic joint infection with the combination.

[0521] Embodiment 5. The method of embodiment 4, wherein the irrigating the localizedinfection comprises soaking the periprosthetic joint infection with the tobramycin sulfate or105228354.485Attorney Docket No.121446-854267 vancomycin hydrochloride and subsequently aspirating the tobramycin sulfate or vancomycin hydrochloride.

[0522] Embodiment 6. The method of embodiment 1, wherein the combination is locallyadministered by irrigation using an irrigation system.

[0523] Embodiment 7. The method of embodiment 6, further comprising: administering 80mg of tobramycin sulfate in 50 mL of normal saline (1.6 mg / mL) by the irrigation system for 7- 10 days (total daily exposure of 1.6 mg / day); following a 2-hour soak, removing the tobramycin sulfate using suction over 30 minutes; administering 125 mg of vancomycin hydrochloride in 50 mL of normal saline (2.5 mg / mL) with the irrigation system every hour for 10 treatments for a duration of 7-10 days (total daily exposure of 1.25 g / day); and following a 30-minute soak, removing the vancomycin hydrochloride using suction over 30 minutes after each administration.

[0524] Embodiment 8. The method of embodiment 7, wherein approximately 21-22consecutive rounds of vancomycin irrigation cycles are administered per day.

[0525] Embodiment 9. The method of embodiment 7, wherein over a 7-day treatment, thereare 7, 2-hour applications of tobramycin and approximately 147, 30-minute applications of vancomycin.

[0526] Embodiment 10. The method of embodiment 1, further comprising monitoring thepatient during administration for ototoxicity and nephrotoxicity.

[0527] Embodiment 11. The method of embodiment 1, further comprising monitoringtobramycin serum trough levels; maintaining tobramycin serum trough levels at <2 mcg / mL; and if tobramycin serum trough levels are >2 mcg / mL or toxicity is a concern, decreasing the total dose of tobramycin based on the tobramycin serum trough levels.

[0528] Embodiment 12. The method of embodiment 11, wherein the total tobramycinadministered is decreased but not total volume.

[0529] Embodiment 13. The method of embodiment 11, wherein the tobramycin serum troughlevels are monitored after 2 or 3 doses, and also at 3- to 4-day intervals during administration.

[0530] Embodiment 14. The method of embodiment 1, wherein the patient has a meantobramycin serum concentration of 0.5 ± 0.2 mcg / mL during administration.

[0531] Embodiment 15. The method of embodiment 1, wherein the patient has a meantobramycin serum trough level of 0.4 ± 0.2 mcg / mL during administration.

[0532] Embodiment 16. The method of embodiment 1, further comprising monitoringvancomycin serum levels; maintaining vancomycin serum levels at <20 mcg / mL; and if serum levels are >20 mcg / mL or if toxicity is a concern, decreasing the total dose of vancomycin based on the vancomycin serum levels.105228354.486Attorney Docket No.121446-854267

[0533] Embodiment 17. The method of embodiment 16, wherein the total vancomycinadministered is decreased but not total volume.

[0534] Embodiment 18. The method of embodiment 1, wherein the patient has a meanvancomycin serum concentration of 5.6 ± 5.4 mcg / mL during administration.

[0535] Embodiment 19. The method of embodiment 1, wherein the dose of tobramycin sulfateis prepared by: using an approximately 3 mL syringe to withdraw a 2 mL volume (80 mg) from a vial comprising tobramycin sulfate and transfer to a 50 mL 0.9% sodium chloride intravenous piggyback (IVPB) bag.

[0536] Embodiment 20. The method of embodiment 1, wherein the dose of vancomycinhydrochloride is prepared by: reconstituting three 1 g vials comprising vancomycin hydrochloride using an approximately 20 mL syringe by adding 20 mL sterile water for injection to each vial; withdrawing the contents of the three 1 g vancomycin hydrochloride vials and adding all 3 g (60 mL) of vancomycin hydrochloride to a 1000 mL normal saline IVPB bag; and using an approximately 100 mL syringe, adding 100 mL of normal saline to the IVPB already containing 3 g of vancomycin hydrochloride.

[0537] Embodiment 21. The method of embodiment 1, wherein the tobramycin sulfate isadministered at a concentration of 1.6 mg / mL.

[0538] Embodiment 22. The method of embodiment 1, wherein vancomycin hydrochloride isadministered at a concentration of 2.5 mg / mL.

[0539] Embodiment 23. The method of embodiment 1, further comprising maintainingtobramycin serum levels at <2 mcg / mL.

