Intradermal injection of antimicrobial and local anesthetic

Abstract

Described are compositions, kits and methods for preventing, minimizing the risk of, or treating a microbial infection at a wound or surgical site. The method comprises injecting a combination of a therapeutically effective microdose of a microbial agent and a local anesthetic into the dermis layer of the skin. The composition can be administered by medical personnel, provided by non-clinical personnel, or self-administered.

Description

Attorney Docket No. 145105-0106DSW-31INTRADERMAL INJECTION OF ANTIMICROBIAL AND LOCAL ANESTHETICCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] The present application claims the benefit of U.S. Provisional Application No. 63 / 689,995, filed September 3, 2024, the contents of which are incorporated herein by reference in their entirety.Technical Field

[0002] This invention relates to methods of preventing, reducing the risk of, and / or treating microbial infections at surgical or wound sites, comprising administering a combination of and least one antimicrobial agent and at least one local anesthetic agent by intradermal injection, and compositions and kits relating to the same.Background

[0003] Despite many advances in surgical procedures and technology, surgical site infections (SSI) and wound site infections remain a significant concern. SSIs are a common complication of surgery. SSIs contribute to prolonged hospital stays, increased healthcare costs, and in severe cases, can even lead to mortality. Using prophylactic oral or intravenous antibiotics has been a cornerstone in preventing SSIs. However, they are often insufficiently effective, especially in high-risk surgeries or with antibiotic-resistant bacterial strains. Microbial infections at wound sites of a subject’s skin or mucosa are also a significant health concern.

[0004] Intra incisional cutaneous delivery of antibiotics is known to result in decreased rates of postoperative wound infection after Mohs surgery when compared to the administration of local anesthetic alone. Griego R, Zitelli J., Arch Dermatol. 734:688-692 (June 1998); Lalla et al., Ini.J. of Surgery Open, 47: 100556 (2022); Soleymani et al., J. Am. Acad, of Dermatol., 83(5): 1501- 1503 (Nov. 2020). However, this method is distinct from the present disclosure, which is directed to intradermal delivery.

[0005] There is long-standing interest in the development of more effective approaches to mitigate the risk of SSIs and microbial infections associated with wound sites. One promising approach is using intra-inci sional 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:14915-3836-0164.1Attorney Docket No. 145105-0106DSW-31 localized drug delivery directly to the target site at high concentration; reduced systemic side effects; reduce the 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 reduce the incidence of Clostridium difficile infection. Despite the promising potential of intra-incisional antibiotics, there remains a need for further advancements in formulation design and delivery techniques.Summary

[0006] This invention is directed to a method of preventing, reducing the risk of, and / or treating microbial infections associated with surgical sites, and compositions and kits related to the same. The method comprises injecting an aqueous composition (injection mixture) into the dermis layer of the skin. The aqueous composition comprises at least one antimicrobial agent and at least one local anesthetic agent. Alternatively, the at least one antimicrobial agent and the at least one local anesthetic agent can be administered sequentially. The skin injection may be performed with a syringe with a needle attached thereto. The skin injection may be administered into both the papillary and the reticular sublayers of the dermis layer.

[0007] In a first aspect, provided is a composition for intradermal administration comprising a combination of (a) a therapeutically effective microdose of at least one antimicrobial agent; and (b) a therapeutically effective amount of at least one local anesthetic agent.

[0008] In one embodiment, the therapeutically effective microdose of the antimicrobial agent ranges from > 0.01 mg / ml up to about 10 mg / ml; and / or the therapeutically effective microdose of the antimicrobial agent is less than the dose for the same antimicrobial agent given systemically; and / or the therapeutically effective microdose of the antimicrobial agent comprises an antimicrobial concentration which is above the MIC value for the antimicrobial agent. In another embodiment, the volume of the composition for intradermal injection ranges from about 1 ml up to about 20 ml.In another aspect of the disclosure, the local anesthetic agent is intradermally administered at a dosage which is less than the dosage required for the same anesthetic to be given systemically. For example, the local anesthetic agent can be present at a concentration of about 0.1% up to about 10%, and administered at a total volume of about 0.1 mL up to about 50 mL. In other aspects of the disclosure, the local anesthetic agent is present at a concentration of: (a) about24915-3836-0164.1Attorney Docket No. 145105-0106 DSW-31 0.1 % up to about 10%; (b) about 0.1 % up to about 5%; (c) about 0.5%, (d) about 1 .0%, (e) about 1.5%, or (f) about 2.0%.

