Injection devices for targeted injection of antimicrobials

Abstract

The present application relates generally to injection devices for targeted delivery of antimicrobial agents, and kits and methods utilizing the same. An injection device comprises: (a) a needle comprising a needle shaft, wherein the needle shaft comprises a length of about 2 to about 15 mm and a diameter of about 24 to about 35 gauge; (b) an injection solution present at a volume of from about 1 ml to about 50 ml, or a sterile powder for reconstitution as the injection solution, wherein the injection solution comprises at least one diluent and at least one antimicrobial agent, wherein the antimicrobial agent is present at a therapeutically effective microdose; and (c) a syringe comprising the injection solution. The injection device enables the use of targeted intradermal delivery of antibiotcs for treatment and / or prevention of surgical site infection (SSI), as well as other conditions.

Description

Attorney Docket No. : 145105-0109INJECTION DEVICES FOR TARGETED INJECTION OF ANTIMICROBIALS CROSS-REFERENCE TO RELATED APPLICATION

[0001] The present application claims the benefit of U.S. Provisional Application No.63 / 778,029, filed March 26, 2025, the contents of which are incorporated herein by reference in its entirety.TECHNICAL FIELD

[0002] This invention relates to an injection device that enables local delivery of antibiotics by injection, as well as methods of using the same.BACKGROUND

[0003] Despite many advances in surgical procedures and technology, surgical site infections (SSI) still remain a significant concern. SSIs are a common complication of surgery. Thus, there is a long-standing interest in the development of more effective approaches to mitigate the risk of SSIs. One promising approach is using intra-incisional antibiotics — a technique involving the localized delivery of antibiotics directly into the surgical incision site. This technique offers potential advantages over systemically administered antibiotics (e.g. oral or intravenous), including the following: localized drug delivery directly to the target site at high concentration; reduced systemic side effects; reduced risk of antibiotic resistance; avoid the nausea that often accompanies oral antibiotics; avoid uncertainty about the timing of administration prior to surgery; avoid altering the beneficial normal gut microbiome; and reduced incidence of Clostridium difficile infection.

[0004] One particular antibiotic that has attracted attention for this purpose is clindamycin. See Huether et al, “Clindamycin for intraincisional antibiotic prophylaxis in dermatologic surgery” (2002) Arch Dermatol. 138(9): 1145-8. However, diluting clindamycin to the proper concentration is problematic because it is very dilute and challenging to mix. There are no commercial diluted products to achieve the microdosing levels needed for intra-incisional antibiotics. Most clinicians do not have the necessary equipment or skills to do this, and even if they did have the equipment, it would be very difficult to arrive at the correct concentration.14938-1265-3208.2Attorney Docket No. : 145105-0109

[0005] The proper concentration of any antibiotic given through localized injection delivery is determined through pre-clinical studies. However, the standard approved dosages for antibiotics do not apply to intradermal injection. For this particular type of local injection, the antibiotics must be given at microdose concentrations. Specifically, the amount of antibiotic given for intradermal injection should only be a small fraction of the standard amount delivered by different routes of administration. The term “microdose” follows the medical literature referencing any dosage form that is substantially less than the standard approved dosages. For example, in the case of clindamycin, 5 the microdosing amount is over 100 times less than that of the intravenous or oral routes of administration. But this high degree of dilution makes the mixing process difficult and imprecise. As such, there is a high likelihood of error when diluting antibiotics for microdosing administration.

[0006] Sophisticated equipment and knowledge of the mixing and dilution process is necessary to achieve the proper microdose concentration. As a solution to this problem, a syringe could be prefilled with a diluted concentration of clindamycin. However, in this situation, the clindamycin would be unstable and degrade quickly. Currently, there is no formulation for microdose administration of clindamycin solution. Likewise, there could be similar interest for microdose formulations of other antibiotics.

[0007] The present disclosure addresses a need in the art for an injection device that enables the use of targeted intradermal delivery of antibiotcs for treatment and / or prevention of SSI, as well as other conditions.SUMMARY

[0008] In a first aspect, the present disclosure is directed to an injection device comprising: (a) a needle comprising a needle shaft, wherein the needle shaft comprises a length of about 2 to about 15 mm and a diameter of about 24 to about 35 gauge; (b) an injection solution present at a volume of from about 1 ml to about 50 ml, or a sterile powder for reconstitution as the injection solution, wherein the injection solution comprises at least one diluent and at least one antimicrobial agent, wherein the antimicrobial agent is present at a a therapeutically effective microdose; and (c) a syringe comprising the injection solution.24938-1265-3208.2Attorney Docket No. : 145105-0109

[0009] In the injection device, the needle shaft length can be about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14 mm, or about 15 mm. In one aspect, the needle shaft length is about 4 mm. In another aspect, the needle gauge can be about 24g, about 25g, about 26g, about 27g, about 28g, about 29g, about 30g, about 31g, about 32g, about 33g, about 34g, or about 35g.

[0010] In another aspect, the needle of the injection device has a thin wall lumen.

[0011] In one embodiment, the syringe is darkened to protect the antimicrobial agent from light exposure degradation.

[0012] The injection solution can be present at a volume of from about 1 ml to about 10 ml. In another aspect, the antimicrobial agent can be an antibacterial agent, an antiviral agent, an antiparasitic agent, or an antifungal agent. For example, the at least one antimicrobial agent can be amoxicillin, ansamycins, arsphenamine, Augmentin (an amoxicillin / Clavulanic acid combination), carbacephems, carbapenems, cefaclor, cefoxitin, cefazolin, cefdinir, ceftaroline, ceftriaxone, cefuroxime, cephalexin, cephalosporins, chloramphenicol, ciprofloxacin, clindamycin, dalbavancin, dapsone, daptomycin, delafloxacin, doxycycline, ethambutol, fosfomycin, fusidic acid, furazolidone, fluoroquinolones, gentamicin, glycylcyclines, glycopeptides, isoniazid, lincosamides, lincomycin, linezolid, lipopeptides, lipoglycopeptides, lofazimine, macrolides, metronidazole, minocycline, monobactams, mupirocin, nafcillin, nitrofurantoin, ofloxacin, oritavancin, oxazolidinones, penicillins, platensimycin, polypeptides, polymyxin, pyrazinamide, quinolones, quinupristin-dalfopristin, rifampicin, streptogramin, sulfonamides, sulfonamide combinations, tedizolid, tetracycline derivatives, thiamphenicol, tigecycline, tinidazole, trimethoprim / sulfa, trimethoprim-sulfamethoxazole, vancomycin, or any combination thereof. In one aspect, the antimicrobial agent is clindamycin, vancomycin, gentamicin, lincomycin, cefazolin, or any combination thereof.

[0013] In another aspect, the at least one antimicrobial agent is an antiviral agent which can be Oseltamivir, Zanamivir, Peramivir, Baloxavir, Nucleoside / Nucleotide Reverse Transcriptase Inhibitors (NRTIs), Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs), Integrase Strand Transfer Inhibitors (INSTIs), Protease inhibitors (Pls), entry / attachment / post-attachment inhibitors, capsid, direct-acting antiviral agents (DAAs) such as Elbasvir, Nucleoside analogues,34938-1265-3208.2Attorney Docket No. : 145105-0109interferons, nucleoside phosphonates, Acyclovir, Famciclovir, Ganciclovir, Foscarnet, Cidofovir, Ribavirin, monoclonal antibodies, Imiquimod, Sinecatechins, Podofilox, Remdesivir, Paxlovid (nirmatrelvir + ritonavir), Molnupiravir, Tecovirimat, or any combination thereof

[0014] In another aspect, the at least one antimicrobial agent is an antiparasitic agent, which can be Albendazole, Mebendazole, Ivermectin, Pyrantel pamoate, Praziquantel, Triclabendazole, Moxidectin, Nitazoxanide, Pyrimethamine, Metronidazole, Tinidazole, Miltefosine, Fexinidazole, Melarsoprol, Eflornithine, Fexinidazole, Miltefosine, or any combination thereof.

[0015] In another aspect, the at least one antimicrobial agent is an antifungal agents, which can be Polyene Antifungals, Azole Antifungals, Echinocandins, Allylamines, Pyrimidine (Nucleic Acid) Analogs, and Glucan Synthase (Novel) Inhibitors, or any combination thereof.

[0016] In another embodiment, the therapeutically effective microdose of the antimicrobial agent present in the injection device (1) is from > about 0.01 mg / ml up to about 10 mg / ml; and / or (2) less than the dose for the same antimicrobial agent given systemically; and / or (3) comprises an antimicrobial concentration which is above the MIC value for the antimicrobial agent.

[0017] In one aspect, the antimicrobial agent is vancomycin, and when formulated into an injection solution, the concentration of vancomycin in the injection solution is about 100 to about 600 pg / ml. In another aspect, the antimicrobial agent is clindamycin, and when formulated into an injection solution, the concentration of clindamycin in the injection solution is about 200 to about 800 pg / ml. In a further aspect, the antimicrobial agent is ceftriaxone, and when formulated into an injection solution, the concentration of ceftriaxone in the injection solution is about 100 to about 700 pg / ml. In another aspect, the antimicrobial agent is flucloxacillin, and when formulated into an injection solution, the concentration of flucloxacillin in the injection solution is about 0.5 mg / ml up to about 25 mg / ml. In a further aspect, the antimicrobial agent is gentamicin, and when formulated into an injection solution, the concentration of gentamicin in the injection solution is about 200 up to about 800 pg / ml. In another aspect, the antimicrobial agent is lincomycin, and when formulated into an injection solution, the concentration of lincomycin in the injection solution is about 100 to about 800 pg / ml. Finally, in one aspect, the44938-1265-3208.2Attorney Docket No. : 145105-0109antimicrobial agent is cefazolin, and when formulated into an injection solution, the concentration of cefazolin in the injection solution is about 200 to about 800 pg / ml.

[0018] In another embodiment of the disclosure, the diluent present in the injection solution of the injection device is an aqueous or non-aqueous diluent. For example, the diluent can be aqueous and can be Water for Injection (WFI), sterile water, bacteriostatic water, saline, normal saline, dextrose in water, or lactated Ringer’s solution. Alternatively, the diluent can be nonaqueous and can be a vegetable oil, medium-chain triglycerides, biocompatible solvents, cyclodextrin, squalene, squalane, silicone oils, or any combination thereof.

[0019] In yet another embodiment, the injection solution further comprises one or more excipients. The excipient can, for example, improve solution stability, improve antimicrobial agent physical and / or chemical stability, adjust pH, prevent precipitation, provide for a long- acting injectable formulation, or any combination thereof. For example, the excipient can comprise sodium chloride, buffering agents, preservatives, chelating agents, lactate, dextrose, nanoporous silicon dioxide, hydrochloric acid, or sodium hydroxide.

[0020] In another aspect of the disclosure, the pH of the injection solution is from about 3.0 to about 7.8, about 7.0 to about 7.8, about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, about 7.5, about 7.6, about 7.7, or about 7.8.

[0021] The disclosure also encompasses a kit comprising the injection device described herein. The kit can be multi-dose (or multi-use) or single use. The kit can also further comprise a guide for needle depth and / or angle insertion. Further, the kit can further comprise directions for use.

[0022] The disclosure also encompasses various methods of using the injection devices described herein. For example, the disclosure encompasses a method of prophylaxis against surgical site infection (SSI) comprising: (a) identifying a skin or mucosal surgical site of a subject; and (b) prior to a surgical incision, intradermally injecting into the subject’s dermis layer of the skin or mucosa at the surgical site a therapeutically effective microdose of at least one antimicrobial agent utilizing the injection device described herein.

[0023] In another embodiument, a surgical incision is made within about 12 hrs following the intradermal injection. Alternatively, a surgical incision is made within about 15 mins, about 2054938-1265-3208.2Attorney Docket No. : 145105-0109mins, about 30 mins, about 45 mins, about 60 mins, about 75 mins, about 90 mins, about 2 hrs, about 3 hrs, about 4 hrs, about 5 hrs, about 6 hrs, about 7 hrs, about 8 hrs, about 9 hrs, about 10 hrs, about 11, hrs or about 12 hrs following the intradermal injection.

[0024] This method can further comprise performing a surgical procedure after making the surgical incision.

[0025] In another aspect of the disclosure, described are methods of preventing, minimizing the risk of, and / or treating a microbial infection associated with a condition or procedure. The method comprises injecting into a subject at an appropriate site a therapeutically effective microdose of at least one antimicrobial agent utilizing the injection device described herein. The condition can be, for example, a skin or mucosal wound, a cutaneous infection, a lesion, a biofdm, surgical antibiotic prophylaxis (SAP) of pacemaker insertions, SAP for insertion of Cardiac Implantable Electronic Device (CIED), SAP of venous access catheters, SAP of ports for administration of oncology drugs, SAP of central line catheters, SAP of tracheotomy placement, SAP for chest tube placement, SAP for removal of a foreign body, Hidradenitis Supprativa, orthopedic trauma, soft tissue injuries, acute bacterial skin and skin structure infections (AB S SSI), Mycetomas, Eumycetoma, Actinomycetes infection, Mycobacterium ulcerans infection, Maduromycosis infection, Actinomycetoma, Pseudomonas infection, Gram Negative bacterial infection, Klebsiella infection, E. Coli infection, necrotizing faciatis, Hidradenitis Suppurativa (HS), or any combination thereof.

[0026] In one aspect of the methods of the disclosure, the site of injection is any dermal or cutaneous site. In another aspect, the site of injection is a wound, abscess, inflammatory nodule, intra-wound, intra-articular, mucosa, or any intradermal layer of the skin. In a further aspect, the injection does not comprise injection of the antimicrobial agent into a muscle tissue of the subject; and / or the injection does not comprise injection of the antimicrobial agent into a hypodermis layer of the skin of the subject. In one embodiment, the methods described herein comprise intradermally injecting the injection solution comprising the antimicrobial agent into a subject in need.

[0027] For all of the devices and methods described herein, the volume of the injection solution is about 1 to about 50 mb. In another aspect, the volume of the injection solution is less than or 64938-1265-3208.2Attorney Docket No. : 145105-0109equal to about 10 mL. Further, the volume of the injection solution administered per injection site can be about 0.1 to about 2.0 mL. In addition, the total volume of injection solution administered, via either a single or multiple injections, can be about <10 mL up to about 50 mL.

[0028] In another embodiment, the methods and injection devices described herein can be administered by medical personnel, non-medical personnel, a caregiver, a first responder, military personnel, self-administered, or any combination thereof.

[0029] In one embodiment of the methods described herein, the method is for use in preventing, minimizing the risk of, and / or treating a microbial infection of a skin or mucosal wound site of a subject. In another aspect, the method is used to treat a patient population having a soft tissue injury and at risk of a microbial infection due to a natural disaster. In a further aspect, the method is used to treat a patient population having a soft tissue injury due to active conflict.BRIEF DESCRIPTION OF THE DRAWINGS

[0030] FIG. 1 shows the three main layers of the skin: epidermis (10), dermis (12), and hypodermis (subcutaneous tissue) (14).

[0031] FIG. 2 shows the two sublayers of the dermis: from top —> bottom, the epidermis is followed by the papillary dermis (16), the reticular dermis (18), and the hypodermis / subcutaneous tissue - fatty layer containing (24). Also shown are capillary loops in the dermal papillae (22) and dermal papillae (20).

[0032] FIG. 3 shows various accessory skin structures, including hair papilla (30), eccrine (sudoriferous) sweat gland (32), sebaceous gland (34), sweat pore (36), hair shaft (38), arrector pili muscle (40), and blood vessels (artery and vein) (42).

[0033] FIG. 4 shows an example of how the invention could be implemented. Depicted is a needle shaft (50), skin surface (58), epidermis (52), dermis (54), hypodermis (56), muscle (66), and sites of injection administration (64), (60), (62).

[0034] FIGs. 5A and 5B show a diagram of a needle positioned in the intradermal layer of the skin (injection into the dermis). FIG. 5 A shows a diagram of a needle positioned in the intradermal layer of the skin as compared to a needle injecting into the muscle layer74938-1265-3208.2Attorney Docket No. : 145105-0109(intramuscular) or subcutaneous layers of the skin, as well as compared to a microneedle. The stratus corneum, epidermis, dermis, subcutaneous layer, and muscle layer are depicted. FIG. 5B shows an intradermal injection site, with the epiderms, dermis, and subcutaneous layer depicted.

[0035] FIGs. 6A and B show a diagram of intradermal injection, with a needed administered at an angle to insert the at least one antibiotic to a surgical site (FIG. 6A), and an exemplary needle angle of 15° shown in FIG. 6B.

[0036] FIG. 7 shows percentages and numbers of patients (n=99) with positive or negative cultures before disinfection (swab 1), after disinfection (swab 2) and after cutting the skin (swab 3). Dark dots represent micro-organisms. Guarch-Perez et al., J. of Hospital Infection, / 0(2023):62-71. FIG. 7 also shows the number of patients with negative or positive cultures of the knife after cutting the skin (skin knife), and of the second knife after cutting the deeper tissue layers (deep-tissue knife).

[0037] FIG. 8 depicts an exemplary injection kit for use in the methods described herein, comprising a sterile vial of at least one antibiotic, an adapter device, a syringe, and a 2.5 mm needle for intradermal delivery.

[0038] FIGs. 9A, B, and C show intradermal injection at a surgical site prior to an incision. FIG. 9 A shows the first injection, FIG. 9B shows a second injection, and FIG. 9C depicts the short hollow hypodermic needle shaft length of 4 mm.

[0039] FIGs. 10A and 10B show an exemplary injection device design according to the invention. FIG. 10A details the challenge of overcoming dermal resistance (dermis requires 65% more injection force, with about 34 Newtons of force needed, which approaches the upper limit of manual injection capability). The optimized system design of the present invention comprises a nanoneeded for precise depth control (e.g., in one embodiment, about 4 mm). This short needle length physically prevents “overshoot” of injection into deeper tissue layers. The injection device also comprises a syring, such as a 3 mL syringe, which provides hydraulic leverage. The small diameter reduces the manual force required for injection. Finally, in one aspect, a prefilled syringe enhances safety and accuracy. Aseptic prefilling minimizes contamination risk and ensure consistent, accurate dosing. FIG. 10B details different elements that can comprise a successful injection device, including an angle of injection that ensures correct bevel placement 84938-1265-3208.2Attorney Docket No. : 145105-0109to build hydrostatic pressure, a suitable syringe (e.g., 3mL) that provides mechanical advantage to overcome high resistance, a suitable needle length (e.g., 4mm), which precisely targets the dermal layer and prevents overshoot, and a preferably thin-wall needle, which reduces fluid dynamic resistance for a smoother injection.