[0540] Embodiment 24. The method of embodiment 1, further comprising maintainingvancomycin serum levels at <20 mcg / mL.

[0541] Embodiment 25. The method of embodiment 1, wherein the combination isadministered to the patient to treat or prevent bacterial infections.

[0542] Embodiment 26. The method of embodiment 1, further comprising modifying the doseof tobramycin sulfate or vancomycin hydrochloride if nephrotoxicity or ototoxicity occurs in the patient.

[0543] Embodiment 27. The method of embodiment 1, further comprising modifying the doseof tobramycin sulfate if tobramycin serum trough level above 2 mcg / mL occurs in the patient.

[0544] Embodiment 28. The method of embodiment 27, wherein modifying the dose oftobramycin sulfate comprises decreasing total drug administered but not total volume.

[0545] Embodiment 29. The method of embodiment 27, wherein the dose of tobramycinsulfate is modified to 40 mg at a concentration of 0.8 mg / mL.105228354.487Attorney Docket No.121446-854267

[0546] Embodiment 30. The method of embodiment 1, further comprising modifying the doseof vancomycin hydrochloride if vancomycin serum trough level above 20 mcg / mL occurs in the patient.

[0547] Embodiment 31. The method of embodiment 30, wherein modifying the dose ofvancomycin hydrochloride comprises decreasing total drug administered but not total volume.

[0548] Embodiment 32. The method of embodiment 30, wherein the dose of vancomycinhydrochloride is modified to 1.5 g at a concentration of 1.25 mg / mL.

[0549] Embodiment 33. The method of embodiment 1, further comprising maintainingsystemic concentrations of tobramycin below 15 mcg / mL, below 14 mcg / mL, below 13 mcg / mL, below 12 mcg / mL, below 11 mcg / mL, or below 10 mcg / mL.

[0550] Embodiment 34. The method of embodiment 1, further comprising discontinuingadministration at appearance of skin rashes, mucosal lesion, or blisters on the patient.

[0551] Embodiment 35. The method of embodiment 1, further comprising assessing thepatient’s auditory function.

[0552] Embodiment 36. The method of embodiment 1, wherein assessing the patient’sauditory function comprises an audiometric test that evaluates hearing up to 8000 Hz.

[0553] Embodiment 37. The method of embodiment 1, further comprising assessing cultureinformation or susceptibility information of the periprosthetic infection.

[0554] Embodiment 38. The method of embodiment 1, further comprising monitoringtoxicities associated with aminoglycosides as a class.

[0555] Embodiment 39. A kit for treating a periprosthetic joint infection in skeletally maturepatients undergoing an exchange arthroplasty procedure, the kit comprising: a plurality of vials, each comprising 1 g of vancomycin hydrochloride lyophilized powder intended for reconstitution / dilution with normal saline; and a second plurality of vials, each comprising 80 mg / 2 mL (40 mg / mL) of tobramycin sulfate solution intended for reconstitution / dilution with normal saline.

[0556] Embodiment 40. The kit of embodiment 39, further comprising: a treatment deliverysystem and / or irrigation device configured to locally irrigate the periprosthetic joint infection with a combination of vancomycin hydrochloride and tobramycin sulfate; and instructions for administration.

[0557] Embodiment 41. The kit of embodiment 39, wherein the kit comprises 21 vials ofvancomycin hydrochloride and 7 vials of tobramycin sulfate.

[0558] Embodiment 42. A method of treating a periprosthetic joint infection in a skeletallymature patient undergoing an exchange arthroplasty procedure, the method comprising: locally105228354.488Attorney Docket No.121446-854267 administering a combination of tobramycin sulfate at a dose of about 80 mg / day and vancomycin hydrochloride at a dose of about 2.6 g / day to about 3 g / day to the patient.

[0559] Embodiment 43. The method of embodiment 42, wherein the combination is onlyadministered to the patient to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.

[0560] Embodiment 44. The method of embodiment 42, wherein the local administrationoccurs daily via irrigation for 7 to 10 days.

[0561] Embodiment 45. The method of embodiment 42, wherein the locally administeringcomprises irrigating the periprosthetic joint infection with the combination.

[0562] Embodiment 46. The method of embodiment 45, wherein the irrigating the localizedinfection comprises soaking the periprosthetic joint infection with the tobramycin sulfate or vancomycin hydrochloride and subsequently aspirating the tobramycin sulfate or vancomycin hydrochloride.