[0009] In a further aspect of the disclosure, the at least one antimicrobial agent and at least one local anesthetic agent are present: (a) in an injectable dosage form; or (b) in a sterile powder for reconstitution as an injectable dosage form.

[0010] In another embodiment of the disclosure, the at least one antimicrobial agent is selected from the group consisting of an antibacterial agent, an antiviral agent, an antiparasitic agent, and an antifungal agent. For example, (a) the at least one antimicrobial agent can be selected from the group consisting of 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, thi amphenicol, tigecycline, tinidazole, trimethoprim / sulfa, trimethoprimsulfamethoxazole, vancomycin, and any combination thereof; (b) the at least one antimicrobial agent can be 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-attachm ent 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; (c) the at least one antimicrobial agent can be an antiparasitic agent, which is selected from the group consisting ofAlbendazole, Mebendazole, Ivermectin, Pyrantel pamoate, Praziquantel, Triclabendazole, Moxidectin, Nitazoxanide, Pyrimethamine, Metronidazole, Tinidazole,34915-3836-0164.1Attorney Docket No. 145105-0106DSW-31Miltefosine, Fexinidazole, Melarsoprol, Eflornithine, Fexinidazole, Miltefosine, and any combination thereof; and / or (d) the at least one antimicrobial agent can be an antifungal agents, which is selected from the group consisting of Polyene Antifungals, Azole Antifungals, Echinocandins, Allylamines, Pyrimidine (Nucleic Acid) Analogs, and Glucan Synthase (Novel) Inhibitors, and any combination thereof.

[0011] In another embodiment of the disclosure, the at least one local anesthetic agent is selected from the group consisting of a nonsteroidal anti-inflammatory drug (NS AID), acetaminophen, articaine, articaine / epinephrine, benzocaine, bupivacaine, bupivacaine / epinephrine, buprenorphine, butorphanol, carbocaine, carfentanil, chloroprocaine, cocaine, codeine, dibucaine, diclofenac, etidocaine, fentanyl, hydrocodone, hydromorphone ibuprofen, ketorolac, lidocaine, lidocaine / epinephrine, lidocaine / tetracaine, marcaine, meloxicam, mepivacaine, methodone, morphine, moxicaine, naproxen, an opioid, oxycodone, oxymorphone, procaine, ropivacaine, tetracaine, toralac, xylocaine / epinephrine, septocaine, tetracaine, tetracine, thebaine, topicaine, tramadol, xylocaine, vivacaine, zorcaine, and any combination thereof.

[0012] In one embodiment, the antimicrobial agent is ceftriaxone and the local anesthetic agent is lidocaine; or the antimicrobial agent is vancomycin and the local anesthetic agent is bupivacaine.

[0013] In another embodiment, (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 flucioxacillin 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; or (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 about44915-3836-0164.1Attorney Docket No. 145105-0106DSW-31800 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.

[0014] In a further aspect of the disclosure, the composition to be administered intradermally further comprises a diluent. The diluent can be, for example, aqueous or non-aqueous. In addition, an aqueous diluent can be, for example, selected from the group consisting of sterile water, bacteriostatic water, saline, dextrose in water, and lactated Ringer’s solution; or the diluent can be non-aqueous and, for example, selected from the group consisting of a vegetable oil, medium-chain triglycerides, biocompatible solvents, cyclodextrin, squalene, squalane, silicone oils, and any combination thereof.

[0015] In another embodiment, the disclosure encompasses kits comprising compositions according to the disclosure. For example, the disclosure encompasses a kit comprising: (a) a container or syringe comprising a therapeutically effective microdose of at least one antimicrobial agent; (b) a therapeutically effective amount of at least one local anesthetic; and (c) a needle having a length of about 2 mm to about 15 mm and a gauge of about 24 up to about 35. In another aspect, the needle length is about 4 mm. In yet another aspect, (a) the at least one antimicrobial agent and the at least one local anesthetic agent are present in the same container or syringe; or (b) the at least one antimicrobial agent and the at least one local anesthetic agent are present in different containers or syringes. In addition, the kit can be multi -dose or single use. Further, the kit can additionally comprise a guide for needle depth and / or angle insertion.