[0040] FIG. 11 details the “intradermal paradox” regarding intradermal injection. Unlike loose fatty tissue, the dermis actively resists fluid expansion, creating substantial back-pressure that acts as a hydraulic “brake” on injection flow. Subcutaneous fat tissue is porous, with low injection resistance, and thus high compliance loose fatty tissue. In contrast, the dermis is a dense collagen matrix, with non-compliant injection features.

[0041] FIG. 12 details a quantification of resistance for intradermal (ID) injection as compared to subcutanoue (SC) delivery. The required plunging force (in Newtons) is compared between ID (34.2N) and SC (20.7N) delivery, showing that there is a 65% increase in required force for ID injection. The force differential is the primary cause of injection variability, risk of “overshoot” (depth error), and operator tremor.

[0042] FIG. 13 graphs the “Cilurzo Injectability Framework,” with Force (Newtons) on the Y axis and Time / Displacement on the X axis. First, the “Break-Loose Force (PBF), which is the peak force required to overcome static friction, occurs. Next, the “Maximum Force (Fmax), which is the peak resistance influenced by tissue back-pressure, occurs. Finally, the Dynamic Glide Force (DGF), which is the sustained effort causing operator fatigue, occurs. DGF is the sustained mechanical “enemy” of the operator, which is an engineering goal to minimize.

[0043] FIGs. 14A and 14B detail optimization level 1, which is the syringe geometry.Hydraulic advantage is exponential. This is due to the mathematical law where F = P x A, with force increasing exponentially with barrel diameter. Thus, reducing barrel diameter provides significant mechanical advantage against dermal back-pressure. Syringes > 5mL cross the > 35 N failure threshold. Shown in FIG. 14A is a ImL (6.3mm ID) syringe, which requires lx the work of a 3 mL (10mm ID) syringe, requiring 3x more work. Shown in FIG. 14B is a 3mL syringe and a 6mL syringe, where a 6mL syringe requires approximately 3 times more work to operate than a 3mL syringe against the same resistance. This is because a smaller syringe barrel94938-1265-3208.2Attorney Docket No. : 145105-0109diameter acts as a more effective force multiplier, providing a critical mechanical advantage against high dermal back-pressure.

[0044] FIG. 15 details the rational for a syringe of about 3mL or less for intradermal delivery (Optimization Lever #1). In sum, achieving an optimal injection requires a syringe volume of 3mL or less to offset the dermal resistance that causes larger syringes to fail. Two suitable syringes are depicted: a ImL syringe, having an inner diameter of 6.3mm, which provides maximum hydraulic leverage against demal back-pressure. A second syringe of 3 mL is shown, with an inner diameter of 10.0 mm. The upper limit for manageable intradermal therapy is preferably about 3 mL for a syringe. This size syringe requires optimization of other variables to prevent clinicial fatigue.

[0045] FIG. 16 details the rational for choosing a needle lumen size (e.g., “the thin-wall paradox” (Optimization Lever #2). The Newtons involved in the glide force decrease exponentially with a wider internal needle daimter. A standard needle lumen size is 30G, where a thin-wall needle lumen (with an internal diameter of effectively 27G), creates exponential flow improvement without increasing external pain.

[0046] FIGs. 17A and B detail an exemplary injection device design according to the present invention. FIG. 17A depicts an injection device comprising a flange, plunger rod, syringe barrel, graduation marks, and a luer lock tip. FIG. 17B depicts a needle hub, nanoneedle (30G, 4 mm), with a bevel tip, and a protective cap. The 30G needle minimizes trauma at the injection site, and the needle preferably has a “thin-wall” widened lumen. A Luer Lock connection prevents leakage under extreme dermal back-pressure. This unique geometry fundamentally alters biomechanics, bypassing flow resistance within the dense dermal lattice.

[0047] FIG. 18 details exemplary needle length and drag (Optimization Lever #3). According to the Bernoulli Principle, resistance is proportional to length. An exemplary 4 mm needle mathematically reduces DGF friction and mechanically prevents the operator from overshooting the 1-2 mm dermal depth. Shown is the dermal layer, comprising the triple layer of epidermis, dermis, and subcutaneous fat. An exemplary 4 mm needle has low drag and precisely targets the intradermal target injection site. In contrast, a conventional 13 mm needle size has high drag, with a significant risk of overshooting the intradermal injection target site.104938-1265-3208.2Attorney Docket No. : 145105-0109

[0048] FIG. 19 details the engineering rational behind thin-wall needle technology. A standard needle wall has a very narrow internal bore size, whereas a thin wall needle has a large internal diameter. For example, a thin-wall 30G needle can have an internal bore equivalent to a standard 27G needle, combining patient comfort with superior flow.

[0049] FIG. 20 summarizes the “best engineering practices” of an intradermal injection device described herein. The engineering design comprises (1) geometry of a 3mL or less syringe, and in particular avoiding a syringe which is about 5 mb or greater in size, to maintain a hydraulic advantage, (2) utilize a lumen having a “thin-wall” to leverage Poiseuille’s law, and (3) needle length: utilize a suitable needle length targeting intradermal delivery, such as about 4 mm, which reduces Bernoulli drag and prevents overshoot of the intradermal injection target site.

[0050] FIG. 21 details the morphological spectrum of HS lesions, starting from inflammatory nodules (acute, localized occlusion of the apocrine-follucular unit), next abscesses (rupture of the follicle spilling keratin, sebum, and bacteria into the dermis), then fistulas (epithelialized subdermal tunnels connecting abscesses), then draining fistulas (tunnels breaching the epidermis, actively discharging purulent fluid), then scarring (fibrotic tissue replacing normal architecture following chronic inflammation), and finally chronic granulomatous lesions (extensive, erreparable tissue damage with persistent deep-seated infection).

[0051] FIG. 22 details the surface phenotype of chronic granulomatous and fistulizing disease, including chronic granulomatous tissue (widespread inflammatory infiltration and irreparable tissue damage), draining fistulas (punctate surface openins linked to massive subdermal sinus networks), and fibrotic scarring (architectural distortion from decades of unmitigated recurrent abscesses).

[0052] FIG. 23 shows a macroscopic view of a recalcitrant draining fistula. Draining fistulas and chronic granulomatous lesions represent the end-stage architecture failure of the skin in HS. These permanent cutaneous breaches act as continuous sources of purulent discharge and systemic inflammation, heavily colonized by multidrug-tolerant microbial communities.

[0053] FIG. 24 shows the architecture of the sinus tract, with epidermal breach (small surface opening (the visible fistula)), anechoic fluid collection (purulent exudate pooling within the cavity), and epithelialized tract (the hardened, fibrotic wall of the subdermal tunnel preventing 114938-1265-3208.2Attorney Docket No. : 145105-0109natural wound closure). Ultrasound reveals that seemingly isolated surface lesions are frequently connected by vast subdermal sinus tracts, serving as protected reservoirs for chronic polymicrobial infection.

[0054] FIG. 25 details the mechanism of recalcitrance of sinus tract biofdms. Biofilms are present in 67% of chronic HS lesions, and 63% of large biofilm aggregates (>50pm) are situated directly within these tunnels. The microbial profile shifts from commensal flora to aggressive strict anaerobes (Prevotella, Porphyromonas) and Gram-negative rods as disease severity progresses.

[0055] FIG. 26 shows fibrotic ischemia (dense scarring around chronic lesions severely restricting blood flow, limiting systemic drug delivery), Metabolic Dormancy (bacteria at the core of the biofilm enter a dormant state, rendering antibiotics that target cell-wall synthesis ineffective), and The EPS Barrier (Extracellular Polymeric Substances physically repels circulating antimicrobial molecules).

[0056] FIG. 27 details exemplary intralesional injection utilizing an injection device described herein. The direct, localized administration of an antimicrobial agent into the inflammatory nodule, abscess, or sinus tract is a mechanical countermeasure to problems encountered with system administration of drugs and biofilm resistance to treatment. The mechanical countermeasure, utilizing antimicrobial administration into a lesion, (1) bybasses systemic circulation, thereby eliminating the dependency on compromised local vascular networks, (2) pierces the EPS shield, as the mechanical force of injection disrupts the biofilm architecture, and (3) local concentration overwhelms bacterial tolerance mechanisms with an ultra-high localized payload without systemic toxicity.

[0057] FIG. 28 details an exemplary flow chart for selection of a suitable antibiotic for intralesional injection utilizing an injection device described herein. Step 1: Culture & Sensitivity Testing (obtain aspirate form deep lesion / sinus tract), Step 2: Identify Pathogen Profile as either Gram-Positive / Aerobe Dominance or Gram-Negative & Anaerobe Dominance. For Gram-Positive, Option 3 could entail Clindamycin administration (lincosamide for targeted Gram-positive and specific anaerobic coverage). For Gram-Negative, Option 1: Ertapenan124938-1265-3208.2Attorney Docket No. : 145105-0109(broad-spectrum carbapenem for severe, mixed infectipons, and Option 2: Amikacin or Gentamicin (aminoglycosides for robus Gram-negative coverage).

[0058] FIG. 29 depicts the targeted, direct intralesional antimicrobial delivery targeting a biofdm barrier, using an injection device described herein, as compared to systemic IV / oral antimicrobial delivery. Systemic IV / oral antimicrobial delivery results in low local antimicrobial concentration, with the EPS matric intact, along with high system antimicrobial exposure. In contrast, direct intralesional delivery results in supraphysiologic local antimicrobial concentration, EPS matrix bypassed, with zero systemic wash-out.

[0059] FIG. 30 shows a diagram of a intra-lesional target site for injection, located within the dermis. The epidermis, dermis, and fibrotic tissue with high density layers of the skin are depicted, along with a complex, biofilm-laden sinus tract system.

[0060] FIG. 31 depicts a direct intralesional injection utilizing an injection device described herein. Recalcitrant HS lesions (nodules, abscesses, fistulas, and granulomas) can be effectively treated with direct intralesional injection of targeted antibiotics. This highly targeted delivery method bypasses the limitations of systemic circulation and poor local vascularity, placing the antimicrobial agent directly into the isolated dermal reservoir.

[0061] FIG. 32 details the structural failure of systemic antimicrobial therapy in treating biofilms. Chronic wounds and fibrotic tunnels suffer from poor vascular perfusion. Systemic antibiotics (oral / IV) simply cannot physically reach the infection site in sufficient quantities. Eradicating sessile biofilm bacteria requires concentrations 100 to 1000 times higher than planktonic bacteria. Achieving this via systemic delivery would result in lethal host toxicity.

[0062] DETAILED DECSCRIPTION OF THE INVENTION

[0063] In one aspect, the present invention is directed to an injection device comprising a syringe specifically designed for intradermal injection, where the device is optionally prefilled with an antimicrobial injection solution. The specific injection device design comprises a specified needle length and gauge and syringe, as detailed herein. The injection solution comprises at least one antibiotic or antimicrobial drug or agent and at least one diluent.134938-1265-3208.2Attorney Docket No. : 145105-0109

[0064] The present injection device and methods and kits utizing the same address a critical problem in the current health care system. Microbial infections of a wound in a subject’s skin or mucosa contribute to significant health care costs and a subject’s recovery. In addition, Surgical site infections (SSIs) are infections that occur at or around the surgical site within 30 days of operation or within 1 year among those with implants, which accounts for 20% of all Hospital- acquired infections (HAIs), with a pooled prevalence of 2.5-41.9% worldwide. Birhanu et al., Ann. Med. Surg. (Land)., 83.A04324 (Aug. 2022). SSIs are the most common type of healthcare- associated infection following surgery, and increase hospital readmission rate by a factor of five and double mortality rates. Andersson et al., Scand. J. Surg., 2021 Mar; 110(1): 110-112. The 30- day crude incidence of SSI is 11% and varies by anatomical site, duration of surgery and global geography. SSI often occur after discharge, underestimating the true prevalence. SSIs can lead to increased morbidity, mortality, longer hospital stays, and higher healthcare costs. In addition, shock, low haemoglobin level, blood transfusion, previous surgery, and longer length of hospital stay were significantly related to surgical site infections. SSIs can significantly impact a patient's quality of life and cause anxiety.

[0065] Intradermal delivery requires the use of short hollow hypodermic needles to successfully deliver at least one antimicrobial agent to the dermis of the skin. The short hollow hypodermic needles used in the methods of the disclosure are shorter than microneedles or standard hypodermic needles. The successful application of intradermal delivery of at least one antimicrobial agent was surprising as at least as of November 2024, “ [t]he understanding of drug penetration through different skin layers, its absorption into blood capillaries or lymphatics, and dermal metabolism remains limited.” Koenitz et al., Eur. J. of Pharmaceutics and Biopharmaceutics, 204'.114517 (Nov. 2024).

[0066] Intradermal microdosing of antimicrobial agents addresses the challenge of preventing wound and / or surgical site infections by delivering an effective antimicrobial dose directly to the operative field. This approach obviates the need for oral or intravenous administration of antimicrobial agents. In cutaneous surgery, intradermal antimicrobial agent delivery can enhance antimicrobial stewardship by minimizing systemic exposure and associated risks, while optimizing local infection prophylaxis. This method achieves a higher antimicrobial agent concentration within the dermal interstitial space — up to 20-fold greater than tissue levels 144938-1265-3208.2Attorney Docket No. : 145105-0109attained via oral administration. Consequently, the concern regarding suboptimal systemic penetration into the surgical site, well -documented for both oral and intravenous routes, becomes irrelevant.

[0067] This strategy offers several advantages, including rapid and targeted drug delivery to a surgical site at the critical pre-incision interval often described as “the golden hour” in the surgical literature. The intradermal delivery route reduces systemic antibiotic selection pressure, as serum and plasma concentrations remain minimal. In addition, this route diminishes the risk of systemic toxicities. The method is straightforward to implement and scalable for high-volume treatment centers. Further, in outpatient surgical settings utilizing intravenous prophylaxis, intradermal delivery has the potential to reduce overall administration costs.

[0068] Delivering a precise, accurate, micro-dosed concentration of an antimicrobial agent is not achievable in a clinical setting with standard available equipment and supplies. This is because reaching the minimal antibiotic concentration with standard dilution techniques is impossible; the instrumentation lacks adequate sensitivity and would require additional resources and training. Compounding and dilutions are so small that they cannot be reliably estimated. Thus, one aspect of the present disclosure is the recognition that a microdose amount of an antimicrobial agent, precisely administered using a microneedle can effectively prevent, minimize and / or treat SSIs. Additionally, only a small syringe can be used for dermal injections. Larger syringes require too much force (LA Plank’s Law) and cannot effectively deliver the active ingredients into the skin’s dermal layer. Syringes with a capacity of 5 mL or more require excessive plunger force to push the solution through a 30-gauge needle, making them unsuitable for intradermal use.

[0069] Intradermal delivery presents unique mechanical challenges that are distinct from subcutaneous or intramuscular injection. The dermis is a dense, non-compliant tissue compartment composed of an interwoven collagen and elastin matrix with low permeability and limited capacity to expand. The dermis is not a passive recipient. Its dense collagen matrix creates significant physical resistance to injection. As a result, the dermal layer exhibits substantial back-pressure to injected fluid. The operator must overcome this biological resistance to form a dermal “wheal” or depot and reliably place a microdosed antimicrobial solution into154938-1265-3208.2Attorney Docket No. : 145105-0109the dermal interstitial space. The formation of a distinct wheal, or bleb, confirms deposition of the microbial agent into the interstitial dermal space.

[0070] In another aspect of the disclosure, the injection device is useful in targeted eradicatin of biofilm microbial infections, as well as targeted intralesional antimicrobial injections.

[0071] From an engineering standpoint, “injectability” can be deconstructed into several force components acting on the syringe plunger. These can include: (1) the plunger-stopper break-loose force, which is the initial static friction that must be overcome to initiate plunger motion; (2) the maximum force encountered during injection, which is influenced by tissue back-pressure and formulation viscosity; and (3) the dynamic glide force, which is the sustained force required to maintain plunger movement at a relatively constant injection rate. Micheels et al., Quantifying Depth of Injection of Hyaluronic Acid in the Dermis: Data from Clinical, Laboratory, and Ultrasound Settings,” J. of Drugs in Dermatology, 15(4):483-490 (2016).Excessive break-loose or glide forces can cause a “jerk” in plunger movement, loss of fine motor control, and substantial operator fatigue, all of which can compromise accurate dermal placement and increase the risk of overshooting into subcutaneous tissue.

[0072] Empirical work in porcine models, which provide a close mechanical analogue to human skin, demonstrates that the average plunger force required for intradermal injections can be approximately 34 N, compared to about 21 N for subcutaneous injections. Thus, intradermal injection typically requires on the order of 60-70% more force than subcutaneous delivery. The highly structured dermis resists expansion, creating substantial back-pressure that must be overcome by the injection system. This higher resistance is a principal cause of user fatigue and contributes to “subcutaneous failure,” in which the operator applies additional force to overcome dermal back-pressure and inadvertently drives the needle tip beyond the dermis into the subcutaneous fat layer. This problem is exacerbated when larger-diameter syringes and narrow-lumen needles are used.

[0073] The relationship between syringe barrel diameter and required plunger force can be described by the hydraulic relationship F = P A, where F is the applied force, P is the pressure, and A is the cross-sectional area of the plunger. Because the area scales with the square of the diameter, small increases in barrel diameter can lead to disproportionate increases in the force 164938-1265-3208.2Attorney Docket No. : 145105-0109required to achieve the same injection pressure. A 1 mL syringe with an inner diameter of approximately 6.3 mm provides a mechanical advantage relative to a 3 mL syringe with an inner diameter of approximately 10.0 mm. To generate the same injection pressure in tissue, the 3 mL syringe may require approximately three times more plunger force than the 1 mL syringe.Syringes of 5 mL capacity or greater exhibit even larger required forces and routinely exceed the comfortable manual force range for intradermal injections, particularly when combined with fine-gauge needles. Thus, a smaller syringe barrel diameter acts as a more effective force multiplier, providing a critical mechanical advantage against high dermal back-pressure. In particular, a 6mL syringe requires approximately three times more work to operate than a 3mL syringe against the same resistance.