[0563] Embodiment 47. The method of embodiment 42, wherein the combination is locallyadministered by irrigation using an irrigation system.

[0564] Embodiment 48. The method of embodiment 47, further comprising: administering 80mg of tobramycin sulfate in 50 mL of normal saline (1.6 mg / mL) by the irrigation system for 7- 10 days (total daily exposure of 1.6 mg / day); following a 2-hour soak, removing the tobramycin sulfate using suction over 30 minutes; administering 125 mg of vancomycin hydrochloride in 50 mL of normal saline (2.5 mg / mL) with the irrigation system every hour for 10 treatments for a duration of 7-10 days (total daily exposure of 1.25 g / day); and following a 30-minute soak, removing the vancomycin hydrochloride using suction over 30 minutes after each administration.

[0565] Embodiment 49. The method of embodiment 48, wherein approximately 21-22consecutive rounds of vancomycin irrigation cycles are administered per day.

[0566] Embodiment 50. The method of embodiment 48, wherein over a 7-day treatment, thereare 7, 2-hour applications of tobramycin and approximately 147, 30-minute applications of vancomycin.

[0567] Embodiment 51. The method of embodiment 42, further comprising monitoring thepatient during administration for ototoxicity and nephrotoxicity.

[0568] Embodiment 52. The method of embodiment 42, further comprising monitoringtobramycin serum trough levels; maintaining tobramycin serum trough levels at less than about 2 mcg / mL; and if tobramycin serum trough levels are greater than about 2 mcg / mL or toxicity is a concern, decreasing the total dose of tobramycin based on the tobramycin serum trough levels.105228354.489Attorney Docket No.121446-854267

[0569] Embodiment 53. The method of embodiment 52, wherein the total tobramycinadministered is decreased but not total volume.

[0570] Embodiment 54. The method of embodiment 52, wherein the tobramycin serum troughlevels are monitored after 2 or 3 doses, and also at 3- to 4-day intervals during administration.

[0571] Embodiment 55. The method of embodiment 42, wherein the patient has a meantobramycin serum concentration of about 0.5 ± 0.2 mcg / mL during administration.

[0572] Embodiment 56. The method of embodiment 42, wherein the patient has a meantobramycin serum trough level of about 0.4 ± 0.2 mcg / mL during administration.

[0573] Embodiment 57. The method of embodiment 42, further comprising monitoringvancomycin serum levels; maintaining vancomycin serum levels at less than about 20 mcg / mL; and if serum levels are greater than about 20 mcg / mL or if toxicity is a concern, decreasing the total dose of vancomycin based on the vancomycin serum levels.

[0574] Embodiment 58. The method of embodiment 57, wherein the total vancomycinadministered is decreased but not total volume.

[0575] Embodiment 59. The method of embodiment 42, wherein the patient has a meanvancomycin serum concentration of about 5.6 ± 5.4 mcg / mL during administration.

[0576] Embodiment 60. The method of embodiment 42, wherein the dose of tobramycinsulfate is prepared by: using an approximately 3 mL syringe to withdraw a 2 mL volume (80 mg) from a vial comprising tobramycin sulfate and transfer to a 50 mL 0.9% sodium chloride intravenous piggyback (IVPB) bag.

[0577] Embodiment 61. The method of embodiment 42, wherein the dose of vancomycinhydrochloride is prepared by: reconstituting three 1 g vials comprising vancomycin hydrochloride using an approximately 20 mL syringe by adding 20 mL sterile water for injection to each vial; withdrawing the contents of the three 1 g vancomycin hydrochloride vials and adding all 3 g (60 mL) of vancomycin hydrochloride to a 1000 mL normal saline IVPB bag; and using an approximately 100 mL syringe, adding 100 mL of normal saline to the IVPB already containing 3 g of vancomycin hydrochloride.

[0578] Embodiment 62. The method of embodiment 42, wherein the tobramycin sulfate isadministered at a concentration of about 1.6 mg / mL.

[0579] Embodiment 63. The method of embodiment 42, wherein vancomycin hydrochlorideis administered at a concentration of about 2.5 mg / mL.

[0580] Embodiment 64. The method of embodiment 42, further comprising maintainingtobramycin serum levels at less than about 2 mcg / mL.105228354.490Attorney Docket No.121446-854267

[0581] Embodiment 65. The method of embodiment 42, further comprising maintainingvancomycin serum levels at less than about 20 mcg / mL.