[0016] The disclosure also encompasses methods 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 combination of a therapeutically effective microdose of at least one antimicrobial agent and a therapeutically effective amount of at least one local anesthetic agent. In another aspect, a surgical incision is made within about 12 hrs following the intradermal injection, or 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. In a further aspect, a surgical procedure is performed after making the surgical incision.54915-3836-0164.1Attorney Docket No. 145105-0106DSW-31

[0017] The disclosure also encompasses methods of preventing, minimizing the risk of, and / or treating a microbial infection of a skin or mucosal wound site of a subject, comprising: intradermally injecting into a subject’s dermis layer of the skin or mucosa at the wound site a combination of a therapeutically effective microdose of at least one antimicrobial agent and a therapeutically effective amount of at least one local anesthetic agent.

[0018] In another aspect of the methods of the disclosure, the combination is administered by medical personnel, non-medical personnel, a caregiver, a first responder, military personnel, self- administered, or any combination thereof. In a further aspect, of the methods of the disclosure, (a) the intradermal injection does not comprise injection of the antimicrobial agent or the local anesthetic agent into a muscle tissue of the subject; and / or (b) the intradermal injection does not comprise injection of the antimicrobial agent or the local anesthetic agent into a hypodermis layer of the skin of the subject.

[0019] For all of the methods described herein, the antimicrobial agent can be selected from the group consisting of an antibacterial agent, an antiviral agent, an antiparasitic agent, and an antifungal agent. For example, (a) the at least one antimicrobial agent can be selected from the group consisting of 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, tigecy cline, tinidazole, trimethoprim / sulfa, trimethoprimsulfamethoxazole, vancomycin, and any combination thereof; and / or (b) the at least one antimicrobial agent can be 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-attachment64915-3836-0164.1Attorney Docket No. 145105-0106 DSW-31 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 can be an antiparasitic agent, which is selected from the group consisting ofAlbendazole, 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 can be an antifungal agents, which is selected from the group consisting of Polyene Antifungals, Azole Antifungals, Echinocandins, Allylamines, Pyrimidine (Nucleic Acid) Analogs, and Glucan Synthase (Novel) Inhibitors, and any combination thereof; and / or (e) the at least one local anesthetic can be selected from the group consisting of a nonsteroidal anti-inflammatory drug (NS AID), meloxicam, diclofenac, morphine, benzocaine, lidocaine, bupivacaine, tetracaine, ropivacaine, marcaine, mepivacaine, cocaine, articaine / epinephrine, carbocaine, lidocaine / epinephrine, bupivacaine / epinephrine, lidocaine / tetracaine, xylocaine / epinephrine, septocaine, tetracine, chloroprocaine, dibucaine, moxicaine, topicaine, xylocaine, vivacaine, zorcaine, and any combination thereof.

[0020] In one embodiment for the methods of the disclosure, (a) the local anesthetic agent suppresses sympathetic activation of an accessory skin structure; and (b) suppression of sympathetic activation of the accessory skin structure prevents and / or minimizes release of bacteria and / or microbes from the accessory skin structure. In another aspect, the accessory skin structure is a hair follicle, sweat gland, sebaceous gland, or any combination thereof.

[0021] In another embodiment for the methods of the disclosure, the method comprises intradermally injecting a mixture of the antimicrobial agent and the local anesthetic agent. Alternative, the method comprises sequentially intradermally administering: (a) a first injection comprising the antimicrobial agent and a second injection comprising the local anesthetic agent; or (b) a first injection comprising the local anesthetic agent and a second injection comprising the antimicrobial agent.74915-3836-0164.1Attorney Docket No. 145105-0106DSW-31

[0022] For all of the methods described herein, the volume of the intradermal injection comprising a combination of a microdose of at least one antimicrobial agent and at least one local anesthetic agent, administered either as a single composition comprising a combination of the antimicrobial agent and the local anesthetic, or administered as two separate compositions, a first composition comprising the antimicrobial agent and a second composition comprising the local anesthetic, can be from about 1 to about 50 ml. In a further aspect, the volume is less than or equal to about 10 ml.