[0074] This is also explained by LaPlace’s Law and the Bernoulli Principle, which describe an inverse relationship between pressure and force. Although a 1 mL syringe allows easy delivery, most procedures need more than 1 mL to cover the typical cutaneous surgical field. Therefore, a 3 mL single-use syringe provides a between the volume requirements and ease of injection. A 1ml syringe will be adequate in surgeries involving limited surface areas.

[0075] An innovative feature of the present disclosure is the use of a short needle explicitly designed for dermal delivery (e.g., in one aspect the microneedle is a 30 or 32-gauge needle, only about 3- about 4 mm long), ensuring that the antimicrobial agent is deposited in the correct skin layer. The resistance to fluid flow through the needle itself is also governed by Poiseuille’s law, which indicates that resistance is inversely proportional to the fourth power of the internal radius of the needle lumen and directly proportional to the needle length. Consequently, even small increases in lumen radius result in exponential decreases in flow resistance, whereas shortening the needle length reduces frictional drag along the inner cannula. The nanoneedle design described herein may utilize a thin-wall 30-gauge outer diameter while providing an inner lumen corresponding approximately to a 27-gauge needle. This configuration significantly reduces flow resistance compared to a conventional 30-gauge needle (with a narrower inner lumen), while preserving a small outer diameter to minimize insertion pain.

[0076] For example, FIG. 19 details the engineering rational behind thin-wall needle technology. A standard needle wall has a very narrow internal bore size, whereas a thin wall174938-1265-3208.2Attorney Docket No. : 145105-0109needle has a large internal diameter. Thin-wall needle technology drastically reduces the force required to push fluid (Glide Force) by increasing the internal lumen without changing the patient-friendly outer gauge. For example, a thin-wall 30G needle can have an internal bore equivalent to a standard 27G needle, combining patient comfort with superior flow. Flow resistance is inversely proportional to the radius to the fourth power. A small increase in the internal lumen creates a significant reduction in the force required for injection.

[0077] In another aspect, the needle utilized in the injection device described herein has a thin- wall lumen size as compared to the lumen size of a standard needle. The lumen of a needle refers to the hollow bore that runs the length of the needle, which is crucial for allowing fluids to pass through. The size of the lumen is determined by the needle's inner diameter. For example, for a 30G needle, a thin wall needle can have an internal size of 27G. In other embodiments, the inner wall (e.g., 27G) can have a width which is about 90% of the external diameter of the needle (e.g., 30G). In yet another aspect, the inner wall can have a width which is about 80%, about 75%, about 70%, about 65%, about 60%, about 55%, about 50%, about 45%, or about 40% of the external diameter of the needle. Thus, the needle configuration may include an outer lumen size different from the inner lumen size. The inner lumen may be engineered to be larger than the standard lumen for that gauge needle. This will allow for a reduction in glide force.

[0078] Ultimately, the device, kits and methods of the disclosure offer a solution to a newly identified source of surgical site infections, specifically the dermal layer of the skin, where bacteria can cause such infections. These bacteria are not eradicated by routine surgical scrubbing. The mechanism of action for the microdosed dermal delivery of antimicrobial agent is placement into the dermis, where bacteria that can cause surgical site infections reside.

[0079] Furthermore, the technique of needle retraction should overcome the primary resistance to fluid flow during intradermal injections. A slight retraction of the needle will allow a transient increase in the fluid flow and more deposition of the at least one antibiotic. An optimal combination of needle length, gauge, and injection angle facilitate the method of the disclosure.

[0080] As detailed in FIG. 6A and 6B, the angle of needle insertion can correctly position the needle’s bevel within the dense dermal tissue. A shallow angle of insertion, e.g., about 15°, correctly positions the needle’s bevel at the target injection site. This orientation maximizes the184938-1265-3208.2Attorney Docket No. : 145105-0109hydrostatic pressure created by the injected flue, forcing the tissue to expand upwards and form a distinct wheal. It ensures the fluid permeates the target tissue rather than leaking into deeper layers.

[0081] Further, reconstituting an antibiotic is problematic in the following scenarios: 1) military combat, 2) catastrophic events, 3) daily emergency department challenges, and 4) austere environments. The preparation and administration of antibiotics are characterized by slow preparation times, inefficiency, high costs, and the need for specialized equipment and trained personnel. Reconstituting an antibiotic for intramuscular use is an inconvenience that untrained personnel have difficulty in performing effectively. Delivering antibiotics via intravenous methods requires pharmacy services, additional equipment, and trained staff.Developing a prefilled, microdosed antimicrobial agent concentration in a disposable plastic syringe could be a major breakthrough for military use, austere environments, emergency departments, and routine surgical antibiotic prophylaxis.Injection Device Design

[0082] Targeting of drug delivery to the dermis requires a short needle, as longer needles increase the risk of going too deep into the subcutaneous tissue, which is not the target area for prophylactic antibiotic placement. Since bacterial reservoirs are in the dermis, delivering the injection outside this layer may reduce effectiveness. The injection device design for targete intradermal delivery comprises a specified needle length, gauge, syringe, and injection volume present in the syringe.

[0083] Intradermal Needle. In one aspect of the disclosure, an intradermal needle is attached to a syringe for performing intradermal injection of the antibiotic drug. The dermal layer in most body regions has a thickness on the order of 2-6 mm, and the target dermal interstitial space is typically located within 1-2 mm beneath the epidermal-dermal junction. The shaft of the intradermal needle may be very thin and short. In some embodiments, the shaft of the intradermal needle has a length of about 2 to about 15 mm and a diameter or gauge of about 24 to about 35 gauge. In other aspects, the needle gauge is about 2 to about 32. In other aspects of the disclosure, a short hollow hypodermic needle having a shaft of about 3 to about 4 mm in length is utilized to target administration to the dermis of a subject’s skin or mucosa. High 194938-1265-3208.2Attorney Docket No. : 145105-0109frequency ultrasound imaging confirms this shaft length, e.g., about 4 mm, or a range of about 2 to about 15 mm, as optimal, and no previous studies report delivering an intradermal antimicrobial agent with a 4 mm needle.

[0084] The needle shaft is the central, hollow body of the needle, but it is not the entire length of the needle. The total length of a needle is measured from the point where the hub meets the shaft up to the tip of the needle. The hub is the base of the needle that connects to the syringe, and may have a color-coded gauge indicator. The length measurement starts at the point where the hub meets the shaft. The measurement ends at the very tip of the needle, which is the beveled point. The shaft itself is the portion between the hub and the bevel. It is the hollow, cylindrical part that carries the lumen (inner channel) for fluid flow.

[0085] One particular needle that can be used in the device, kits and methods of the disclosure is the JBP Nanoneedle having ultrathin walls that permits a wider inner diameter. This is a 4 mm length, 30 gauge needle having an outer diameter of 0.30 mm. This is the standard outer diameter for a 30-gauge needle. The JBP Nanoneedle has a relatively wide inner diameter of 0.20 mm. This is wider as compared to the 0.15 mm inner diameter of conventional 30 gauge needles. This wider inner diameter combined with the 30 gauge needle size aids in smoother and more efficient drug delivery. The advantage of this thin 30-gauge needle is that it causes less patient discomfort, while also allowing more of the drug to be delivered through the wider inner diameter, which is essential in delivering an antibiotic drug. Without this ultrathin wall technology, a larger needle gauge would be required to deliver the same amount of drug (which would cause more patient discomfort).

[0086] From a fluid dynamics perspective, the thin-wall nanoneedle design offers a critical advantage. By increasing the internal radius of the lumen while maintaining a small outer diameter, the hydraulic resistance to flow can be markedly reduced according to Poiseuille’s law, which states that resistance is inversely proportional to the fourth power of the radius. Thus, a small increment in lumen diameter from about 0.15 mm (conventional 30-gauge) to about 0.20 mm (thin-wall 30-gauge) produces a disproportionately large decrease in flow resistance. The shorter shaft length (for example, about 4 mm) further reduces frictional drag along the cannula and decreases the distance through which the fluid must travel before reaching the dermal204938-1265-3208.2Attorney Docket No. : 145105-0109interstitial space. Together with the selected syringe size, this nanoneedle configuration contributes to a substantial reduction in plunger force and can enhance fine motor control during intradermal injection.

[0087] In another aspect, a suitable syringe can be paired with an injection needle having a hole located on the needle barrel about 1 - about 2 mm from the tip, resulting in targeting delivery to the intradermal space. In a further aspect, a suitable syringe can be paired with a needle having a solid tip with one or more holes bored into the barrel enabling targeting of drug delivery to the intradermal space.

[0088] The chosen needle gauge must enable efficient infiltration of the dermal layer without excessive resistance or damage to the dermal structure. It should also reduce patient discomfort while allowing a manageable plunger force for the operator. Larger needles tend to cause more discomfort to patients. Using larger syringes with fine-gauge needles (e.g., 30G) requires significant plunger pressure, making intradermal delivery more difficult. An exemplary protocol employs a 30 or 32-gauge needle with a 3 mL syringe to balance patient comfort and operator control. Specifically, an exemplary short hollow hypodermic needle design, which has an outer diameter similar to a 30G needle but an inner lumen equivalent to a 27G, offers less resistance and less discomfort, while also optimizing the injectable volume required.

[0089] In one aspect of the disclosure, the use of a suitable short hollow hypodermic needle length allows for targeted placement within the intradermal space and maximizes the amount of antimicrobial agent solution to be injected while utilizing a retraction technique described herein. See FIGs. 5 A and 5B. In one aspect of a method of the disclosure, at least one antimicrobial agent is administered intradermally (1) to a surgical site prior to, during, or after surgery, or (2) to a wound site of a subject’s skin or mucosa.

[0090] The observation of a suitable length for a short hollow hypodermic needle remaining in the dermis after partial withdrawal of the needle has not been previously reported in the literature.

[0091] Prior publications teach the exact width of the dermis in male and female subjects, which can be useful in selecting suitable needle lengths for targeting drug delivery to the dermis. Oltulu et al., Turkish J of Plastic Surgery, 2018;26:56-61, which reports that the mean epidermal 214938-1265-3208.2Attorney Docket No. : 145105-0109thickness of skin samples from six major body regions of 90 males and 90 females ranged from 76.9 ± 26.2 to 267.4 ± 120.6 pm. The thickest epidermis was found in the dorsum of foot in women (267.4 ± 120.6 pm) while the thinnest was found in the breast in women (76.9 ± 26.2 pm). The mean dermal thickness ranged from 2115 ± 946.4 to 5888 ± 2422.3 pm. The thickest dermis was found in the breast in men (5888 ± 2422.3 pm), while the thinnest dermis was found in the dorsum of hand in women (2115 ± 946.4 pm).

[0092] Syringe. In one aspect of the disclosure the volume of injection solution in the syringe may be < about 15 ml, < about 10 ml, or < about 5 ml. To define a lower limit, the volume of the injection solution in the syringe could be > 1.0 ml, > 0.5 ml, or > 0.1 ml,. In some embodiments, the volume of the injection solution in the syringe is about 0.1 to about 10 ml, about 2 to about 8 ml, about 1 ml to about 5 ml, about 0.1 ml to about 3 ml, or about 1 ml to about 3ml. The antibiotic drug may be light sensitive and vulnerable to degradation when exposed to UV light. As such, the syringe used in this invention could be designed for lightsensitive drugs. In particular, the syringe may be darkened to avoid light exposure to the antibiotic drug. One particular example is called an “amber syringe” because it is made with amber-colored plastic, which effectively filters out harmful UV light, thereby protecting the antibiotic drug from degradation caused by light exposure.

[0093] An exemplary syringe that can be utilized with an appropriate needle is the BD 3 ml luer-lok (SKU 309577), but any suitable syringe can be utilized in the methods of the disclosure.

[0094] The plunger force is proportional to the cross-sectional area of the syringe barrel. A 3 mL syringe with a larger inner diameter requires substantially more operator force to achieve the same dermal injection pressure than a 1 mL syringe, and a 5 mL syringe requires still greater force, often exceeding the range that permits steady, controlled plunger motion. For example, the injection device can comprise a syringe comprising an injection solution present in the syringe at a volume of <10 ml, and further wherein the injection solution comprises at least one diluent and at least one antimicrobial or antibiotic agent or drug at a microdose concentration. The syringe can comprise an intradermal needle comprising a needle shaft, wherein the needle shaft has a length of about 2 to about 15 mm and a diameter of about 2 to about 35 gauge. In other aspects,224938-1265-3208.2Attorney Docket No. : 145105-0109the needle gauge has a diameter of about 2 to about 32. Any suitable antimicrobial agent can be used in the devices and methods of the disclosure.

[0095] Angle of needle insertion: The angle of needle insertion influences the depth and layer of deposition. Shallow angles (<10°) keep delivery within the dermis, while steeper angles (>20°) raise the risk of subcutaneous placement. Ultra-high-frequency ultrasound imaging confirmed that the optimal angle for reliable dermal delivery is about 10 degrees or less. To standardize assessment, custom 3D-printed insertion wedges precisely measuring 5°, 10°, 15°, 20°, and 30° were created. The needles were then aligned on the insertion wedges to determine the best angles while varying needle length. The studies confirm that a 10-degree angle is ideal for intradermal delivery with a 4mm needle, although other insertion angles are also effective, e.g., a range of from about 5° up to about 20°. Insertion wedges can also be utilized in the kits of the disclosure to function as needle guides for depth and angle of intradermal delivery.

[0096] A suitable needle injection angle can be from about 5° up to about 20°, or about 5°, about 6°, about 7°, about 8°, about 9°, about 10°, about 11°, about 12°, about 13°, about 14°, about 15°, about 16°, about 17°, about 18°, about 19°, or about 20°.

[0097] Suitable combinations of short hollow hypodermic needle length, needle diameter, and injection angle are useful for targeting drug delivery to the dermis. For example, utilizing a suitable short hollow hypodermic needle length, needle gauge, and a suitable injection angle, it is possible to direct the therapeutically effective microdose of at least one antimicrobial agent directly into the intradermal space. In particular, a suitable needle shaft length can be from about 2 mm to about 15 mm, or about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14 mm, or about 15 mm. A suitable needle gauge can be from about 24g up to about 35g, and can be for example, 24g, 25g, 26g, 27g, 28g, 29g, 30g, 31g, 32g, 33g, 34g, or 35g. In one aspect, the needle gauge is from about 30g to about 32- gauge in diameter.

[0098] In another aspect, an intradermal adapter (IDA) can be utilized, which provides the ideal angle and depth of needle insertion for consistently successful intradermal administration. I. Tsais, Vaccine, 35:1797-1801 (2017).Aspects of the Injection Composition234938-1265-3208.2Attorney Docket No. : 145105-0109

[0099] Diluent. A liquid diluent for the injection solution comprising the at least one antimicrobial agent is selected on the basis of various considerations such as drug compatibility, pH balancing, drug stability, drug solubility, intradermal tolerability, device compatibility, etc. Both aqueous and non-aqueous diluents can be utilized in the devices and methods of the disclosure. Examples of aqueous diluents that can be used include sterile water, bacteriostatic water (with 0.9% benzyl alcohol, 9 mg / ml), saline or normal saline (0.9% sodium chloride), 5% dextrose in water (D5W), lactated Ringer’s solution, etc. Examples of non-aqueous media suitable for intradermal injections include, but are not limited to, vegetable oils (e.g., sesame oil, cottonseed oil, peanut oil, castor oil (often modified, e.g., polyoxyethylated castor oil = Cremophor EL), and medium-chain triglycerides (MCT oil, e.g., Miglyol®)), Esters / Synthetic Oils (e.g., Ethyl oleate and Isopropyl myristate), Biocompatible Solvents / Co-solvents (e.g., Propylene glycol, Polyethylene glycol (PEG 300, PEG 400), Glycerin), and Other Specialized Vehicles, such as cyclodextrin inclusion complexes (improve solubility, sometimes in mixed aqueous / non-aqueous systems), squalene or squalane (used in vaccine adjuvant emulsions), and silicone oils. In some embodiments, the liquid diluent further comprises a buffering agent such as sodium bicarbonate.

[0100] pH. The pH of the injection solution comprising the at least one antimicrobial agent is selected on the basis of various considerations such as patient comfort (e.g. avoid burning sensation), minimizing precipitation, preventing drug degradation, enhancing drug solubility, etc. In some embodiments, the pH of the injection solution is in the range of about 7.0 up to about 7.8; and in some cases, about 7.4. In some embodiments, the pH of the injection solution is in the range of about 3.0 to about 7.5.

[0101] The pH of the injection solution comprising the at least one antimicrobial agent can be adjusted in any suitable manner. One example is using mild alkaline buffers (such as sodium phosphate, sodium citrate, Tromethamine (Tris buffer), etc.). Another example is using weak bases (such as sodium bicarbonate, Tromethamine (Tris buffer), sodium acetate, etc.). Another example is using pH adjusters in small increments (such as sodium hydroxide, potassium hydroxide, etc.). Another example is adding a co-solvent (such as ethanol, propylene glycol, PEG-400, etc.). Another example is using cyclodextrins (such as P-cyclodextrin, hydroxypropyl- P-cyclodextrin, etc.). Another example is using chelating agents (such as EDTA, citric acid, etc.),244938-1265-3208.2Attorney Docket No. : 145105-0109which prevent metal-ion-induced instability at higher pH levels. Another example is adjusting the ionic strength (such as using sodium chloride, mannitol, etc.).