[0582] Embodiment 66. The method of embodiment 42, wherein the combination isadministered to the patient to treat or prevent bacterial infections.

[0583] Embodiment 67. The method of embodiment 42, further comprising modifying thedose of tobramycin sulfate or vancomycin hydrochloride if nephrotoxicity or ototoxicity occurs in the patient.

[0584] Embodiment 68. The method of embodiment 42, further comprising modifying thedose of tobramycin sulfate if a tobramycin serum trough level above about 2 mcg / mL occurs in the patient.

[0585] Embodiment 69. The method of embodiment 68, wherein modifying the dose oftobramycin sulfate comprises decreasing total drug administered but not total volume.

[0586] Embodiment 70. The method of embodiment 68, wherein the dose of tobramycinsulfate is modified to about 40 mg at a concentration of about 0.8 mg / mL.

[0587] Embodiment 71. The method of embodiment 42, further comprising modifying thedose of vancomycin hydrochloride if a vancomycin serum trough level above about 20 mcg / mL occurs in the patient.

[0588] Embodiment 72. The method of embodiment 71, wherein modifying the dose ofvancomycin hydrochloride comprises decreasing total drug administered but not total volume.

[0589] Embodiment 73. The method of embodiment 71, wherein the dose of vancomycinhydrochloride is modified to about 1.5 g at a concentration of about 1.25 mg / mL.

[0590] Embodiment 74. The method of embodiment 42, further comprising maintainingsystemic concentrations of tobramycin below about 15 mcg / mL, below about 14 mcg / mL, below about 13 mcg / mL, below about 12 mcg / mL, below about 11 mcg / mL, or below about 10 mcg / mL.

[0591] Embodiment 75. The method of embodiment 42, further comprising discontinuingadministration at appearance of skin rashes, mucosal lesion, or blisters on the patient.

[0592] Embodiment 76. The method of embodiment 42, further comprising assessing thepatient’s auditory function.

[0593] Embodiment 77. The method of embodiment 76, wherein assessing the patient’sauditory function comprises an audiometric test that evaluates hearing up to 8000 Hz.

[0594] Embodiment 78. The method of embodiment 42, further comprising assessing cultureinformation or susceptibility information of the periprosthetic infection.

[0595] Embodiment 79. The method of embodiment 42, further comprising monitoringtoxicities associated with aminoglycosides as a class.105228354.491Attorney Docket No.121446-854267

[0596] Embodiment 80. The method of any one of embodiments 42-79, wherein suchtreatment results in: an overall success rate at 90 days in a population of patients who have received such treatment of at least about 80%; an overall success rate at 180 days in a population of patients who have received such treatment of at least about 55%; and / or iii) an overall success rate at 360 days in a population of patients who have received such treatment of at least about 50%.

[0597] Embodiment 81. The method of embodiment 80, wherein the overall success rate iscalculated as the proportion of patients in a treatment group who, at a defined timepoint satisfy the criteria for an overall success.

[0598] Embodiment 82. The method of embodiment 81, wherein the overall success isachieved when the patient has 1) received a revision prosthesis; 2) no evidence of periprosthetic joint infection following reimplantation; 3) not undergone reoperation of the affected joint prior to or following reimplantation; 4) not continued antibiotics for joint infection; and 5) not died.

[0599] Embodiment 83. The method of any one of embodiments 42-82, wherein suchtreatment results in an improved quality of life score in the patient.

[0600] Embodiment 84. The method of embodiment 83, wherein the quality-of-life score iscalculated from a European Quality of Life 5 Dimensions 3 Levels of Severity (EQ-5D-3L) questionnaire, a Knee Disability and Osteoarthritis Outcome Score (KOOS) questionnaire, or a Hip Disability and Osteoarthritis Outcome Score (HOOS) questionnaire.

[0601] Embodiment 85. Vancomycin hydrochloride and tobramycin sulfate for use accordingto the method of any one of embodiments 42-82.

[0602] Embodiment 86. A method of treating or preventing a local infection in a wound, themethod comprising: locally administering to a human patient a plurality of doses of at least one antiseptic agent in solution and at least one antibiotic in solution by irrigating the wound, wherein the locally administering of each solution is performed at least once in a 24-hour period.

[0603] Embodiment 87. The method of embodiment 86, wherein the at least one antisepticagent comprises hypochlorous acid, sodium hypochlorite, citric acid, acetic acid, polyhexamethylene biguanide, chlorhexidine glutonate, povidone iodine, copper sulfate / potassium iodide, taurolidine, or combinations thereof.