[0023] In one embodiment of the methods of the disclosure, the combination of a therapeutically effective microdose of at least one antimicrobial agent and at least one local anesthetic agent is formulated into an injection composition comprising a diluent. In another aspect, the method of claim 35, wherein the diluent is aqueous or non-aqueous. For example, the diluent can be aqueous and can be, for example, selected from the group consisting of sterile water, bacteriostatic water, saline, dextrose in water, and lactated Ringer’s solution; or the diluent can be non-aqueous and can be, for example, selected from the group consisting of a vegetable oil, medium-chain triglycerides, biocompatible solvents, cyclodextrin, squalene, squalane, silicone oils, and any combination thereof.

[0024] In a further aspect, the compositions of the disclosure for injection have a pH of about 7.0 to about 7.8.

[0025] In yet another embodiment, the methods of the disclosure can be 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 embodiment, the methods are used to treat a patient population having a soft tissue injury due to active conflict.

[0026] In some embodiments, the injection mixture is injected exclusively in the dermis layer of the skin. In some cases, the aqueous injection mixture is not injected into muscle tissue. In some cases, the aqueous injection mixture is not injected into the hypodermis (i.e. the fatty layer or subcutaneous layer).

[0027] The method may further comprise making the injection mixture using a syringe. The local anesthetic agent may be provided as an aqueous solution and is drawn into the syringe. The antimicrobial agent is provided in a vial. The local anesthetic agent (comprised in the syringe) is then instilled into the vial containing the antimicrobial agent. The local anesthetic agent and the84915-3836-0164.1Attorney Docket No. 145105-0106DSW-31 antimicrobial agent are mixed together within the vial to create the aqueous injection mixture. The aqueous injection mixture is drawn up into the syringe.Brief Description of the Drawings

[0028] FIG. 1 shows the three main layers of the skin.

[0029] FIG. 2 shows the two sublayers of the dermis.

[0030] FIG. 3 shows various accessory skin structures.

[0031] FIG. 4 shows an example of how the invention could be implemented.

[0032] FIG. 5 shows a diagram of a needle positioned in the intradermal layer of the skin (injection into the dermis) as compared to a needle injecting into the muscle layer or subcutaneous layers of the skin.

[0033] FIG. 6 shows a diagram of intradermal injection, with a needed administered at an angle to insert the mixture of at least one antibiotic and at least one anesthetic to a surgical site (alternatively, the at least one antibiotic and at least one anesthetic can be administered sequentially, or simultaneously using separate needles).

[0034] 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, 140 2Q2 .62-7 . 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). Guarch-Perez et al.

[0035] FIG. 8 depicts an exemplary injection kit for use in the methods described herein, comprising a sterile vial of at least one antibiotic, at least one local anesthetic which can also function as a diluent (e.g., lidocaine), an adapter device, a syringe, and a 2.5 mm needle for intradermal delivery.

[0036] FIGs. 9A, B, and C show intradermal injection at a surgical site prior to an incision. FIG. 9A shows the first injection, FIG. 9B shows a second injection, and FIG. 9C depicts the short hollow hypodermic needle length of 4 mm.94915-3836-0164.1Attorney Docket No. 145105-0106DSW-31Detailed Description of Example EmbodimentsI. Overview

[0037] The present invention is directed to the surprising and unexpected discovery that a combination of a therapeutically effective microdose of at least one antimicrobial agent and at least one local anesthetic agent can be intradermally administered, resulting in effective treatment and / or prevention of microbial infection in combination with providing localized pain relief. This combination is useful, for example, in preventing, minimizing the risk of, and / or treating microbial infections at surgical and wound sites.

[0038] Intradermal microdosing of antimicrobial agents addresses the challenge of preventing wound and / or surgical site infections by delivering an effective antimicrobial and local anesthetic 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 attained via oral administration. Consequently, the concern regarding suboptimal systemic penetration into the surgical site, well-documented for both oral and intravenous routes, becomes irrelevant.

[0039] 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.

[0040] 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 personnel104915-3836-0164.1Attorney Docket No. 145105-0106 DSW-31 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, and a local anesthetic, in a disposable plastic syringe could be a major breakthrough for military use, austere environments, emergency departments, and routine surgical antibiotic prophylaxis.

[0041] 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. Siirg. (Land)., 83: 104324 (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.

[0042] The present disclosure addressees a long felt need for improved compositions, 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 and animal), puncture wounds (animal / human / penetrating debris), as well as any injury that compromises the skin or mucosal barrier.

[0043] 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, oral114915-3836-0164.1Attorney Docket No. 145105-0106DSW-31 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.