[0102] Excipients. The injection solution may further comprise excipient ingredients for various purposes such as improving solution stability, improving drug physical and / or chemical stability, adjusting pH, avoiding precipitation, etc. Excipients can also provide for a long acting injectable formulation. Examples of excipient ingredients that can be added include water for injection (WFI), sodium chloride, buffering agents (e.g. sodium bicarbonate), preservatives (e.g. benzyl alcohol), chelating agents (e.g. disodium edetate), lactate, dextrose, nanoporous silicon dioxide, hydrochloric acid and / or sodium hydroxide (for pH adjustment), etc. Examples of drug delivery systems that may be employed regarding the intradermal injection formulation described herein include, for example, (1) for formulating sparingly soluble APIs, drug delivery systems such as nanomilling, polymeric micelles, nanoporous silicon dioxide carriers, etc. can be utilized; (2) to enhance the physical and / or chemical stability of an active pharmaceutical ingredient (API), drug delivery systems such as encapsulation in a polymeric matrix (such as PLGA or other biodegradable / bioerodible matrices) or nanoporous silicone dioxide carriers can be utilized; or (3) for long acting ingredients (LAIs), drug delivery systems such as encapsulation in a polymeric matrix (such as PLGA or other biodegradable / bioerodible matrices), nanoporous silicone dioxide carriers, and in situ depot formulations (such as PLGA solubilized in N-methyl pyrrolidone) can be utilized.

[0103] Antimicrobial Agents: Any pharmaceutically acceptable antimicrobial agent can be utilized in the injection devices, kits and methods of the disclosure. The at least one antimicrobial agent is present in an injectable composition, such as an aqueous, non-aqueous, or saline formulation. The at least one antimicrobial agent used in this invention can be effective against any of various types of microorganisms. As such, the antimicrobial agent can be an antibacterial, antiviral, antiparasitic, antifungal, etc.

[0104] Minimum Inhibitory Concentration as a Standard: The selection of an antimicrobial agent is based on the minimum inhibitory concentrations (MIC), and the total plasma concentrations of an antimicrobial agent are used to determine the MIC requirements. The unbound concentration of antibiotics at an infection site is a much better parameter. The MIC is a254938-1265-3208.2Attorney Docket No. : 145105-0109static measure, whereas in vivo antibiotic concentrations change over time. MIC is a timeaverage parameter that does not reflect bacterial adaptation or the selection of resistant mutants that may occur within a few hours of administration. This does not reflect a dynamic situation in a target organ such as the skin or mucosa. The development of antimicrobial resistance with surgical antibiotic prophylaxis has been documented in the literature. However, the development of antimicrobial resistance with intradermal administration has not been documented in the literature.

[0105] Examples of antimicrobial agents include but are not limited to amikacin, ceftaroline, ceftriaxone, cephalexin, cefdinir, cefuroxime, cefaclor, clindamycin, ciprofloxacin, ertapenem, nafcillin, ofloxacin, vancomycin, gentamicin, doxycycline, trimethoprim / sulfa, daptomycin,. In some embodiments, the antibacterial agent is a member of the cephalosporin class of antibacterial agents, such as cefaclor, cephalexin, ceftriaxone, cefazolin, cefoxitin, or cefuroxime).

[0106] Other exemplary antimicrobial agents, or antibiotics, that can be utilized in the injection devices, kits and methods of the invention include, but are not limited to, ertapenem (Invanz®), Quadrivalent Human Papillomavirus Vaccine (Merck), penicillins (e.g., amoxicillin), Augmentin (an amoxicillin / Clavulanic acid combination), Augmentin IV (intravenous), glycopeptides (e.g., Vancomycin), lipopeptides (e.g., daptomycin (Cubicin®)), oxazolidinones (e.g., linezolid (Zyvox®), tedizolid (Sivextro®)), cephalosporins (Ceftaroline (Teflaro®)), lipogly copeptides (Dalbavancin (Dalvance®), oritavancin (Orbactiv®)), lincosamides (e.g., clindamycin), sulfonamide combinations (e.g., Trimethoprim-sulfamethoxazole (TMP-SMX)), tetracycline derivatives (e.g., doxycycline, minocycline), glycylcyclines (e g., tigecycline (Tygacil®), fluoroquinolones (e.g., delafloxacin (Baxdela®)), Quinupristin-dalfopristin (Synercid®), Streptogramin, quinolones, fluroquinalones, delafloxacin (Delavega®), metronidazole and ciprofloxacin aminoglycosides, Ansamycins, Carbacephems, Carbapenems, Cephalosporins, Glycopeptides, Macrolides, Monobactams, Penicillins, Polypeptides, Polymyxin, Quinolones, Sulfonamides, Tetracyclines, and others (e.g., Arsphenamine, Chloramphenicol, Clindamycin, Lincomycin, Ethambutol, Fosfomycin, Fusidic acid, Furazolidone, Isoniazid, Linezolid, Metronidazole, Mupirocin, Nitrofurantoin, Platensimycin, Pyrazinamide, Quinupristin / Dalfopristin, Rifampicin (Rifampin in US), Thiamphenicol, Tinidazole, Dapsone,264938-1265-3208.2Attorney Docket No. : 145105-0109and lofazimine). Examples of these classes of antibiotics include, but are not limited to, Amikacin®, Kanamycin®, Neomycin®, Netilmicin®, Streptomycin®, Tobramycin®, Paromomycin®, Geldanamycin®, Herbimycin®, Loracarbef®, Ertapenem®, Doripenem®, Imipenem® / Cilastatin®, Meropenem®, Cefadroxil®, Cefazolin®, Cefalotin® or Cefalothin®, Cefalexin®, Cefaclor®, Cefamandole®, Cefoxitin®, Cefprozil®, Cefuroxime®, Cefixime®, Cefdinir®, Cefditoren®, Cefoperazone®, Cefotaxime®, Cefpodoxime®, Ceftazidime®, Ceftibuten®, Ceftizoxime®, Ceftriaxone®, Cefepime®, Ceftobiprole®, Teicoplanin®, Vancomycin®, Azithromycin®, Clarithromycin®, Dirithromycin®, Erythromycin®, Roxithromycin®, Troleandomycin®, Telithromycin®, Spectinomycin®, Aztreonam®, Amoxicillin®, Ampicillin®, Azlocillin®, Carbenicillin®, Cloxacillin®, Dicloxacillin®, Flucioxacillin®, Mezlocillin®, Meticillin®, Nafcillin®, Oxacillin®, Penicillin®, Piperacillin®, Ticarcillin®, Bacitracin®, Colistin®, Polymyxin® B, Ciprofloxacin®, Enoxacin®, Gatifloxacin®, Levofloxacin®, Lomefloxacin®, Moxifloxacin®, Norfloxacin®, Ofloxacin®, Trovafloxacin®, Grepafloxacin®, Sparfloxacin®, Temafloxacin®, Mafenide®, Sulfonamidochrysoidine® (archaic), Sulfacetamide®, Sulfadiazine®, Sulfamethizole®, Sulfanilimide® (archaic), Sulfasalazine®, Sulfisoxazole®, Trimethoprim®, rimethoprim-Sulfamethoxazole® (Co-trimoxazole) (TMP- SMX), Demeclocy cline®, Doxycycline®, Minocycline®, Oxytetracycline®, and Tetracycline.

[0107] Exemplary antiviral agents include, but are not limited to, Oseltamivir, Zanamivir, Peramivir, Baloxavir, Nucleoside / Nucleotide Reverse Transcriptase Inhibitors (NRTIs), Non- Nucleoside Reverse Transcriptase Inhibitors (NNRTIs), Integrase Strand Transfer Inhibitors (INSTIs), Protease inhibitors (Pls), entry / attachment / post-attachment inhibitors, capsid, direct- acting antiviral agents (DAAs) such as Elbasvir, Nucleoside analogues, interferons, nucleoside phosphonates, Acyclovir, Famciclovir, Ganciclovir, Foscamet, Cidofovir, Ribavirin, monoclonal antibodies, Imiquimod, Sinecatechins, Podofilox, Remdesivir, Paxlovid (nirmatrelvir + ritonavir), Molnupiravir, Tecovirimat, and any combination thereof.

[0108] Exemplary antiparasitic agents include, but are not limited to, (1) for Nematodes / Helminths: Albendazole, Mebendazole, Ivermectin, Pyrantel pamoate, Praziquantel, Triclabendazole, Moxidectin; (2) for Protozoa: Nitazoxanide, Pyrimethamine (w / leucovorin), Metronidazole, Tinidazole, Miltefosine, Fexinidazole; (3) for Trypanosomes: Melarsoprol, Eflornithine, Fexinidazole; (4) for Leishmania / Amoebae: Miltefosine.274938-1265-3208.2Attorney Docket No. : 145105-0109

[0109] Exemplary antifungal agents include, but are not limited to, Polyene Antifungals, such as Amphotericin B and Nystatin, (2) Azole Antifungals, such as Fluconazole, Itraconazole, Voriconazole, Posaconazole, Isavuconazonium, Clotrimazole, Econazole, Ketoconazole, Miconazole, Luliconazole, Butenafine, Oteseconazole (Vivjoa®), and Efinaconazole, (3) Echinocandins, such as Caspofungin, Micafungin, Anidulafungin, and Rezafungin (Rezzayo®), (4) Allylamines, such as Terbinafine and Naftifme, (5) Pyrimidine (Nucleic Acid) Analogs such as Flucytosine (5-FC), (6) Glucan Synthase (Novel) Inhibitors such as Ibrexafungerp (Brexafemme®), and any combination thereof.

[0110] In particular aspects of the disclosure, the antimicrobial agent is clindamycin, vancomycin, gentamicin, lincomycin, cefazolin, or any combination thereof.

[0111] Clindamycin. In some embodiments, the antibiotic drug is clindamycin. The clindamycin in the injection solution may be at any suitable dilute concentration for microdosing. In some embodiments, the concentration of clindamycin in the injection solution is < about 1.0 mg / ml. To define a lower limit, the concentration of clindamycin in the injection solution could be > about 0.01 mg / ml. In some embodiments, the concentration of clindamycin in the injection solution is about 200 to about 800 pg / ml; and in some cases, about 300 to about 600 pg / ml. These concentrations of clindamycin are substantially lower than the concentrations used in the prior art.

[0112] Vancomycin. In some embodiments, the antibiotic drug is vancomycin. The vancomycin in the injection solution may be at any suitable dilute concentration for microdosing. In some embodiments, the concentration of vancomycin in the injection solution is < about 1.0 mg / ml. To define a lower limit, the concentration of vancomycin in the injection solution could be > about 0.01 mg / ml. In some embodiments, the concentration of vancomycin in the injection solution is about 100 to about 600 pg / ml; and in some cases, about 200 to about 500 pg / ml. These concentrations of vancomycin are substantially lower than the concentrations used in the prior art.

[0113] Gentamicin. In some embodiments, the antibiotic drug is gentamicin. The gentamicin in the injection solution may be at any suitable dilute concentration for microdosing. In some embodiments, the concentration of gentamicin in the injection solution is < about 1.0 mg / ml. To284938-1265-3208.2Attorney Docket No. : 145105-0109define a lower limit, the concentration of gentamicin in the injection solution could be > about 0.01 mg / ml. In some embodiments, the concentration of gentamicin in the injection solution is about 200 to about 800 pg / ml; and in some cases, about 300 to about 600 pg / ml. These concentrations of gentamicin are substantially lower than the concentrations used in the prior art.

[0114] Lincomycin. In some embodiments, the antibiotic drug is lincomycin. The lincomycin in the injection solution may be at any suitable dilute concentration for microdosing. In some embodiments, the concentration of lincomycin in the injection solution is < about 1.0 mg / ml. To define a lower limit, the concentration of lincomycin in the injection solution could be > about 0.01 mg / ml. In some embodiments, the concentration of lincomycin in the injection solution is 100-800 pg / ml; in some cases, about 200 to about 700 pg / ml; and in some cases, about 300 to about 600 pg / ml. These concentrations of lincomycin are substantially lower than the concentrations used in the prior art.

[0115] Cefazolin. In some embodiments, the antibiotic drug is cefazolin. The cefazolin in the injection solution may be at any suitable dilute concentration for microdosing. In some embodiments, the concentration of cefazolin in the injection solution is < about 1.0 mg / ml. To define a lower limit, the concentration of cefazolin in the injection solution could be > about 0.01 mg / ml. In some embodiments, the concentration of cefazolin in the injection solution is about 200 to about 800 pg / ml; and in some cases, about 300 to about 600 pg / ml. These concentrations of cefazolin are substantially lower than the concentrations used in the prior art.

[0116] Amikacin. In some embodiments, the antibiotic drug is amikacin. The amikacin in the injection solution may be at any suitable dilute concentration for microdosing. In some embodiments, the concentration of amikacin in the injection solution is < about 1.0 mg / ml. To define a lower limit, the concentration of amikacin in the injection solution could be > about 0.01 mg / ml. In some embodiments, the concentration of amikacin in the injection solution is about 200 to about 800 pg / ml; and in some cases, about 300 to about 600 pg / ml. These concentrations of amikacin are substantially lower than the concentrations used in the prior art.

[0117] Ertapenem. In some embodiments, the antibiotic drug is ertapenem. The ertapenem in the injection solution may be at any suitable dilute concentration for microdosing. In some embodiments, the concentration of ertapenem in the injection solution is < about 1.0 mg / ml. To294938-1265-3208.2Attorney Docket No. : 145105-0109define a lower limit, the concentration of ertapenem in the injection solution could be > about 0.01 mg / ml. In some embodiments, the concentration of ertapenem in the injection solution is about 200 to about 800 pg / ml; and in some cases, about 300 to about 600 pg / ml. These concentrations of ertapenem are substantially lower than the concentrations used in the prior art.Microdose of Antimicrobial Agent

[0118] For intradermal injection of an antimicrobial agent, the standard FDA approved dosages for antimicrobial agents are not applicable, as intradermal injection only requires a microdose amount to obtain a therapeutically effective result. Specifically, the amount of antimicrobial agent given for intradermal injection should only be a small fraction of the standard amount delivered by different routes of administration. After oral intake, an antibiotic or antimicrobial agent must be absorbed through the gastrointestinal tract, go through first-pass hepatic metabolism, and reach a steady-state level in serum and plasma before diffusing into the dermal interstitial space. This pharmacokinetic process does not happen when a drug is injected directly into the dermis. There is no first-pass metabolism by the liver. Instead, a small dose can achieve high local concentrations of free, unbound antibiotic / antimicrobial agent at the targeted surgical site / wound site. The free unbound portion is the active portion of an antibiotic responsible for its effectiveness.

[0119] In particular, the antimicrobial agent can be at any therapeutically effective, suitable dilute concentration for microdosing. The term “microdose” follows the medical literature referencing any dosage form that is substantially less than the standard approved dosages. For example, in the case of clindamycin, the microdosing amount is over 100 times less than that of the intravenous or oral routes of administration. When administering an antimicrobial agent into the skin, the formulation should be optimized to maximize antimicrobial efficacy while minimizing both local tissue irritation and systemic antimicrobial serum levels.

[0120] Suitable therapeutically effective microdoses for intradermal antibiotics will vary depending upon the antimicrobial agent administered, but generally the concentration of the antimicrobial agent in the injection solution for intradermal delivery will range from > about 0.01 mg / ml up to about 10 mg / ml, from about > 0.01 mg / ml up to about < 5 mg / ml, from about > 0.01 mg / ml up to about < 2.5 mg / ml, and from about > 0.01 mg / ml up to about < 1.0 mg / ml.304938-1265-3208.2Attorney Docket No. : 145105-0109

[0121] The volume of the injectable composition for intradermal injection will typically range from about 1 ml up to about 20 ml (and any value in between these two numbers), about 2 mL, about 3 mL, about 4 mL, about 5 mL, about 6 mL, about 7 mL, about 8 mL, about 9 mL, about 10 mL, about 11 mL, about 12 mL, about 13 mL, about 14 mL, about 15 mL, about 16 mL, about 17 mL, about 18 mL, or about 19 mL. To define a lower limit, the volume of the injection solution in the syringe could be > 1.0 ml. In some embodiments, the volume of the injection solution in the syringe is about 2 up to about 8 ml.

[0122] In one aspect of the methods of the invention, the therapeutically effective antimicrobial dose given intradermally is less than the typical dose of the same antimicrobial agent given systemically or orally. In a further aspect, the antimicrobial concentration is above the MIC value for the antimicrobial agent.

[0123] Systemic delivery of antimicrobial agents can be correlated with adverse events. For example, clindamycin phosphate carries a boxed warning for Clostridioides difficile-associated diarrhea, which may range from mild illness to fatal colitis. Additional potential adverse effects include severe hypersensitivity reactions, nephrotoxicity, and gastrointestinal complications such as antibiotic-associated colitis. Microdosed intradermal injections substantially reduce or eliminate these risks.

[0124] In an exemplary aspect, the table below provides proposed dosing ranges for several exemplary antimicrobial agents that can be utilized in the intradermal delivery devices and methods of the disclosure.

[0125] In some embodiments, the antimicrobial agent is clindamycin. The clindamycin in the injection solution may be at any suitable dilute concentration for microdosing. For example, the concentration of clindamycin in the injection solution for intradermal delivery can be from > 0.01 mg / ml up to about 800 pg / mL (including any value in-between these two numbers), from > 0.01 mg / ml up to about < 1.0 mg / ml, about 200 to about 800 pg / ml, about 300 up to about 600 pg / ml, or about 100 pg / ml, about 200 pg / ml, about 300 pg / ml, about 400 pg / ml, about 500 pg / ml, about 600 pg / ml, about 700 pg / ml, or about 800 pg / ml. In some aspects of the disclosure, an optimal intradermal clindamycin phosphate concentration ranges from about 300 to about 600 pg / mL. At 500 pg / mL, intradermal delivery can achieve tissue concentrations estimated to be 29314938-1265-3208.2Attorney Docket No. : 145105-0109to 58 times higher than the steady-state serum levels obtained through standard systemic administration. These concentrations of clindamycin are substantially lower than the concentrations used in the prior art. Huether et al., Arch Dermatol. , 138: 1145-1148. (2002); Goh et al., JAMA Surgery, 755(7)1718-726 (Jul. 1, 2023). These concentrations of clindamycin are substantially lower than the concentrations used in the prior art.

[0126] Currently, there are no commercially available formulations of clindamycin phosphate at concentrations between about 300- about 600 pg / mL, nor are there any prefdled syringes specifically designed for intradermal injection. An example of a product according to the present disclosure is a stable solution of clindamycin phosphate at about 500 pg / mL, stored at room temperature, and packaged in a sterile, single-use, prefilled syringe for direct use (e.g., surgical use, self-administered, first responder use, etc.). Clindamycin phosphate is widely accessible worldwide as a generic medication, available in vials, bags, and solid oral forms. This broad availability facilitates large-scale production and distribution, as well as acceptance by the medical community. The product has FDA approval for surgical antibiotic prophylaxis (excluding the intradermal route).