[0604] Embodiment 88. The method of embodiment 86 or embodiment 87, wherein theinfection comprises a bacterial pathogen, a fungal pathogen, or a polymicrobial pathogen.

[0605] Embodiment 89. The method of any one of embodiments 86-88, wherein irrigating thewound with the at least one antiseptic agent in solution is performed prior to irrigating the wound with the at least one antibiotic solution.105228354.492Attorney Docket No.121446-854267

[0606] Embodiment 90. The method of embodiment 89, wherein irrigating the wound with theat least one antiseptic agent comprises instillation of the at least one antiseptic agent in solution followed by a dwell period followed by aspiration of the at least one antiseptic agent in solution to remove the at least one antiseptic agent in solution.

[0607] Embodiment 91. The method of embodiment 90, wherein about 50 mL of the at leastone antiseptic agent in solution is instilled with about a 5-minute dwell period followed by about a 5-minute aspiration.

[0608] Embodiment 92. The method of embodiment 90 or embodiment 91, wherein a sterilefluid is irrigated after the at least one antiseptic agent in solution to remove or otherwise dilute the at least one antiseptic agent.

[0609] Embodiment 93. The method of embodiment 92, wherein the sterile fluid comprisesnormal saline.

[0610] Embodiment 94. The method of any one of embodiments 86-93, wherein irrigating thewound with the at least one antiseptic agent in solution is accomplished by simultaneously instilling and aspirating the at least one antiseptic agent in solution.

[0611] Embodiment 95. The method of embodiment 94, wherein at least about 100 mL, atleast about 250 mL, at least about 500 mL, at least about 1000 mL or at least about 2000 mL of the at least one antiseptic agent in solution is irrigated.

[0612] Embodiment 96. The method of embodiment 95, wherein the at least one antisepticagent in solution is irrigated in less than about 15 minutes.

[0613] Embodiment 97. A method of treating or preventing a local infection in a human patientat a localized site, the method comprising locally administering by irrigation to the localized site of the human patient a plurality of doses of: at least one antiseptic agent in solution; and at least one antibiotic in solution.

[0614] Embodiment 98. The method of embodiment 97, wherein the at least one antisepticagent comprises hypochlorous acid, sodium hypochlorite, citric acid, acetic acid, polyhexamethylene biguanide, chlorhexidine glutonate, povidone iodine, copper sulfate / potassium iodide, taurolidine, or combinations thereof.

[0615] Embodiment 99. The method of embodiment 97, wherein the antiseptic agentcomprises fluconazole, isavuconazole, posaconazole, voriconazole, amphotericin B, anidulafungin, caspofungin, or micafungin.

[0616] Embodiment 100. The method of any one of embodiments 97-99, wherein the at leastone antibiotic comprises vancomycin, daptomycin, and / or tobramycin.105228354.493Attorney Docket No.121446-854267

[0617] Embodiment 101. The method of any one of embodiments 97-100, wherein the localinfection comprises a bacterial pathogen, a fungal pathogen, or a polymicrobial pathogen.

[0618] Embodiment 102. The method of any one of embodiments 97-101, wherein irrigatingthe localized site with the at least one antiseptic agent comprises instillation of the at least one antiseptic agent in solution followed by a dwell period followed by aspiration of the at least one antiseptic agent in solution to remove the at least one antiseptic agent in solution.

[0619] Embodiment 103. The method of embodiment 102, wherein about 50 mL of the at leastone antiseptic agent in solution is instilled with about a 5-minute dwell period followed by about a 5-minute aspiration.

[0620] Embodiment 104. The method of any one of embodiments 97-103, wherein the leastone antiseptic agent in solution is: locally administered by irrigation prior to the at least one antibiotic in solution; locally administered by irrigation following the at least one antibiotic in solution; or locally administered by irrigation concurrently with the at least one antibiotic in solution.

[0621] Embodiment 105. A kit for treating a periprosthetic joint infection in skeletally maturepatients undergoing an exchange arthroplasty procedure, the kit comprising: a plurality of vials, each comprising 1 g of vancomycin hydrochloride lyophilized powder intended for reconstitution / dilution with normal saline; and a second plurality of vials, each comprising 80 mg / 2 mL (40 mg / mL) of tobramycin sulfate solution intended for reconstitution / dilution with normal saline.

[0622] Embodiment 106. The kit of embodiment 105, further comprising: a treatment deliverysystem and / or irrigation device configured to locally irrigate the periprosthetic joint infection with a combination of vancomycin hydrochloride and tobramycin sulfate; and instructions for administration.