[0044] Notably, it was surprisingly and unexpectedly discovered that the combination of a therapeutically effective microdose of at least one antimicrobial agent and at least one local anesthetic agent, administered intradermally either simultaneously or sequentially, produced synergistic results. In particular, it is believed that the local anesthetic agent (injected into the dermis) has a protective effect against microbial infection by suppressing the sympathetic activation of the accessory skin structures, thereby preventing the release of bacteria or microbes that reside therein. That is, the local anesthetic agent causes an analgesia effect on the sympathetic nerve fibers, thereby suppressing activation of the innervated accessory skin structures and avoiding bacterial spillage therefrom. This was not known or suggested prior to the present disclosure.

[0045] Previously, the US FDA evaluated a kit comprising a combination of lidocaine and clindamycin for intramuscular injection, and after the clinical studies were completed and reviewed by the FDA, it was determined that these two active pharmaceutical ingredients were compatible. (Hoffmann La Roche previously offered a Rocephin Kit under NDA 50585). This product was packaged as 500 mg and 1 g vials of Ceftriaxone Sodium and Lidocaine Injection 1% (2.1 mL fill). This product was marketed as the Rocephin Intramuscular Convenience Kit, but this product was only approved for intramuscular use and not approved or evaluated for intradermal use.

[0046] 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, 74d(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; -7: 1431. Bacteria reside in the124915-3836-0164.1Attorney Docket No. 145105-0106DSW-31 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.

[0047] 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, 207:114517 (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).

[0048] The present invention is directed to the surprising and expected discovery that a combination of a therapeutically effective microdose of at least one antimicrobial agent and at least one local anesthetic can be administered to the dermis, resulting in synergistic and effective treatment and / or prevention of microbial infection in combination with providing localized pain relief. This combination is useful, for example, in preventing and / or treating infections at surgical sites and wound sites, along with providing pain relief and / or prevention at such surgical sites and wound sites. In particular, high local tissue concentrations of at least one antimicrobial agent in combination with at least one local anesthetic agent delivered intradermally within the “golden hour” timeframe is a primary factor for success in surgical antibiotic prophylaxis.

[0049] The compositions, kits and methods of the disclosure enable targeted delivery of at least one antimicrobial agent, at a therapeutically effective microdosed concentration, in combination with at least one local anesthetic. Dermal interstitial antimicrobial tissue levels of 30 to 60 times (Huether et al., Arch Dermatol. 2002 Sept; 73S:1145-1148) greater than systemic routes can be achieved (FIG. 6). Such high local active agent concentrations ensure an effective antimicrobial agent and local anesthetic 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.134915-3836-0164.1Attorney Docket No. 145105-0106DSW-31

[0050] Intradermal delivery advantages of the combination of a therapeutically effective microdose of at least one antimicrobial agent and at least one local anesthetic agent for the present invention include, for example: (1) preoperative antimicrobial agent and local anesthetic agent administration tailored to the onset of a surgical procedure, (2) minimally invasive administration for the at least one antimicrobial agent in combination with at least one local anesthetic agent, (3) increased antimicrobial efficacy as compared to systemic delivery of the same antimicrobial agent, (4) increased anesthetic efficacy as compared to systemic delivery of the same local anesthetic agent, (5) reduced human toxicity relating to the antimicrobial agent and / or local anesthetic agent as compared to systemic delivery of the same antimicrobial and / or anesthetic agent, (6) a reduced drug dosage for the antimicrobial agent and / or local anesthetic agent required to effectively treat and / or prevent an infection and / or pain as compared to systemic administration of the same antimicrobial agent and / or local anesthetic 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, (8) the intradermal administration method results in higher local anesthetic agent tissue levels with greater efficacy as compared to systemic administration of the same local anesthetic agent, (9) a reduced risk of systemic adverse events for the antimicrobial agent and / or local anesthetic agent as compared to systemic delivery, (10) elimination of nausea associated with oral administration of antimicrobial agents and / or local anesthetic agents, (11) minimal exposure of major organ systems of the body, including renal and CNS, to the antimicrobial agent and / or local anesthetic agent, as compared to systemic delivery of the same antimicrobial agent and / or local anesthetic 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 and / or local anesthetic 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 and / or local anesthetic 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 or injectable, to an intradermal144915-3836-0164.1Attorney Docket No. 145105-0106DSW-31 method for surgical antimicrobial agent prophylaxis, in combination with providing a local anesthetic, facilitates these objectives.