[0127] In one embodiment, the antimicrobial agent comprises a stable solution of clindamycin phosphate at 500 pg / mL and a target pH of 7.0, stored in a sterile vial or prefdled syringe that remains stable at room temperature. The clindamycin phosphate solution will be prepared within a pH range of 6.8-7.2 and at a concentration of 500 pg / mL.

[0128] In some embodiments, the antimicrobial agent is flucloxacillin. The flucioxacillin in the injection solution may be at any suitable dilute concentration for microdosing. In some embodiments, the concentration of flucloxacillin in the injection solution for intradermal delivery is < 1.0 mg / ml. In other aspects, e concentration of flucloxacillin in the injection solution for intradermal delivery from > 0.01 mg / ml up to about 750 pg / mL (including any value in-between these two numbers), about 100 pg / mL, about 250 pg / mL, about 300 pg / mL, about 400 pg / mL, about 500 pg / mL, about 600 pg / mL, or about 700 pg / mL. Goh et al., JAMA Surgery, 755(7)1718-726 (Jul. 1, 2023). These concentrations of flucloxacillin are substantially lower than the concentrations used in the prior art.324938-1265-3208.2Attorney Docket No. : 145105-0109

[0129] In some embodiments, the antimicrobial agent is ceftriaxone. The ceftriaxone in the injection solution may be at any suitable dilute concentration for microdosing. In some embodiments, the concentration of ceftriaxone in the injection solution for intradermal delivery is < 1.0 mg / ml. To define a lower limit, the concentration of ceftriaxone in the injection solution could be > 0.01 mg / ml. In other aspects of the disclosure, concentration of ceftriaxone in the injection solution for intradermal delivery can be from > 0.01 mg / ml up to about 100 mg / ml (including any value in-between these two numbers), about 0.5 mg / ml up to about 25 mg / ml, about 0.5 mg / ml up to about 10 mg / ml, about 300 pg / mL, about 400 pg / mL, about 500 pg / mL, about 600 pg / mL, about 700 pg / mL, about 800 pg / mL, about 900 pg / mL, or about 1000 pg / mL. Jenitta et al., Int J AcadMed Pharm., 5(4)4024-1028 (2023); Gunasekaran B, Sivasankaran K., Int J Acad Med Pharm., 5(6):46-51 (2023). These concentrations of ceftriaxone are substantially lower than the concentrations used in the prior art.

[0130] In some embodiments, the antimicrobial agent is vancomycin. The vancomycin in the injection solution may be at any suitable dilute concentration for microdosing. In some embodiments, the concentration of vancomycin in the injection solution for intradermal delivery is < 1.0 mg / ml. To define a lower limit, the concentration of vancomycin in the injection solution could be > 0.01 mg / ml. In some embodiments, the concentration of vancomycin in the injection solution for intradermal delivery is about 100 up to about 600 pg / ml (including any value inbetween these two numbers), about 200 up to about 500 pg / ml, about 100 pg / ml, about 200 pg / ml, about 300 pg / ml, about 400 pg / ml, or about 500 pg / ml. These concentrations of vancomycin are substantially lower than the concentrations used in the prior art.

[0131] In some embodiments, the antimicrobial agent is gentamicin. The gentamicin in the injection solution may be at any suitable dilute concentration for microdosing. In some embodiments, the concentration of gentamicin in the injection solution is < 1.0 mg / ml. To define a lower limit, the concentration of gentamicin in the injection solution could be > 0.01 mg / ml. In some embodiments, the concentration of gentamicin in the injection solution is from > 0.01 mg / ml up to about 800 pg / ml (including any value in-between these two numbers), about 200 up to about 800 pg / ml; and in some cases, about 300 up to about 600 pg / ml, about 100 pg / ml, about 200 pg / ml, about 300 pg / ml, about 400 pg / ml, about 500 pg / ml, about 600 pg / ml, or about 700334938-1265-3208.2Attorney Docket No. : 145105-0109pg / ml. These concentrations of gentamicin are substantially lower than the concentrations used in the prior art.

[0132] In some embodiments, the antimicrobial agent is lincomycin. The lincomycin in the injection solution for intradermal delivery may be at any suitable dilute concentration for microdosing. In some embodiments, the concentration of lincomycin in the injection solution for intradermal delivery is < 1.0 mg / ml. To define a lower limit, the concentration of lincomycin in the injection solution could be > 0.01 mg / ml. In some embodiments, the concentration of lincomycin in the injection solution is from > 0.01 mg / ml up to about 800 pg / ml (including any value in-between these two numbers), about 100 to about 800 pg / ml, about 200 up to about 700 pg / ml, about 300 up to about 600 pg / ml, about 100 pg / ml, about 200 pg / ml, about 300 pg / ml, about 400 pg / ml, about 500 pg / ml, about 600 pg / ml, or about 700 pg / ml. These concentrations of lincomycin are substantially lower than the concentrations used in the prior art.

[0133] In some embodiments, the antimicrobial agent is cefazolin. The cefazolin in the injection solution for intradermal delivery may be at any suitable dilute concentration for microdosing. In some embodiments, the concentration of cefazolin in the injection solution for intradermal delivery is < 1.0 mg / ml. To define a lower limit, the concentration of cefazolin in the injection solution could be > 0.01 mg / ml. In some embodiments, the concentration of cefazolin in the injection solution is from > 0.01 mg / ml up to about 800 pg / ml (including any value inbetween these two numbers), about 200 up to about 800 pg / ml, about 300 up to about 600 pg / ml, about 100 pg / ml, about 200 pg / ml, about 300 pg / ml, about 400 pg / ml, about 500 pg / ml, about 600 pg / ml, or about 700 pg / ml. These concentrations of cefazolin are substantially lower than the concentrations used in the prior art.Table 1: Exemplary Antimicrobials and Proposed Dosages for the Same Antimicrobial Dose (Reference) Proposed Dosing Range (concentration of the drug in the injection solution) Clindamycin 408 pg / mL (Huether et al., Arch From > 0.01 mg / ml up to about Dermatol. 2002 Sept; 138:1145- 800 pg / mL1148); is 29 - 58x the ss serumconcentration and achieves 40 xthe local tissue concentration ofthe IV dose344938-1265-3208.2Attorney Docket No. : 145105-0109Table 1: Exemplary Antimicrobials and Proposed Dosages for the Same Antimicrobial Dose (Reference) Proposed Dosing Range (concentration of the drug in the injection solution) Flucloxacillin Goh et al., JAMA Surgery, From > 0.01 mg / ml up to about 75S(7):718-726 (Jul. 1, 2023) 750 pg / mLCeftriaxone 2 g in 20 mL (Petrakis et al., About 0.5 mg / ml up to about 1001998, Eur. Rev. for Med. & mg / mlPharmacological Sci., 2(3- 4):141-145)Vancomycin 500 mg. 250 mg From > 0.01 mg / ml up to about 600 pg / mLGentamicin From > 0.01 mg / ml up to about 800 pg / mLCefazolin From > 0.01 mg / ml up to about800 pg / mLKits

[0134] In one aspect of the disclosure, encompassed is a kit comprising an injection device described herein, and which may be used in the methods described herein. The kit can comprise at least one antimicrobial agent, a syringe, and a needle suitable for intradermal injection. The kit can comprise any suitable components or design features desirable, such as, for example, autoinjector / dual-chamber, side-port needle, multi-dose, etc. The kit may optionally comprise directions for use.

[0135] The antimicrobial agent may be light sensitive and vulnerable to degradation when exposed to UV light. As such, in one embodiment the syringe used can be designed for lightsensitive drugs. In particular, the syringe may be darkened to avoid light exposure to the antimicrobial agent. One particular example is called an “amber syringe” because it is made with amber-colored plastic, which effectively fdters out harmful UV light, thereby protecting the antibiotic drug from degradation caused by light exposure.

[0136] In one aspect of the disclosure, encompassed are pre-fdled, single-use syringes for use in methods of the disclosure. The pre-filled syringes can comprise at least one therapeutically effective microdose of at least one antimicrobial agent, which can be utilized in the methods of the disclosure.354938-1265-3208.2Attorney Docket No. : 145105-0109

[0137] In another aspect of the disclosure, encompassed are dual chamber syringes that comprise a powder for reconstitution in a first chamber and a diluent in a second chamber. This is an option for example if the drug (API), is susceptible to hydrolytic degradation, or if the drug is thermally unstable. This type of device can also be useful in harsh environments to ensure stability and effectiveness of the API to be delivered (e.g., sub-Saharan environments or sub-zero environments). In a further aspect, the duel chamber design can comprise a mix-confirmation window and a target mix time (e.g., <10 s) to facilitate use by non-medical personnel.

[0138] In a further aspect, the kit can comprise an indicator to confirm proper intradermal administration, e.g., visible wheel window / confirmation, to enable both clinical personnel as well as a layperson to confirm that the intradermal dose was administered in the correct location of the dermis. Other indicators of correct intradermal site dosing include, for example, high frequency ultrasound verification. Finally, another aspect includes providing in the kits of the disclosure the use of a wedge as a guide for needle insertion, which can provide a guide for both the angle and depth of needle insertion. Further, a pressure-limited actuation can also be utilized to avoid subcutaneous administration / drift.

[0139] In yet another aspect, the kit can be field-tough by design. The kit can provide simple instructions (e.g., pictograms, tactile / audible cues), ruggedization (drop shatter resistant, heat / cold resistant / tolerant, humidity resistant / tolerant, water ingress resistant / tolerant), glove / low-light usability, auto-retract sharps, and tamper-evident / child-resistant features.

[0140] In another aspect, the kits are designed for self-administration, or administration by non-medical personnel, such as a caregiver. In a further aspect, the kits are designed for use military personnel, and can be for example, single use, disposable administration kits.

[0141] In another aspect, the kits are designed to be incorporated in a first-aid kit.Methods of Using the Injection Device

[0142] The present disclosure addressees a long-felt need for improved injection devices, kits and methods for preventing and / or minimizing infections associated with a wound in a subject’s skin or mucosa as well as surgical site infections. Examples of mucosal sites include, for example, oral, nasal, anogenital, etc. In addition, examples of wounds include bites (insect and364938-1265-3208.2Attorney Docket No. : 145105-0109animal), puncture wounds (animal / human / penetrating debris), as well as any injury that compromises the skin or mucosal barrier.

[0143] Intradermal injection can be sensitive to needle length and insertion angle. Longer needles and steep insertion angles may increase the likelihood of deposition into subcutaneous tissue. Shallow insertion angles (for example, about 5-20 degrees relative to the skin surface, and in particular around 10 degrees) with a 4 mm needle shaft length may maintain the needle tip within the dermis for the duration of the injection. Reverse bevel or side-port configurations, and the use of insertion wedges or intradermal adapters, can further standardize the angle and depth of delivery.

[0144] The injection forces experienced by clinicians using the device disclosed herein can be grouped into qualitative “comfort bands.” Forces below approximately 10 N are typically perceived as very comfortable; forces between about 10 and 20 N are comfortable; between about 20 and 30 N are moderately difficult and associated with some fatigue; between about 30 and 40 N are difficult and associated with significant fatigue and tremor; and forces exceeding about 40 N are generally unacceptable for controlled intradermal injection. Standard intradermal injections with non-optimized hardware often fall into the 30-40 N range. By contrast, a microdosed, low-viscosity solution, a small-diameter syringe (for example, 1-3 mb), and a thin-wall nanoneedle, as described herein, can reduce the required plunger force into the comfortable range, dramatically improving control and reproducibility.

[0145] Exemplary Conditions to be Treated: The injection devices and methods described herein can be used to treat and / or prevent any condition with a risk of a infection, such as a cutaneous infection, including but not limited to propylaxis of surgical site infections, surgical antibiotic prophylaxis (SAP) of pacemaker insertions, SAP for insertion of Cardiac Implantable Electronic Device (CIED), SAP of venous access catheters, SAP of ports for administration of oncology drugs, SAP of central line catheters, SAP of tracheotomy placement, SAP for chest tube placement, and SAP for removal of a foreign body.

[0146] Another exemplary indication for prevention and / or treatment of infection utilizing a device described herein is Hidradenitis Supprativa (HS). These are skin wounds that occur under arms, breasts, groin. HS is a chronic, relapsing inflammatory disease of the hair follicle that 374938-1265-3208.2Attorney Docket No. : 145105-0109predominantly affects apocrine gland-bearing areas such as the axillae, inframammary folds, groin, perineum, and buttocks. Clinically, HS is characterized by recurrent and often painful skin lesions, including nodules, inflammatory nodules, abscesses, pyogenic abscesses, fistulas, draining fistulas and sinus tracts, interconnected fistulous networks, pyogenic abscesses, and pyogenic granulomatous lesions that may progress to extensive scarring and tissue destruction. Many of these lesions harbor dense bacterial communities and biofilms within sinus tracts and deep dermal reservoirs that are poorly accessible to topical agents and difficult to eradicate with conventional systemic oral or intravenous antibiotics alone.

[0147] There are three companies that in particular have biological products that target this condition: Abbvie, Pfizer, and UCB. However, combining such products with an antimicrobial injection would make a more desirable product. While any antimicrobial agent can be used in the devices described herein with regarding to treatment and / or prevention of infections relating to Hidradenitis Supprativa, exemplary antibiotics are ertapenem and gentamycin, e.g., an intralesional antibiotic. However, prolonged intravenous therapy is resource-intensive, associated with systemic risks, and does not provide a practical long-term solution for localized, recurrent lesions.

[0148] The injection devices and microdosed antimicrobial formulations described herein can be used for intradermal and intralesional injection directly into HS lesions, including abscesses, inflammatory nodules, fistulas, draining fistulas, sinus tracts, and pyogenic granulomatous lesions. In this context, “intralesional” encompasses delivery into the dermal and subdermal components of the lesion wall, tract, or cavity rather than superficial placement in uninvolved skin. By injecting a microdosed antibiotic solution directly into and around the lesion, high local antimicrobial concentrations can be achieved within the infected tissue and associated biofilm environment, while systemic exposure and associated toxicities remain low.

[0149] The methods and injection devices disclosed herein can be used to prevent, reduce the risk of, and / or treat microbial infection in association with any subset or clinical stage of hidradenitis suppurativa (HS). This includes, without limitation, patients with: (1) early or mild HS characterized predominantly by recurrent painful inflammatory nodules and small abscesses (corresponding, for example, to Hurley stage I disease); (2) moderate HS with chronic384938-1265-3208.2Attorney Docket No. : 145105-0109suppurative lesions, draining sinus tracts, hypertrophic scars, and perilesional inflammation involving discrete anatomic regions (for example, Hurley stage II disease); and (3) severe HS with extensive involvement of one or more anatomic regions, characterized by chronic deep abscesses, multiple and often interconnected sinus tracts, and widespread scarring (for example, Hurley stage III disease). The methods can also be applied to HS patients with recalcitrant or treatment-resistant disease who have had inadequate responses to prior oral antibiotic regimens, combinations of broad-spectrum systemic antibiotics, anti-androgen therapies, biologic or small-molecule immunomodulators, or prior surgical interventions. In all such subsets, intradermal and / or intralesional microdosed antibiotic injection using the devices described herein can be directed to HS-associated lesions such as inflammatory nodules, abscesses, pyogenic abscesses, sinus tracts, fistulas, draining fistulas, and pyogenic granulomatous lesions, including those that harbor polymicrobial anaerobic flora and biofilm-based bacterial communities.

[0150] For HS applications, the syringe used for intralesional injection can be about 3 mL in capacity or smaller (for example, about 1 up to about 3 mL), paired with a short, thin-wall needle as described elsewhere herein to reduce glide force and improve fine motor control during injection into tender, anatomically constrained areas. The volume of injection per lesion can vary according to lesion size, depth, and complexity, but will typically range from about 0.1 mL up to about 3.0 mL per lesion, delivered through one or multiple passes to line the walls of nodules, abscess cavities, or sinus tracts. Any suitable antimicrobial agent disclosed herein can be used for the treatment and / or prevention of infections relating to HS, including agents active against mixed aerobic and anaerobic flora and biofilm-forming organisms. By way of example, ertapenem, gentamicin, clindamycin, vancomycin, cefazolin, or other antibiotics selected on the basis of culture and susceptibility testing can be formulated at microdosed concentrations for intralesional use. Local intradermal / intralesional administration using the present device can thereby complement systemic antibiotics and biologic agents, offering a targeted strategy for managing recalcitrant HS lesions, particularly in patients with severe, biofilm-associated nodules, abscesses, and draining fistulas.

[0151] Another exemplary indication for prevention and / or treatment of infection utilizing a device described herein is biofilm-associated infenction. Biofilms are structured microbial 394938-1265-3208.2Attorney Docket No. : 145105-0109communities encased in a self-produced extracellular polymeric substance (EPS) matrix composed of polysaccharides, proteins, extracellular DNA, and lipids. This matrix functions as a protective barrier or “fortress” that markedly increases bacterial tolerance to antimicrobials and shields the bacteria from host immune defenses. Biofdms are implicated in a high percentage of chronic, non-healing wounds and device-related infections, including surgical site infections, chronic ulcers, and infections involving implanted hardware or leads.

[0152] Systemically administered antibiotics (for example, oral, intravenous, or intramuscular) are typically unable to achieve tissue concentrations at the biofilm site that are sufficient to penetrate the EPS matrix and eradicate the embedded bacteria without causing unacceptable systemic toxicity. In contrast, localized microdosed delivery of antimicrobial agents using the injection devices described herein can produce high antibiotic levels directly within or adjacent to the biofilm environment. In particular, intradermal, intra-incisional, intralesional, and intra-wound injections can be used to create a high-concentration antibiotic field within the dermal interstitial space, wound bed, or soft tissue pocket harboring the biofilm. When combined with appropriate wound care and, where indicated, sharp debridement to mechanically disrupt the biofilm structure, these locally delivered microdosed antibiotics can overcome the diffusion barrier of the EPS matrix, enhance bacterial susceptibility, and promote resolution of biofilm-mediated infections that are refractory to conventional systemic therapy.