[0623] Embodiment 107. The kit of embodiment 105, wherein the kit comprises 21 vials ofvancomycin hydrochloride and 7 vials of tobramycin sulfate.

[0624] Embodiment 108. The kit of embodiment 105, further comprising a plurality of vialscomprising an antiseptic agent.105228354.494

Claims

Attorney Docket No.121446-854267 CLAIMS What is claimed is:

1. A method of treating a periprosthetic joint infection in a skeletally mature patientundergoing an exchange arthroplasty procedure, the method comprising: locally administering a combination of tobramycin sulfate at a dose of about 80 mg / day and vancomycin hydrochloride at a dose of about 2.6 g / day to about 3 g / day to the patient.

2. The method of claim 1, wherein the combination is only administered to the patient to treator prevent infections that are proven or strongly suspected to be caused by bacteria.

3. The method of claim 1, wherein the local administration occurs daily via irrigation for 7 to10 days.

4. The method of claim 1, wherein the locally administering comprises irrigating theperiprosthetic joint infection with the combination.

5. The method of claim 4, wherein the irrigating the localized infection comprises soakingthe periprosthetic joint infection with the tobramycin sulfate or vancomycin hydrochloride and subsequently aspirating the tobramycin sulfate or vancomycin hydrochloride.

6. The method of claim 1, wherein the combination is locally administered by irrigation usingan irrigation system.

7. The method of claim 6, further comprising:administering 80 mg of tobramycin sulfate in 50 mL of normal saline (1.6 mg / mL) by the irrigation system for 7-10 days (total daily exposure of 1.6 mg / day); following a 2-hour soak, removing the tobramycin sulfate using suction over 30 minutes; administering 125 mg of vancomycin hydrochloride in 50 mL of normal saline (2.5 mg / mL) with the irrigation system every hour for 10 treatments for a duration of 7-10 days (total daily exposure of 1.25 g / day); and following a 30-minute soak, removing the vancomycin hydrochloride using suction over 30 minutes after each administration.

8. The method of claim 7, wherein approximately 21-22 consecutive rounds of vancomycinirrigation cycles are administered per day.

9. The method of claim 7, wherein over a 7-day treatment, there are 7, 2-hour applications oftobramycin and approximately 147, 30-minute applications of vancomycin.105228354.495Attorney Docket No.121446-85426710. The method of claim 1, further comprising monitoring the patient during administrationfor ototoxicity and nephrotoxicity.

11. The method of claim 1, further comprising monitoring tobramycin serum trough levels;maintaining tobramycin serum trough levels at less than about 2 mcg / mL; and if tobramycin serum trough levels are greater than about 2 mcg / mL or toxicity is a concern, decreasing the total dose of tobramycin based on the tobramycin serum trough levels.

12. The method of claim 11, wherein the total tobramycin administered is decreased but nottotal volume.

13. The method of claim 11, wherein the tobramycin serum trough levels are monitored after2 or 3 doses, and also at 3- to 4-day intervals during administration.

14. The method of claim 1, wherein the patient has a mean tobramycin serum concentration ofabout 0.5 ± 0.2 mcg / mL during administration.

15. The method of claim 1, wherein the patient has a mean tobramycin serum trough level ofabout 0.4 ± 0.2 mcg / mL during administration.

16. The method of claim 1, further comprising monitoring vancomycin serum levels;maintaining vancomycin serum levels at less than about 20 mcg / mL; and if serum levels are greater than about 20 mcg / mL or if toxicity is a concern, decreasing the total dose of vancomycin based on the vancomycin serum levels.

17. The method of claim 16, wherein the total vancomycin administered is decreased but nottotal volume.

18. The method of claim 1, wherein the patient has a mean vancomycin serum concentrationof about 5.6 ± 5.4 mcg / mL during administration.

19. The method of claim 1, wherein the dose of tobramycin sulfate is prepared by: using anapproximately 3 mL syringe to withdraw a 2 mL volume (80 mg) from a vial comprising tobramycin sulfate and transfer to a 50 mL 0.9% sodium chloride intravenous piggyback (IVPB) bag.

20. The method of claim 1, wherein the dose of vancomycin hydrochloride is prepared by:reconstituting three 1 g vials comprising vancomycin hydrochloride using an approximately 20 mL syringe by adding 20 mL sterile water for injection to each vial; withdrawing the contents of the three 1 g vancomycin hydrochloride vials and adding all 3 g (60 mL) of vancomycin hydrochloride to a 1000 mL normal saline IVPB bag; and105228354.496Attorney Docket No.121446-854267 using an approximately 100 mL syringe, adding 100 mL of normal saline to the IVPB already containing 3 g of vancomycin hydrochloride.