[0153] Other exemplary conditions that can be treated with the injection devices, kits and methods of the disclosure include, for example, Mycetomas, Eumycetoma, Actinomycetes, Mycobacterium ulcerans, Maduromycosis, Actinomycetoma, Pseudomonas, Gram Negatives, Klebsiella, E. Coli, Orthopedic trauma, Soft Tissue Injuries, and Acute Bacterial Skin and Skin Structure Infections (ABSSSI).

[0154] Site of Administration: The site of administration can be any dermal or cutaneous site, including a wound, abscess, inflammatory nodule, intra-wound, intra-articular, and all intradermal layers of the skin (e.g., epidermis, dermis and Sub Q).

[0155] Both local and intradermal delivery are encompassed by the disclosure. With IM administration, the goal is local and not systemic administration. For example, this administration method may be applicable in treating necrotizing faciatis.404938-1265-3208.2Attorney Docket No. : 145105-0109

[0156] The site of the surgical incision can be any part of the body in which surgical incisions into skin or mucosa are made. Examples of mucosal sites include, for example, oral, nasal, anal, vaginal, anogenital, etc. Examples of such surgical procedures include, but are not limited to, skin cancer surgery, Mohs skin surgery, inguinal hernia surgery, cholecystectomy, hysterectomy, inguinal hernia repair, spinal surgery joint surgery, tonsillectomy, hemorrhoidectomy, oral surgery, etc. The skin wound can be, for example, a laceration, abrasion, bites (insect and animal), puncture wound (animal / human / penetrating debris), avulsion, cut, or skin tear, as well as any injury that compromises the skin or mucosal barrier, and the mucosal wound can be, for example, an ulcer, erosion, or fissure.

[0157] Topically disinfecting a surgical site prior to surgery does not prevent surgical site infection. One reason for this is that bacteria deeper in the skin (e.g. in sweat glands or sebaceous glands) may not be reached with topical skin disinfection. Guarch-Perez et al., J. of Hospital Infection, 740(2023): 62-71, which reports that cutaneous microbiota colonize the wound when released from the skin upon cutting, resulting in contamination which may cause biomaterial- associated infection. In other words, when an incision is made into the skin, the surgical blade comes into contact with the bacteria below the skin. Shroff et al., J. Shoulder Elbow Surg.(2023), 32(9): 1924-1928; Nakatsuji et al., Nat. Commun. 2013; 4:1431. Bacteria reside in the intradermal space as well as epidermal surface. Thus, surgical scrubbing alone cannot prevent bacterial infections at surgical sites. The present disclosure targets prevention of infection, in combination with pain management and prevention, at surgical sites, where potential infection can be the result of bacteria that reside below the skin surface.

[0158] In particular, while cutaneous drug delivery has been used for surgical site treatment, intradermal and cutaneous drug delivery are distinct, and there are significant pharmacokinetic differences between the two delivery methods. Koenitz et al., Eur. J. of Pharmaceutics and Biopharmaceutics, 204:114517 (Nov. 2024). Further, cutaneous preoperative disinfection does not completely mitigate infection, which can be caused by bacteria released from the intradermal space in the skin or surgical equipment (FIGs. 7 and 8).

[0159] The injection devices, kits and methods of the disclosure enable targeted delivery of at least one antimicrobial agent, at a therapeutically effective microdosed concentration. Dermal414938-1265-3208.2Attorney Docket No. : 145105-0109interstitial antimicrobial tissue levels of 30 to 60 times (Huether et al., Arch Dermatol. 2002 Sept; 138: 1145-1148) greater than systemic routes can be achieved (FIG. 6). Such high local active agent concentrations ensure an effective antimicrobial agent tissue concentration at the time of skin closure. Ensuring target tissue concentrations within the “golden hour” period following incision is vital, as this is when microbes remain antibiotic-susceptible in the planktonic phase (Sharma D., Antimicrob Resist Infect Control 8:76 (2019)). Beyond this time, microbes are more likely to adopt a biofilm phenotype with a fibrin matrix and are less susceptible to antibiotics.

[0160] Intradermal delivery advantages of the therapeutically effective microdose of at least one antimicrobial agent for the present invention include, for example: (1) preoperative antimicrobial agent administration tailored to the onset of a surgical procedure, (2) minimally invasive administration for the at least one antimicrobial agent, (3) increased antimicrobial efficacy as compared to systemic delivery of the same antimicrobial agent, (4) reduced human toxicity relating to the antimicrobial agent as compared to systemic delivery of the same antimicrobial agent, (6) a reduced drug dosage for the antimicrobial agent required to effectively treat and / or prevent an infection as compared to systemic administration of the same antimicrobial agent, (7) the intradermal administration method results in higher antimicrobial agent tissue levels with greater efficacy as compared to systemic administration of the same antimicrobial agent, (9) a reduced risk of systemic adverse events for the antimicrobial agent as compared to systemic delivery, (10) elimination of nausea associated with oral administration of antimicrobial agents, (11) minimal exposure of major organ systems of the body, including renal and CNS, to the antimicrobial agent, as compared to systemic delivery of the same antimicrobial agent, (12) a reduction or elimination of the development of antibiotic-resistant bacteria as compared to systemic delivery, (13) a reduced risk of medical errors and IV mishaps as compared to systemic delivery of an antimicrobial agent, (14) the gastrointestinal microbiome is not altered by the intradermal delivery, resulting in a reduced risk of the emergence or development colitis as compared to systemic administration of an antimicrobial agent, (15) avoid uncertainty about the timing of administration prior to surgery, (16) enhances patient acceptance by reducing pain and injection site discomfort, and (17) a reduction in global use and wastage runoff of antimicrobial products. The transition from a conventional delivery route such as oral 424938-1265-3208.2Attorney Docket No. : 145105-0109or injectable, to an intradermal method for surgical antimicrobial agent prophylaxis facilitates these objectives.

[0161] At 15% of the world’s antimicrobial consumption, surgical antibiotic prophylaxis (SAP) represents a predictable point of intervention to curtail the global antimicrobial resistance crisis. Skilled antimicrobial stewardship becomes critical since inappropriate SAP increases SSI rates by a factor of 6.7 and drives antimicrobial resistance. It is estimated that a staggering 60% of SSI’s could be reduced with evidence-based measures.

[0162] Other advantages of the present disclosure include that a greater immune response may be obtained via skin or mucosal injection due to the presence of epidermal Langerhans Cells, which are a tissue-resident macrophage of the skin. In addition, intradermal injections eliminate the first pass effect, which is the process by which the concentration of a drug is significantly reduced before it reaches systemic circulation, primarily due to metabolism in the liver. Thus, intradermal injections avoid premature metabolism by the gastrointestinal tract or the liver. Finally, intradermal injections do not result in a reduction of drug concentration which is observed with systemically administered drugs.

[0163] Intradermal Volumn: In another aspect of the disclosure, an intradermal volume of about 0.1 to about 2.0 mL per injection site is administered, with a total volume of about <10 mL up to about 50 mL, via multiple injection sites.

[0164] Skin Tissue as a Deformable Porous Medium: Skin is the largest organ of the human body and possesses capillary and lymphatic systems. The three distinct layers of the skin are potential sites for drug delivery: (1) transdermal, (2) intradermal, and (3) subcutaneous (see e.g., FIGs. 5 A and 5B). The skin functions as a deformable, porous medium, comparable to a sponge, absorbing fluid through local expansion rather than creating a singular, fluid-filled cavity. The tissue's volumetric expansion closely aligns with the volume of fluid introduced. Skin tissue is thus regarded as analogous to a sponge saturated with fluid. When fluid is injected into the intradermal space, the porous medium develops numerous fluid-filled spherical cavities, allowing fluid to flow into the adjacent tissue. This behavior is characterized as that of a mechanically nonlinear, deformable porous medium. This is important for consideration in that the intradermal layer has the slowest drug release as compared to other delivery routes.434938-1265-3208.2Attorney Docket No. : 145105-0109

[0165] Mechanically Limiting Tissue Expansion: An essential feature of intradermal delivery is that mechanically restricting tissue expansion limits fluid absorption into the tissue. The main resistance to fluid flow during intradermal injections is caused by the skin, and not a microneedle used for injection. Studies demonstrate that partially retracting the needle after entry into the skin decreases dermal resistance and increases flow. P. Shrestha & B. Stoeber, “Fluid absorption by skin tissue during intradermal injections through hollow microneedles,” Scientific Reports, 8: 13749 (2018). This fact has broader implications beyond simple observation. When a 4mm needle is completely inserted into the intradermal space at a 15° angle, it can then be withdrawn 1 to 2 mm. Once the needle is withdrawn, there are fewer mechanical limitations imposed by the skin and the transient flow rate immediately increases following retraction. Medical personnel are aware that retraction of the needle allows more fluid to be injected but the significance in the intradermal space can be significant.

[0166] The Dermal Interstitial Space: The infection site on the skin or mucosa aligns with the dermal interstitial fluid. Ideally, the antimicrobial agent concentration should be measured in the dermal interstitial fluid instead of in the plasma. Using plasma concentration and pharmacokinetic, (pk) data has been shown to produce inconsistent correlations. The concentration of antibiotics in the interstitial fluid is consistently lower than in the plasma.Previously, the total drug concentration within the tissue was measured to access tissue antibiotic levels, which reflects both intracellular and extracellular drug amounts. Some antibiotics target intracellular bacteria, while others act extracellularly, making the total tissue concentration level of antibiotics an unreliable marker.

[0167] Intradermal Delivery: Understanding the pharmacokinetics of antibiotics is essential; however, it is not enough to establish suitable dosage regimens on its own. An additional requirement is determining the minimal inhibitory concentration (MIC), which is vital for setting susceptibility breakpoints by comparing the antibiotic concentration with the MIC. Usually, a tenfold ratio between the Cmax and the MIC is deemed sufficient for antimicrobial effectiveness. This may not be true for intradermal delivery, as the plasma concentration maximum (C max) IS HO longer relevant and could lead to incorrect conclusions. Intradermal therapy typically produces concentrations of antibiotics in the interstitial space 20 to 60 times greater than that achieved by444938-1265-3208.2Attorney Docket No. : 145105-0109oral or intravenous delivery. Thus, this delivery route is unique in that the previous reliance on plasma concentration levels is not a requirement.

[0168] Advances in high-frequency ultrasound imaging now enable real-time visualization of drug delivery into the dermis, allowing both qualitative confirmation of placement and quantitative assessment of the injected volume.

[0169] The potential advantage of intradermal therapy as compared to other routes of delivery is that it considers the complex pharmacodynamics (PD) behavior in the presence of adaptation phenomena. This cannot be reflected in traditional PK-PD indices based on the MIC. Various validated methodologies exist for characterizing the diffusion of anti-infectives into tissues. Intradermal delivery offers distinct advantages from a PK / PD perspective when the antimicrobial is directly deposited in the dermal interstitial fluid. The drugs are not prematurely metabolized by the gastrointestinal tract and liver, thereby eliminating the first-pass effect. These antimicrobials can then exert their impact on the commensal bacteria and pain receptors residing in this area with greater efficacy than non-intradermal delivery routes. Moreover, the bacteria adaption phenomena with the development of resistance is not the same as the intravenous or oral delivery route.

[0170] Method of Prophylaxis. In another aspect, the invention is a method of performing intra-inci sional injection of antibiotic drug for prophylaxis against surgical site infection using the injection device described herein. In preparation for making an incision for a surgical procedure, inject the injection solution into a target incision site for the surgery. The site of the incision could be any part of the body in which surgical incisions into skin or mucosa are made, such as oral, nasal, anal, vaginal, etc. Examples of such surgical procedures include Mohs skin surgery, inguinal hernia surgery, cholecystectomy, hysterectomy, inguinal hernia repair, spinal surgeryjoint surgery, tonsillectomy, hemorrhoidectomy, oral surgery, etc. Make a surgical incision at the target incision site. The method may further comprise performing the surgical procedure.Biofilms

[0171] In another aspect of the disclosure, the injection device described herein is useful in treating intralesional infections, such as those related to biofilms. Traditional antibiotics cannot 454938-1265-3208.2Attorney Docket No. : 145105-0109treat biofilm formation. Direct injection of antibiotics can target biofilms, which are protective layers where bacteria hide. Antibiotics, administered orally or intravenously, cannot achieve the blood levels required to penetrate the biofilm barrier. The only effective method is a direct intralesional injection of the antibiotic into the draining fistula, abscess, or sinus tract. This approach allows the necessary blood levels to disrupt the biofilm and treat the infection.

[0172] Systemic antibiotics reliably perturb the human microbiome, with effects that extend beyond short-lived dysbiosis to include altered metabolic function, impaired colonization resistance, resistome expansion, and immune remodeling. These durable changes have been described as antibiotic scarring: a state in which microbial communities recover incompletely after exposure and may remain biologically altered for months or longer. In dermatology, hidradenitis suppurativa (HS) is a particularly relevant disease model because patients commonly receive repeated or prolonged systemic antibiotic courses despite the fact that HS is not simply a conventional acute bacterial infection.

[0173] Table 2 below summarizes a comparisoin of systemic vs intralesional antibiotic exposure in Hidradenitis Suppurativa, which is a model indication for demonstrating the effectiveness of the described injection device in treating biofilm infections. The systemic exposure column is supported directly by the cited literature on antibiotic dysbiosis, antibiotic- associated colitis, stewardship, antimicrobial resistance, and immune-checkpoint toxicity. The intralesional / local column reflects the microbiome-sparing rationale and lesion-targeted logic presented in the data shown in Example 4, together with general stewardship principles.Table 2Comparison Systemic oral / IV Intralesional / local HS-specific Key source domain antibiotics antibiotics implication anchors Primary site of Diffuse body-wide Concentrated del ix c ry HS is anatomically focal 3-5, 10-11, drug exposure exposure; large fraction into the lesion, abscess but often treated Example 4 of effect is off-target cavity, draining tract, or systemically; thisfrom the perspective of surrounding inflamed mismatch can exposea localized HS lesion. tissue with markedly the gut to harm whilenarrower exposure under-serving biofilm- footprint. heavy lesions.Gut Best-documented harm Conceptual microbiome Relevant in HS because 3-5, microbiome profile: reduced advantage: bypasses the repeated or chronic Example 4 impact microbial diversity, gastrointestinal tract and courses are common.depletion of should sharply reducecommensals, functional gut ecologicaldisruption, and disruption compared4938-1265-3208.2Attorney Docket No. : 145105-0109Table 2Comparison Systemic oral / IV Intralesional / local HS-specific Key source domain antibiotics antibiotics implication anchors prolonged dysbiosis or with prolonged systemic'antibiotic scarring.' courses.Risk of Systemic exposure Expected to lower gut- Important for patients 4, 5, 7, antibiotic- increases selective mediated collateral with recurrent flares or Example 4 associated pressure and damage because prior antibiotic burden.colitis / C susceptibility to intestinal exposure isdifficile pathogen overgrowth, minimized; however,including Clostridioides direct HS comparativedifficile, especially with outcome data are stillrepeated courses and limited.broad-spectrum agents.Selection for Higher ecological Potentially lower Supports a stewardship 5-9, antimicrobial selection pressure whole-body selection argument against Example 4 resistance across gut and other pressure because reflexive chronicmicrobial reservoirs; exposure is localized systemic suppression inrepeated exposure and total systemic HS.promotes resistant burden is reduced.strains and resistancegene exchange.Ability to May reduce Designed to place high Mechanistically 10-11. address HS inflammation, but concentrations at the appealing for HS Example 4 lesion biology penetration into chronic actual site of disease, because disease issinus tracts, biofilm- where nodules, localized, recurrent, andladen cavities, and abscesses, and draining structurallypoorly perfused tissue tracts reside. compartmentalized.can be suboptimal.Interaction Prior antibiotic Microbiome-sparing Worth caution when 1. 2. with biologies exposure has been local treatment could escalating from repeated Example 4 / immune associated with theoretically reduce this antibiotics to biologiescheckpoint era microbiome risk by avoiding a large in high-risk patients.perturbation and pre-biologic antibioticincreased immune- insult, though thisrelated toxicity in remains a forwardimmune checkpoint looking inference ratherblockade settings; this than proven HS trialraises caution about a evidence.possible 'double-hit' inalready antibiotic- exposed patients wholater receive immune- modifying therapy.Stewardship Weak fit when Better conceptual fit Encourages a route6-9, 11, alignment prolonged empiric with stewardship: treat based rethink rather Example 4 courses are used tire target while reducing than a drug-escalationrepeatedly despite unnecessary exposure reflex.collateral damage, elsewhere.resistance pressure, andlimited durability.474938-1265-3208.2Attorney Docket No. : 145105-0109Table 2Comparison Systemic oral / IV Intralesional / local HS-specific Key source domain antibiotics antibiotics implication anchors Overall riskMay still be appropriate Attractive as a The main unanswered 4-11, benefit for selected severe microbiome-sparing question is not Example 4 framing infections, cellulitis, or adjunct or alternative for plausibility, but thetrue systemic focal lesions, especially need for formal HSinvolvement, but when the goal is local trials and protocolizedchronic routine use control without chronic lesion-selection criteria.carries a substantial gut toxicity.collateral-cost profile.

[0174] 1. Kraehenbuehl et al. Antimicrobial exposure and immune-related cutaneous adverse events during immune checkpoint blockade therapy. JAMA Dermatol. 2026; 162(3):311-313. doi : 10.1001 / j amadermatol .2025.4904.

[0175] 2. Postow et al., Immune-related adverse events associated with immune checkpoint blockade. N Engl J Med. 2018;378(2): 158-168. doi :10.1056 / NEJMral 703481.

[0176] 3. Ruppe et al. Impact of antibiotics on the intestinal microbiota needs to be re-defined to optimize antibiotic usage. Clin Microbiol Infect. 2018;24(l):3-5. doi:10.1016 / j.cmi.2017.09.017.

[0177] 4. Kesavelu D, Jog P. Current understanding of antibiotic-associated dysbiosis and approaches for its management. Ther Adv Infect Dis. 2023;10:20499361231154443.doi : 10.1177 / 20499361231154443.