21. The method of claim 1, wherein the tobramycin sulfate is administered at a concentrationof about 1.6 mg / mL.

22. The method of claim 1, wherein vancomycin hydrochloride is administered at aconcentration of about 2.5 mg / mL.

23. The method of claim 1, further comprising maintaining tobramycin serum levels at lessthan about 2 mcg / mL.

24. The method of claim 1, further comprising maintaining vancomycin serum levels at lessthan about 20 mcg / mL.

25. The method of claim 1, wherein the combination is administered to the patient to treat orprevent bacterial infections.

26. The method of claim 1, further comprising modifying the dose of tobramycin sulfate orvancomycin hydrochloride if nephrotoxicity or ototoxicity occurs in the patient.

27. The method of claim 1, further comprising modifying the dose of tobramycin sulfate if atobramycin serum trough level above about 2 mcg / mL occurs in the patient.

28. The method of claim 27, wherein modifying the dose of tobramycin sulfate comprisesdecreasing total drug administered but not total volume.

29. The method of claim 27, wherein the dose of tobramycin sulfate is modified to about 40mg at a concentration of about 0.8 mg / mL.

30. The method of claim 1, further comprising modifying the dose of vancomycinhydrochloride if a vancomycin serum trough level above about 20 mcg / mL occurs in the patient.

31. The method of claim 30, wherein modifying the dose of vancomycin hydrochloridecomprises decreasing total drug administered but not total volume.

32. The method of claim 30, wherein the dose of vancomycin hydrochloride is modified toabout 1.5 g at a concentration of about 1.25 mg / mL.

33. The method of claim 1, further comprising maintaining systemic concentrations oftobramycin below about 15 mcg / mL, below about 14 mcg / mL, below about 13 mcg / mL, below about 12 mcg / mL, below about 11 mcg / mL, or below about 10 mcg / mL.105228354.497Attorney Docket No.121446-85426734. The method of claim 1, further comprising discontinuing administration at appearance ofskin rashes, mucosal lesion, or blisters on the patient.

35. The method of claim 1, further comprising assessing the patient’s auditory function.

36. The method of claim 35, wherein assessing the patient’s auditory function comprises anaudiometric test that evaluates hearing up to 8000 Hz.

37. The method of claim 1, further comprising assessing culture information or susceptibilityinformation of the periprosthetic infection.

38. The method of claim 1, further comprising monitoring toxicities associated withaminoglycosides as a class.

39. The method of any one of claims 1-38, wherein such treatment results in:i) an overall success rate at 90 days in a population of patients who have receivedsuch treatment of at least about 80%; ii) an overall success rate at 180 days in a population of patients who have receivedsuch treatment of at least about 55%; and / oriii) an overall success rate at 360 days in a population of patients who have received such treatment of at least about 50%.

40. The method of claim 39, wherein the overall success rate is calculated as the proportion ofpatients in a treatment group who, at a defined timepoint satisfy the criteria for an overall success.

41. The method of claim 40, wherein the overall success is achieved when the patient has 1)received a revision prosthesis; 2) no evidence of periprosthetic joint infection following reimplantation; 3) not undergone reoperation of the affected joint prior to or following reimplantation; 4) not continued antibiotics for joint infection; and 5) not died.

42. The method of any one of claims 1-41, wherein such treatment results in an improvedquality of life score in the patient.

43. The method of claim 42, wherein the quality-of-life score is calculated from a EuropeanQuality of Life 5 Dimensions 3 Levels of Severity (EQ-5D-3L) questionnaire, a Knee Disability and Osteoarthritis Outcome Score (KOOS) questionnaire, or a Hip Disability and Osteoarthritis Outcome Score (HOOS) questionnaire.

44. Vancomycin hydrochloride and tobramycin sulfate for use according to the method of anyone of claims 1-41.105228354.498Attorney Docket No.121446-85426745. A method of treating or preventing a local infection in a wound, the method comprising:locally administering to a human patient a plurality of doses of at least one antiseptic agent in solution and at least one antibiotic in solution by irrigating the wound, wherein the locally administering of each solution is performed at least once in a 24-hour period.

46. The method of claim 45, wherein the at least one antiseptic agent compriseshypochlorous acid, sodium hypochlorite, citric acid, acetic acid, polyhexamethylene biguanide, chlorhexidine glutonate, povidone iodine, copper sulfate / potassium iodide, taurolidine, or combinations thereof.

47. The method of claim 45 or claim 46, wherein the infection comprises a bacterialpathogen, a fungal pathogen, or a polymicrobial pathogen.

48. The method of any one of claims 45-47, wherein irrigating the wound with the at leastone antiseptic agent in solution is performed prior to irrigating the wound with the at least one antibiotic solution.

49. The method of claim 48, wherein irrigating the wound with the at least one antisepticagent comprises instillation of the at least one antiseptic agent in solution followed by a dwell period followed by aspiration of the at least one antiseptic agent in solution to remove the at least one antiseptic agent in solution.

50. The method of claim 49, wherein about 50 mL of the at least one antiseptic agent insolution is instilled with about a 5-minute dwell period followed by about a 5-minute aspiration.

51. The method of claim 49 or claim 50, wherein a sterile fluid is irrigated after the at leastone antiseptic agent in solution to remove or otherwise dilute the at least one antiseptic agent.

52. The method of claim 51, wherein the sterile fluid comprises normal saline.

53. The method of any one of claims 45-52, wherein irrigating the wound with the at leastone antiseptic agent in solution is accomplished by simultaneously instilling and aspirating the at least one antiseptic agent in solution.

54. The method of claim 53, wherein at least about 100 mL, at least about 250 mL, at leastabout 500 mL, at least about 1000 mL or at least about 2000 mL of the at least one antiseptic agent in solution is irrigated.105228354.499Attorney Docket No.121446-85426755. The method of claim 54, wherein the at least one antiseptic agent in solution is irrigatedin less than about 15 minutes.

56. A method of treating or preventing a local infection in a human patient at a localized site,the method comprising locally administering by irrigation to the localized site of the human patient a plurality of doses of: i) at least one antiseptic agent in solution; andii) at least one antibiotic in solution.

57. The method of claim 56, wherein the at least one antiseptic agent comprises hypochlorousacid, sodium hypochlorite, citric acid, acetic acid, polyhexamethylene biguanide, chlorhexidine glutonate, povidone iodine, copper sulfate / potassium iodide, taurolidine, or combinations thereof.

58. The method of claim 56, wherein the antiseptic agent comprises fluconazole,isavuconazole, posaconazole, voriconazole, amphotericin B, anidulafungin, caspofungin, or micafungin.

59. The method of any one of claims 56-58, wherein the at least one antibiotic comprisesvancomycin, daptomycin, and / or tobramycin.

60. The method of any one of claims 56-59, wherein the local infection comprises a bacterialpathogen, a fungal pathogen, or a polymicrobial pathogen.

61. The method of any one of claims 56-60, wherein irrigating the localized site with the atleast one antiseptic agent comprises instillation of the at least one antiseptic agent in solution followed by a dwell period followed by aspiration of the at least one antiseptic agent in solution to remove the at least one antiseptic agent in solution.

62. The method of claim 61, wherein about 50 mL of the at least one antiseptic agent insolution is instilled with about a 5-minute dwell period followed by about a 5-minute aspiration.

63. The method of any one of claims 56-62, wherein the least one antiseptic agent in solutionis: i) locally administered by irrigation prior to the at least one antibiotic in solution;ii) locally administered by irrigation following the at least one antibiotic in solution;or105228354.4100Attorney Docket No.121446-854267 iii) locally administered by irrigation concurrently with the at least one antibiotic insolution.

64. A kit for treating a periprosthetic joint infection in skeletally mature patients undergoingan exchange arthroplasty procedure, the kit comprising: a plurality of vials, each comprising 1 g of vancomycin hydrochloride lyophilized powder intended for reconstitution / dilution with normal saline; and a second plurality of vials, each comprising 80 mg / 2 mL (40 mg / mL) of tobramycin sulfate solution intended for reconstitution / dilution with normal saline.

65. The kit of claim 64, further comprising:a treatment delivery system and / or irrigation device configured to locally irrigate the periprosthetic joint infection with a combination of vancomycin hydrochloride and tobramycin sulfate; and instructions for administration.

66. The kit of claim 64, wherein the kit comprises 21 vials of vancomycin hydrochloride and7 vials of tobramycin sulfate.

67. The kit of claim 64, further comprising a plurality of vials comprising an antiseptic agent.105228354.4101

Images