[0178] 5. Patangia et al., Impact of antibiotics on the human microbiome and consequences for host health. Mi cro bio logy Open . 2022; 11(1 ):el 260. doi:10.1002 / mbo3.1260.

[0179] 6. Antimicrobial Resistance Collaborators. Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis. Lancet. 2022;399(10325):629-655. doi:10.1016 / S0140- 6736(21)02724-0.

[0180] 7. Centers for Disease Control and Prevention. Core Elements of Antibiotic Stewardship. Updated September 10, 2025. Accessed March 20, 2026.

[0181] 8. Metz M, Shlaes DM. Eight more ways to deal with antibiotic resistance. Antimicrob Agents Chemother. 2014;58(8):4253-4256. doi:10.1128 / AAC.02623-14.4938-1265-3208.2Attorney Docket No. : 145105-0109

[0182] 9. Rynkiewich K. Finding 'What's wrong with us': antibiotic prescribing practice among physicians in the United States. Front Sociol. 2020;5:5. doi: 10.3389 / fsoc.2020.00005.

[0183] 10. Dreno et al., Hidradenitis suppurativa: the role of deficient cutaneous innate immunity. Arch Dermatol. 2012; 148(2): 182- 186. doi: 10.1001 / archdermatol.2011.315.

[0184] 11 Wellcome. The global response to AMR: momentum, success, and critical gaps. Published November 16, 2020. Accessed March 20, 2026.

[0185] Systemic delivery of antimicrobial agents can result in microbiome scarring. Prolonged use of systemic, broad-spectrum antibiotics causes profound, long-lasting iatrogenic disruption to the gut microbiome, eradicating beneficial short-chain fatty acid-producing bacteria. This profound “antibiotic scarring” leaves patients entering subsequent immunomodulatory biologic therapy at a highly elevated risk for debilitating immune-related adverse events.

[0186] Intralesional injection actively saturates the soft tissue, safely achieving extreme local concentrations (greater than or equal to 1000 pg / mL) without systemic toxicity. This massive local concentration physically breaks down the tolerance of the EPS matrix, penetrating the shield to eradicate both active and metabolically dormant bacterial subpopulatoins that perpetuate chronic HS inflammation.

[0187] Systemic administration of antibiotics does not effectively treat biofilm microbial infections. This is detailed in FIG. 26. Systemic mono-therapies face alarming resistance in HS isolates (e.g., clindamycin 65.7%, rifampicin 69.3%), necessitating a paradigm shift in antibiotic delivery methods. In particular, FIG. 26 shows fibrotic ischemia (dense scarring around chronic lesions severely restricting blood flow, limiting systemic drug delivery), Metabolic Dormancy (bacteria at the core of the biofilm enter a dormant state, rendering antibiotics that target cellwall synthesis ineffective), and The EPS Barrier (Extracellular Polymeric Substances physically repels circulating antimicrobial molecules).

[0188] FIG. 27 details exemplary intralesional injection utilizing an injection device described herein. The direct, localized administration of an antimicrobial agent into the inflammatory nodule, abscess, or sinus tract is a mechanical countermeasure to problems encountered with system administration of drugs and biofilm resistance to treatment. The mechanical494938-1265-3208.2Attorney Docket No. : 145105-0109countermeasure, utilizing antimicrobial administration into a lesion, (1) bybasses systemic circulation, thereby eliminating the dependency on compromised local vascular networks, (2) pierces the EPS shield, as the mechanical force of injection disrupts the biofilm architecture, and (3) local concentration overwhelms bacterial tolerance mechanisms with an ultra-high localized payload without systemic toxicity.

[0189] FIG. 28 details an exemplary flow chart for selection of a suitable antibiotic for intralesional injection utilizing an injection device described herein. Step 1: Culture & Sensitivity Testing (obtain aspirate form deep lesion / sinus tract), Step 2: Identify Pathogen Profile as either Gram-Positive / Aerobe Dominance or Gram-Negative & Anaerobe Dominance. For Gram-Positive, Option 3 could entail Clindamycin administration (lincosamide for targeted Gram-positive and specific anaerobic coverage). For Gram-Negative, Option 1: Ertapenan (broad-spectrum carbapenem for severe, mixed infectipons, and Option 2: Amikacin or Gentamicin (aminoglycosides for robus Gram-negative coverage).

[0190] Localized ertapenem demonstrates an exceptionally low resistance rate (less than 1%) against typical HS anaerobes and Gram-negative organisms. In addition, localized ertapenem is highly potent against Prevotella, Porphyromonas, and other strict anaerobes that dominate Hurley Stage III biofilsm. Further, ertapenem has successfully been used via IV to rapidly downregulate severe inflammation prior to surgical resection in advanced cases. Thus, translating ertapenem’s proven IV efficacy into an intralesional delivery utilizing the injection device described herein creates the ultimate targeted strike against recalcitrant, polymicrobial HS tunnels.

[0191] FIG. 29 depicts the targeted, direct intralesional antimicrobial delivery targeting a biofilm barrier, using an injection device described herein, as compared to systemic IV / oral antimicrobial delivery. Systemic IV / oral antimicrobial delivery results in low local antimicrobial concentration, with the EPS matric intact, along with high system antimicrobial exposure. In contrast, direct intralesional delivery results in supraphysiologic local antimicrobial concentration, EPS matrix bypassed, with zero systemic wash-out.504938-1265-3208.2Attorney Docket No. : 145105-0109

[0192] Table 3 below compares the therapeutic targeting matrix of a systemic route of antimicrobial administration (IV / oral) as compared to an intralesional route of antimicrobial administration.Table 3Systemic Route (IV / Oral) Intralesional Route Biofilm Excellent; mechanical Penetration lililiiiiiiiliiiii bypass of EPS.Local Drug Extremely High;supraphysiologic local Concentration payload.Systemic Toxicity Negligible; confmed to & Side Effects target tissue.Promotes stewardship via Antibiotic iiiiiiiiiiiiiliiiiiiii targeted, high-doseStewardshiperadication.

[0193] FIG. 32 details the structural failure of systemic antimicrobial therapy in treating biofilms. Chronic wounds and fibrotic tunnels suffer from poor vascular perfusion. Systemic antibiotics (oral / IV) simply cannot physically reach the infection site in sufficient quantities. Eradicating sessile biofilm bacteria requires concentrations 100 to 1000 times higher than planktonic bacteria. Achieving this via systemic delivery would result in lethal host toxicity.

[0194] Definitions

[0195] The following definitions are provided to facilitate understanding of certain terms used throughout this specification.

[0196] Technical and scientific terms used herein have the meanings commonly understood by one of ordinary skill in the art, unless otherwise defined. Any suitable materials and / or methodologies known to those of ordinary skill in the art can be utilized in carrying out the methods described herein.

[0197] Any use of the word “or” herein is intended to be inclusive and is equivalent to the expression “and / or,” unless the context clearly indicates otherwise. As such, for example, the 514938-1265-3208.2Attorney Docket No. : 145105-0109expression “A or B” means A, or B, or both A and B. Similarly, for example, the expression “A, B, or C” means A, or B, or C, or any combination thereof.

[0198] As used herein, the term “comprising” is intended to mean that the compounds, compositions and methods include the recited elements, but not exclude others. “Consisting essentially of’ when used to define compounds, compositions and methods, shall mean excluding other elements of any essential significance to the combination. Thus, a composition consisting essentially of the elements as defined herein would not exclude trace contaminants, e.g., from the isolation and purification method and pharmaceutically acceptable carriers, preservatives, and the like. “Consisting of’ shall mean excluding more than trace elements of other ingredients. Embodiments defined by each of these transition terms are within the scope of this technology.

[0199] The term “about” will be understood by persons of ordinary skill in the art and will vary to some extent depending upon the context in which it is used. If there are uses of the term which are not clear to persons of ordinary skill in the art given the context in which it is used, “about” will mean up to plus or minus 10% of the particular term. For example, in some embodiments, it will mean plus or minus 5% of the particular term. Certain ranges are presented herein with numerical values being preceded by the term "about." The term "about" is used herein to provide literal support for the exact number that it precedes, as well as a number that is near to or approximately the number that the term precedes. In determining whether a number is near to or approximately a specifically recited number, the near or approximating unrecited number may be a number, which, in the context in which it is presented, provides the substantial equivalent of the specifically recited number.

[0200] The terms “antimicrobial agent” and “antibacterial agent” are used herein interchangeably with the terms “antimicrobial drug” and “antibacterial drug”, respectively.

[0201] “Optional” or “optionally” means that the subsequently described circumstance may or may not occur, so that the description includes instances where the circumstance occurs and instances where it does not.524938-1265-3208.2Attorney Docket No. : 145105-0109

[0202] “Pharmaceutically acceptable excipient or carrier” refers to an excipient that may optionally be included in the injection devices, kits and methods of the disclosure and that causes no significant adverse toxicological effects to the patient / subject.

[0203] As used herein, "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, isotonic and absorption delaying agents, and the like. Examples of carriers, stabilizers and adjuvants have been described and are known in the art (See e.g., Martin, Remington's Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, Pa. (1975)).

[0204] “Substantially” or “essentially” means nearly totally or completely, for instance, 95% or greater of some given quantity. In some embodiments, “substantially” or “essentially” means 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.9%.

[0205] As used in the description of the disclosure and the appended claims, the singular forms “a”, “an” and “the” are used interchangeably and intended to include the plural forms as well and fall within each meaning, unless the context clearly indicates otherwise. Also, as used herein, “and / or” refers to and encompasses any and all possible combinations of one or more of the listed items, as well as the lack of combinations when interpreted in the alternative (“or”).

[0206] The term “administering” as used herein includes prescribing for administration as well as actually administering and includes physically administering by the subject being treated or by another.

[0207] As used herein “subject,” “patient,” or “individual” refers to any subject, patient, or individual, and the terms are used interchangeably herein. In this regard, the terms “subject,” “patient,” and “individual” includes mammals, and, in particular humans. When used in conjunction with “in need,” the term “subject,” “patient,” or “individual” intends any subject, patient, or individual having or at risk for a specified symptom or disorder.

[0208] The foregoing description and following examples merely illustrate the invention and are not intended to be limiting. Each of the disclosed aspects and embodiments of the invention may be considered individually or in combination with other aspects, embodiments, and variations of the invention. Also, unless otherwise specified, the steps of the methods of the invention are not limited to any particular order of performance. Persons skilled in the art may534938-1265-3208.2Attorney Docket No. : 145105-0109perceive modifications to these embodiments that incorporate the spirit and substance of the invention. Such modifications are within the scope of the invention.Examples

[0209] Example 1

[0210] This example demonstrates an exemplary method according to the disclosure for surgical antibiotic prophylaxis using an injection device for intradermal injection as described herein. The injection device comprises a 3 ml syringe and a 4 mm, 30-gauge needle, and the device comprises a clindamycin formulation.

[0211] The antimicrobial agent comprises a stable solution of clindamycin phosphate at 500 pg / mL and a target pH of 7.0.

[0212] Conventional techniques for administering antibiotics in surgical prophylaxis have demonstrated inadequate tissue concentrations within the intended surgical region. To enhance this, the intradermal injection of a microdosed antibiotic solution at the surgical site can be employed, resulting in drug levels that are thirtyfold higher than those attained through conventional methods. The intradermal administration of antibiotics for surgical prophylaxis represents an innovative delivery method, optimized through the placement of the antibiotic within the dermal layer of the skin. This refinement is essential for effectively targeting commensal pathogens residing beneath the surface of the skin but above the subcutaneous layer. An in vivo ultrahigh-frequency ultrasound imaging confirms the positioning of the antibiotic within the dermal region of the skin.

[0213] The 3 ml syringe cap will be removed, and a 30-gauge, 4 mm needle will be attached to the Luer lock syringe (BD 3 ml luer-lok; SKU 309577). The clindamycin solution is then drawn up into the syringe. This setup is similar to the commercial product that contains a prefilled clindamycin solution, 500 pg / ml, in a 3 ml syringe. Administration of the solution into the dermal layer can be visualized using high-frequency ultrasound with a transducer operating at 20-40 MHz, with a needle inserted at a 10° angle. Approximately 0.05 to 0.1 ml will be injected per needle stick. The size of the surgical field will determine the number of needle sticks needed. FIGs. 9A, B, and C show intradermal injection at a surgical site prior to an incision. FIG. 9A544938-1265-3208.2Attorney Docket No. : 145105-0109shows the first injection, FIG. 9B shows a second injection, and FIG. 9C depicts the needle length of 4 mm.

[0214] The volume of injectable composition required has been calculated as about 0.6 to about 1.0 ml per centimeter.

[0215] Example 2

[0216] The purpose of this example is to detail a method according to the present disclosure using an injection device as described herein, comprising the antimicrobial agent ceftriaxone.

[0217] Ceftriaxone can be reconstituted in a diluted concentration of 10 mg / ml, and provided in a vial.

[0218] A syringe, such as a BD 3 ml luer-lok (SKU 309577), is provided, ge. The ceftriaxone solution is then drawn up into the syringe.

[0219] A 4 mm, 30-32g, needle is attached to the syringe. The injection composition is then administered intradermally to a subject at a surgical site prior to surgery, utilizing a 15° angle for needle insertion. The volume of the injection mixture administered is about 1 to about 50 ml.

[0220] Within about 90 minutes following intradermal injection of the ceftriaxone, a surgical incision is made at the surgical site. The surgical incision is then followed by a surgical procedure.

[0221] It is anticipated that the intradermal injection of the ceftriaxone at the surgical site prior to a surgical incision will prevent or minimize the risk of the subject contracting an SSI.Example 3

[0222] The purpose of this example is to detail application of intradermal injections of an antibiotic (Clindamycin phosphate) at surgical sites for prevention of microbial infection in a dermatology clinic, utizling an injection device as described herein.

[0223] Patients at risk for surgical site infections were deemed candidates for clindamycin phosphate solution, administered in a combined mixture with 1% lidocaine hydrochloride.

[0224] To qualify for the injection of the clindamycin phosphate / lidocaine mixture, patients were required to have a biopsy diagnosis of either basal cell carcinoma or squamous cell554938-1265-3208.2Attorney Docket No. : 145105-0109carcinoma. Additionally, they were required to be considered at risk for a surgical site infection. The risk assessment was made by the attending surgeon. Patients deemed at risk had one or more of the following: significant defects, extremity location, multiple surgical layers taken before achieving negative margins, a history of infection with methicillin-resistant Staphylococcus aureus, a history of previous surgical site infection, diabetes, low serum albumin with frailty, or classified as immunocompromised due to medical history. Other factors not listed above may also influence the physician's decision to use an intradermal antibiotic for surgical prophylaxis.

[0225] The skin was prepared with a standard surgical scrub using chlorhexidine gluconate at the proposed surgical site. The antibiotic solution was prepared on the same day as use by the following method.

[0226] A sterile, multi-use 50 mb vial of 1% lidocaine hydrochloride was opened for the first time and diluted with a solution of clindamycin phosphate at 0.15 mg / mL. The clindamycin phosphate used was in a standard approved concentration of 150 mg / mL and stored in a 2 mb sterile, single-use vial. Exactly 0.15 mb of the clindamycin phosphate solution was withdrawn from the vial and added to the entire contents of the 50 mL lidocaine hydrochloride vial. The vial was gently agitated to ensure proper mixing of the two active ingredients. The final clindamycin phosphate concentration in the lidocaine 50 mL vial was estimated to be 408 pg / mL. The 50 mL vial was relabeled as "Lidocaine plus clindamycin 408 pg / mL." Sterile single-use, plastic, 3 mL BD Luer-Lok syringes were then filled to the 3 mL mark with this solution. The final step involved attaching a sterile single-use, 30-gauge, 4 mm needle to the 3 mL syringe.

[0227] All patients were screened for clindamycin allergies. They were informed to notify the clinic immediately if they experience symptoms such as hives, nausea, vomiting, chills, fever, or fainting, and to undergo screening for an allergic reaction. Patients were also advised to inform the clinic if they develop diarrhea, as clindamycin can cause colitis.

[0228] The size of the cancer to be excised was recorded along with any features indicating a previous wound infection before surgery. If a wound infection from the biopsy site was identified prior to surgery, these patients were then excluded from the study.

[0229] The patients received the antibiotic solution through injection with a 30-gauge, 4-mm needle, administered circumferentially around the skin cancer to be removed. The volume of 564938-1265-3208.2Attorney Docket No. : 145105-0109antibiotic was proportional to the size of the area to be excised. Cancers measuring 2 cm or less required 3 ml or less of the mixture, while those between 2 and 4 cm needed approximately 5-6 ml, delivered intradermally. The injections were given in a very superficial plane, producing a small bleb or wheal on the skin surface. These injections were positioned much more superficially than standard anesthetic injections. The 4-mm needle used pierced the skin at a 10° angle, and this combination of angle and short needle length consistently created a bleb, indicating deposition into the dermal layer.

[0230] No allergic reactions to this mixture were reported, and no cases of colitis were observed.

[0231] All patients were evaluated in the clinic between days 5 and 7 after surgery. Wound assessment was performed using a validated wound scoring technique upon return to the clinic. The wounds were classified as clean with no infection, suspected infection, or overt wound infection. Patients who required additional antibiotics due to suspected surgical site infection received antibiotics at that time.

[0232] About a dozen patients were successfully treated with this approach. This procedure was repeated to confirm the novelty of the method and ensure that the medication was deposited into the intradermal plane.Example 4

[0233] This example describes eradicating sinus tract biofilms via direct intralesional antibiotic therapy using an injection device described herein.

[0234] A 49 year old male patient, with a 20 year progressive disease history, with prior therapy failure, namely unresponsive to 8 months of adalimumab (40 mg / week) + oral clindamycin. The surface burden consisted of extensive, actively purulent, malodorous draining fistulas across bilateral gluteal and femoral regions. Additionally, the patient exhibited subdermal and systemic burden, comprising a 40 cm primary sinus tract, severe pain (NRS 8- 9 / 10), systemic inflammation (leukocytes: 17.11 / nL), and immobility causing hip / knee contractures, and a DLQI core of 19 (very severe).574938-1265-3208.2Attorney Docket No. : 145105-0109

[0235] The patient improved after intralesional antibiotic administration. Further surgery to remove the sinus tracts will be necessary. The intralesional therapy slows disease progression, calms inflammation, and effectively treats biofdm formation.

[0236] FIG. 21 details the morphological spectrum of HS lesions, starting from inflammatory nodules (acute, localized occlusion of the apocrine-follucular unit), next abscesses (rupture of the follicle spilling keratin, sebum, and bacteria into the dermis), then fistulas (epithelialized subdermal tunnels connecting abscesses), then draining fistulas (tunnels breaching the epidermis, actively discharging purulent fluid), then scarring (fibrotic tissue replacing normal architecture following chronic inflammation), and finally chronic granulomatous lesions (extensive, erreparable tissue damage with persistent deep-seated infection).

[0237] FIG. 22 details the surface phenotype of chronic granulomatous and fistulizing disease, including chronic granulomatous tissue (widespread inflammatory infiltration and irreparable tissue damage), draining fistulas (punctate surface openins linked to massive subdermal sinus networks), and fibrotic scarring (architectural distortion from decades of unmitigated recurrent abscesses). At this advanced stage, topical treatments are mechanically unable to penetrate the fibrotic tissue, and systemic treatments fail to reach therapeutic concentrations within the lesions.

[0238] FIG. 23 shows a macroscopic view of a recalcitrant draining fistula. Draining fistulas and chronic granulomatous lesions represent the end-stage architecture failure of the skin in HS. These permanent cutaneous breaches act as continuous sources of purulent discharge and systemic inflammation, heavily colonized by multidrug-tolerant microbial communities.

[0239] FIG. 24 shows the architecture of the sinus tract, with epidermal breach (small surface opening (the visible fistula)), anechoic fluid collection (purulent exudate pooling within the cavity), and epithelialized tract (the hardened, fibrotic wall of the subdermal tunnel preventing natural wound closure). Ultrasound reveals that seemingly isolated surface lesions are frequently connected by vast subdermal sinus tracts, serving as protected reservoirs for chronic polymicrobial infection.

[0240] FIG. 25 details the mechanism of recalcitrance of sinus tract biofilms. Biofilms are present in 67% of chronic HS lesions, and 63% of large biofilm aggregates (>50pm) are situated directly within these tunnels. The microbial profile shifts from commensal flora to aggressive 584938-1265-3208.2Attorney Docket No. : 145105-0109strict anaerobes (Prevotella, Porphyromotias) and Gram-negative rods as disease severity progresses.

[0241] In sum, severe HS is defined by subdermal sinus tracts that evade topical therapies and lack the vascularity required for systemic therapies. Further biofilms dictate recalcitrance. 67% of chronic lesions harbor polymicrobial biofilms. The Extracellular Polymeric Substance (EPS) creates a physical barrier that traditional delivery methods cannot overcome. Direct intralesional injection of antibiotics, utilizing an injection device described herein, of culture-directed antimicrobial agents (e.g., ertapenem, amikacin, gentamicin, clindamycin, etc) bypasses systemic shortfalls, shatters the biofilm matrix, and delivers curative concentrations directly to the epicenter of the disease.

[0242] FIG. 30 shows a diagram of an intra-lesional target site for injection, located within the dermis. The epidermis, dermis, and fibrotic tissue with high density layers of the skin are depicted, along with a complex, biofilm-laden sinus tract system.

[0243] FIG. 31 depicts a direct intralesional injection utilizing an injection device described herein. Recalcitrant HS lesions (nodules, abscesses, fistulas, and granulomas) can be effectively treated with direct intralesional injection of targeted antibiotics. This highly targeted delivery method bypasses the limitations of systemic circulation and poor local vascularity, placing the antimicrobial agent directly into the isolated dermal reservoir.* * *

[0244] While certain embodiments have been illustrated and described, it should be understood that changes and modifications can be made therein in accordance with ordinary skill in the art without departing from the technology in its broader aspects as defined in the following claims.

[0245] The embodiments illustratively described herein may suitably be practiced in the absence of any element or elements, limitation or limitations, not specifically disclosed herein. Thus, for example, the terms “comprising,” “including,” “containing,” etc. shall be read expansively and without limitation. Additionally, the terms and expressions employed herein have been used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described594938-1265-3208.2Attorney Docket No. : 145105-0109or portions thereof, but it is recognized that various modifications are possible within the scope of the claimed technology. Additionally, the phrase “consisting essentially of’ will be understood to include those elements specifically recited and those additional elements that do not materially affect the basic and novel characteristics of the claimed technology. The phrase “consisting of’ excludes any element not specified.

[0246] The present disclosure is not to be limited in terms of the particular embodiments described in this application. Many modifications and variations can be made without departing from its spirit and scope, as will be apparent to those skilled in the art. Functionally equivalent methods and injection compositions within the scope of the disclosure, in addition to those enumerated herein, will be apparent to those skilled in the art from the foregoing descriptions. Such modifications and variations are intended to fall within the scope of the appended claims. The present disclosure is to be limited only by the terms of the appended claims, along with the full scope of equivalents to which such claims are entitled. It is to be understood that this disclosure is not limited to particular methods, reagents, compounds, or compositions, which can of course vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

[0247] In addition, where features or aspects of the disclosure are described in terms of Markush groups, those skilled in the art will recognize that the disclosure is also thereby described in terms of any individual member or subgroup of members of the Markush group.

[0248] As will be understood by one skilled in the art, for any and all purposes, particularly in terms of providing a written description, all ranges disclosed herein also encompass any and all possible subranges and combinations of subranges thereof, inclusive of the endpoints. Any listed range can be easily recognized as sufficiently describing and enabling the same range being broken down into at least equal halves, thirds, quarters, fifths, tenths, etc. As a non-limiting example, each range discussed herein can be readily broken down into a lower third, middle third and upper third, etc. As will also be understood by one skilled in the art all language such as “up to,” “at least,” “greater than,” “less than,” and the like, include the number recited and refer to ranges which can be subsequently broken down into subranges as discussed above. Finally, as will be understood by one skilled in the art, a range includes each individual member.604938-1265-3208.2Attorney Docket No. : 145105-0109

[0249] All publications, patent applications, issued patents, and other documents referred to in this specification are herein incorporated by reference as if each individual publication, patent application, issued patent, or other document was specifically and individually indicated to be incorporated by reference in its entirety. Definitions that are contained in text incorporated by reference are excluded to the extent that they contradict definitions in this disclosure.

[0250] Other embodiments are set forth in the following claims.4938-1265-3208.2

Claims

Attorney Docket No. : 145105-0109I CLAIM:

1. An injection device, comprising:(a) a needle comprising a needle shaft, wherein the needle shaft comprises a length of about 2 to about 15 mm and a diameter of about 24 to about 35 gauge;(b) an injection solution present at a volume of from about 1 ml to about 50 ml, or a sterile powder for reconstitution as the injection solution, wherein the injection solution comprises at least one diluent and at least one antimicrobial agent, wherein the antimicrobial agent is present at a a therapeutically effective microdose; and(c) a syringe comprising the injection solution.

2. The injection device of claim 1, wherein the needle shaft length is selected from the group consisting of about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14 mm, and about 15 mm.

3. The injection device of claim 1 or 2, wherein the needle shaft length is about 4mm.

4. The injection device of any one of the preceeding claims, wherein the needle gauge is selected from the group consisting of about 24g, about 25g, about 26g, about 27g, about 28g, about 29g, about 30g, about 31g, about 32g, about 33g, about 34g, and about 35g.

5. The injection device of any one of the preceeding claims, wherein the needle has a thin wall lumen.

6. The injection device of any one of the preceeding claims, wherein the syringe is darkened to protect the antimicrobial agent from light exposure degradation.

7. The injection device of any one of the preceeding claims, wherein the injection solution is present at a volume of from about 1 ml to about 10 ml.

8. The injection device of any one of the preceeding claims, wherein the antimicrobial agent is selected from the group consisting of an antibacterial agent, an antiviral agent, an antiparasitic agent, and an antifungal agent.Attorney Docket No. : 145105-01099. The injection device of any one of the proceeding claims, wherein:(a) the at least one antimicrobial agent is selected from the group consisting of amikacin, amoxicillin, ansamycins, arsphenamine, Augmentin (an amoxicillin / Clavulanic acid combination), carbacephems, carbapenems, cefaclor, cefoxitin, cefazolin, cefdinir, ceftaroline, ceftriaxone, cefuroxime, cephalexin, cephalosporins, chloramphenicol, ciprofloxacin, clindamycin, dalbavancin, dapsone, daptomycin, delafloxacin, doxycycline, ertapenem, ethambutol, fosfomycin, fusidic acid, furazolidone, fluoroquinolones, gentamicin, glycylcyclines, glycopeptides, isoniazid, lincosamides, lincomycin, linezolid, lipopeptides, lipoglycopeptides, lofazimine, macrolides, metronidazole, minocycline, monobactams, mupirocin, nafcillin, nitrofurantoin, ofloxacin, oritavancin, oxazolidinones, penicillins, platensimycin, polypeptides, polymyxin, pyrazinamide, quinolones, quinupristin-dalfopristin, rifampicin, streptogramin, sulfonamides, sulfonamide combinations, tedizolid, tetracycline derivatives, thiamphenicol, tigecy cline, tinidazole, trimethoprim / sulfa, trimethoprimsulfamethoxazole, vancomycin, ertapenem, and any combination thereof; and / or(b) the at least one antimicrobial agent is an antiviral agent which is selected from the group consisting of Oseltamivir, Zanamivir, Peramivir, Baloxavir, Nucleoside / Nucleotide Reverse Transcriptase Inhibitors (NRTIs), Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs), Integrase Strand Transfer Inhibitors (INSTIs), Protease inhibitors (Pls), entry / attachment / post-attachment inhibitors, capsid, direct-acting antiviral agents (DAAs) such as Elbasvir, Nucleoside analogues, interferons, nucleoside phosphonates, Acyclovir, Famciclovir, Ganciclovir, Foscarnet, Cidofovir, Ribavirin, monoclonal antibodies, Imiquimod, Sinecatechins, Podofilox, Remdesivir, Paxlovid (nirmatrelvir + ritonavir), Molnupiravir, Tecovirimat, and any combination thereof; and / or(c) the at least one antimicrobial agent is an antiparasitic agent, which is selected from the group consisting of Albendazole, Mebendazole, Ivermectin, Pyrantel pamoate, Praziquantel, Triclabendazole, Moxidectin, Nitazoxanide, Pyrimethamine, Metronidazole, Tinidazole, Miltefosine, Fexinidazole, Melarsoprol, Eflornithine, Fexinidazole, Miltefosine, and any combination thereof; and / or(d) the at least one antimicrobial agent is an antifungal agents, which is selected from the group consisting of Polyene Antifungals, Azole Antifungals, Echinocandins,Attorney Docket No. : 145105-0109Allylamines, Pyrimidine (Nucleic Acid) Analogs, and Glucan Synthase (Novel) Inhibitors, and any combination thereof.

10. The injection device of any one of the preceeding claims, wherein the antimicrobial agent is clindamycin, vancomycin, gentamicin, lincomycin, cefazolin, or any combination thereof.

11. The injection device of any one of the preceeding claims, wherein:(a) the therapeutically effective microdose of the antimicrobial agent is from > about 0.01 mg / ml up to about 10 mg / ml; and / or(b) the therapeutically effective microdose of the antimicrobial agent is less than the dose for the same antimicrobial agent given systemically; and / or(c) the therapeutically effective microdose of the antimicrobial agent comprises an antimicrobial concentration which is above the MIC value for the antimicrobial agent.

12. The injection device of any one of the preceeding claims wherein:(a) the antimicrobial agent is vancomycin, and when formulated into an injection solution, the concentration of vancomycin in the injection solution is about 100 to about 600 pg / ml; or(b) the antimicrobial agent is clindamycin, and when formulated into an injection solution, the concentration of clindamycin in the injection solution is about 200 to about 800 pg / ml; or(c) the antimicrobial agent is ceftriaxone, and when formulated into an injection solution, the concentration of ceftriaxone in the injection solution is about 100 to about 700 pg / ml; or(d) the antimicrobial agent is flucl oxacillin, and when formulated into an injection solution, the concentration of flucl oxacillin in the injection solution is about 0.5 mg / ml up to about 25 mg / ml; or(e) the antimicrobial agent is gentamicin, and when formulated into an injection solution, the concentration of gentamicin in the injection solution is about 200 up to about 800 pg / ml; orAttorney Docket No. : 145105-0109(f) the antimicrobial agent is lincomycin, and when formulated into an injection solution, the concentration of lincomycin in the injection solution is about 100 to about 800 pg / ml; or(g) the antimicrobial agent is cefazolin, and when formulated into an injection solution, the concentration of cefazolin in the injection solution is about 200 to about 800 pg / ml.

13. The injection device of any one of the preceeding claims, wherein the diluent is an aqueous or non-aqueous diluent.

14. The injection device of claim 13, wherein:(a) the diluent is aqueous and is selected from the group consisting of Water for Injection (WFI), sterile water, bacteriostatic water, saline, normal saline, dextrose in water, and lactated Ringer’s solution; and / or(b) the diluent is non-aqueous and is selected from the group consisting of a vegetable oil, medium-chain triglycerides, biocompatible solvents, cyclodextrin, squalene, squalane, silicone oils, and any combination thereof.

15. The injection device of any one of the preceeding claims, wherein the injection solution further comprises one or more excipients.

16. The injection device of claim 15, wherein the excipient improves solution stability, improves antimicrobial agent physical and / or chemical stability, adjusts pH, prevents precipitation, provides for a long-acting injectable formulation, or any combination thereof.

17. The injection device of claim 15 or 16, wherein the excipient is selected from the group consisting of sodium chloride, buffering agents, preservatives, chelating agents, lactate, dextrose, nanoporous silicon dioxide, hydrochloric acid, and sodium hydroxide.

18. The injection device of any one of the preceeding claims, wherein the pH of the injection solution is from about 3.0 to about 7.8, about 7.0 to about 7.8, about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, about 7.5, about 7.6, about 7.7, or about 7.8.

19. A kit comprising the injection device of any one of the preceeding claims.Attorney Docket No. : 145105-010920. The kit of claim 19, wherein the kit is multi-dose or single use.

21. The kit of claim 19 or 20, further comprising a guide for needle depth and / or angle insertion.

22. The kit of any one of claims 19-21, further comprising directions for use.

23. A method of prophylaxis against surgical site infection (SSI) comprising:(a) identifying a skin or mucosal surgical site of a subject; and(b) prior to a surgical incision, intradermally injecting into the subject’s dermis layer of the skin or mucosa at the surgical site a therapeutically effective microdose of at least one antimicrobial agent utilizing the injection device of any one of claims 1-17.

24. The method of claim 232, wherein a surgical incision is made within about 12 hrs following the intradermal injection.

25. The method of claim 24, wherein a surgical incision is made within about 15 mins, about 20 mins, about 30 mins, about 45 mins, about 60 mins, about 75 mins, about 90 mins, about 2 hrs, about 3 hrs, about 4 hrs, about 5 hrs, about 6 hrs, about 7 hrs, about 8 hrs, about 9 hrs, about 10 hrs, about 11, hrs or about 12 hrs following the intradermal injection.

26. The method of any one of claims 23-25, further comprising performing a surgical procedure after making the surgical incision.

27. A method of preventing, minimizing the risk of, and / or treating a microbial infection associated with a condition or procedure, comprising injecting into a subject at an appropriate site a therapeutically effective microdose of at least one antimicrobial agent utilizing the injection device of any one of claims 1-17,wherein the condition is selected from the group consisting of:(a) a skin or mucosal wound;(b) a cutaneous infection;(c) a lesion;(d) a biofilm;Attorney Docket No. : 145105-0109(e) surgical antibiotic prophylaxis (SAP) of pacemaker insertions;(f) SAP for insertion of Cardiac Implantable Electronic Device (CIED);(g) SAP of venous access catheters;(h) SAP of ports for administration of oncology drugs;(i) SAP of central line catheters;(j) SAP of tracheotomy placement;(k) SAP for chest tube placement;(l) SAP for removal of a foreign body;(m) Hidradenitis Supprativa;(n) orthopedic trauma;(o) soft tissue injuries;(p) acute bacterial skin and skin structure infections (ABSSSI);(q) Mycetomas;(r) Eumycetoma;(s) Actinomycetes infection;(t) Mycobacterium ulcerans infection;(u) Maduromycosis infection;(v) Actinomycetoma infection;(w) Pseudomonas infection;(x) Gram Negative bacterial infections;(y) Klebsiella infection;(z) E. Coli infection;(aa) necrotizing faciatis;(bb) Hidradenitis Suppurativa (HS), and(cc) any combination thereof.

28. The method of any one of claim 23-27, wherein the site of injection is any dermal or cutaneous site.

29. The method of claim 28, wherein the site of injection is a wound, abscess, inflammatory nodule, intra-wound, intra-articular, mucosa, or any intradermal layer of the skin.Attorney Docket No. : 145105-010930. The method of any one of claims 23-29, administered by medical personnel, nonmedical personnel, a caregiver, a first responder, military personnel, self-administered, or any combination thereof.

31. The method of any one of claims 23-30, wherein:(a) the injection does not comprise injection of the antimicrobial agent into a muscle tissue of the subject; and / or(b) the injection does not comprise injection of the antimicrobial agent into a hypodermis layer of the skin of the subject.

32. The method of any one of claims 23-31, comprising intradermally injecting the injection solution comprising the antimicrobial agent.

33. The method of any one of claims 23-32, wherein the volume of the injection solution is about 1 to about 50 mb.

34. The method of any one of claims 23-33, wherein the volume of the injection solution is less than or equal to about 10 mb.

35. The method of any one of claims 23-34, wherein the volume of the injection solution administered per injection site is about 0.1 to about 2.0 mL.

36. The method of any one of claims 23-35, wherein the total volume of injection solution administered, via either a single or multiple injections, is about <10 mL up to about 50 mL.

37. The method of any one of claims 23-36, for use in preventing, minimizing the risk of, and / or treating a microbial infection of a skin or mucosal wound site of a subject.

38. The method of any one of claims 23-36, used to treat a patient population having a soft tissue injury and at risk of a microbial infection due to a natural disaster.

39. The method of any one of claims 23-36, wherein the method is used to treat a patient population having a soft tissue injury due to active conflict.

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