[0051] 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.

[0052] 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.

[0053] 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., Fig. 5). 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.

[0054] 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 skin154915-3836-0164.1Attorney Docket No. 145105-0106DSW-31 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.

[0055] 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 a static 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.

[0056] 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.

[0057] Intradermal Delivery: Understanding the pharmacokinetics of antibiotics is essential; however, it is not enough to establish suitable dosage regimens on its own. An additional164915-3836-0164.1Attorney Docket No. 145105-0106 DSW-31 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 110 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 by oral or intravenous delivery. Thus, this delivery route is unique in that the previous reliance on plasma concentration levels is not a requirement.

[0058] 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.

[0059] 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 and anesthetic are 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 and anesthetics 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.II. Intradermal Administration Device

[0060] Intradermal delivery requires the use of short hollow hypodermic needles to successfully deliver at least one antimicrobial agent and at least one local anesthetic 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 and at least one local anesthetic agent was surprising as at least as of November 2024, “[t]he understanding of drug penetration through different skin174915-3836-0164.1Attorney Docket No. 145105-0106DSW-31 layers, its absorption into blood capillaries or lymphatics, and dermal metabolism remains limited.” Koenitz et al.

[0061] Any suitable short hollow hypodermic needle for targeting drug delivery to the dermis can be used in the methods of the disclosure. 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. In one aspect, a short hollow hypodermic needle of about 4 mm in length, is utilized, but shorter and longer short hollow hypodermic needle lengths can also be effectively used, e.g., a short hollow hypodermic needle length of about 2 mm to about 15 mm in length, and an about 24 to about 35 gauge, can be used to target administration to the dermis of a subject’s skin or mucosa. High frequency ultrasound imaging confirms this length, e.g., about 4 mm, or a range of about 2 - about 15 mm, as optimal, and no previous studies report delivering an intradermal antimicrobial agent with a 4 mm needle.

[0062] 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.

[0063] 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.

[0064] 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 and / or local anesthetic agent solution to be injected while utilizing the184915-3836-0164.1Attorney Docket No. 145105-0106DSW-31 retraction technique. See FTG. 5. In a first aspect of a method of the disclosure, a mixture of at least one antimicrobial agent and at least one local anesthetic 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. In another aspect, a solution of at least one antimicrobial agent and a separate solution of at least one local anesthetic agent are administered sequentially to a skin or mucosa wound site, or to a surgical site prior to, during, or after surgery. Either the at least one antimicrobial agent or the at least one local anesthetic agent can be delivered first, when the two are delivered separately and sequentially.

[0065] 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.

[0066] The angle of 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.

[0067] 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 and local anesthetic agent directly into the intradermal space. In particular, a suitable needle 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, or about 14, mm. A suitable needle gauge can be from about 24g up to about 35g, and can be for example, 24g, 25g, 26g, 27g, 28g,194915-3836-0164.1Attorney Docket No. 145105-0106 DSW-3129g, 30g, 31g, 32g, 33g, 34g, or 35g. In one aspect, the needle gauge is from about 30g to about 32-gauge in diameter.

[0068] Further, 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°.

[0069] An example of a needle that can be used in the 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 can cause more patient discomfort).

[0070] 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.

[0071] 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, in combination with a local anesthetic agent, precisely administered using a microneedle can effectively prevent, minimize and / or treat SSIs. Additionally, only a small syringe, between 1 and 3 mL, 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. This is204915-3836-0164.1Attorney Docket No. 145105-0106 DSW-31 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.

[0072] In one 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 sites.

[0073] Another 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 and local anesthetic agent are deposited in the correct skin layer. Ultimately, this compositions, 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 and local anesthetic is placement into the dermis, where bacteria that can cause surgical site infections reside.

[0074] 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 and at least one anesthetic. An optimal combination of needle length, gauge, and injection angle facilitate the method of the disclosure.

[0075] 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 thickness 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 thickest214915-3836-0164.1Attorney Docket No. 145105-0106 DSW-31 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).

[0076] In one aspect, the short hollow hypodermic needle utilized in the methods of the disclosure has a length of about 2 to about 6 mm, and an about 28 to about 33G. In other aspects, a “microneedle array” (about 300- about 900 pm) can be utilized for intradermal delivery of the antimicrobial agent and local anesthetic. The microneedle array can comprise dissolving or hollow needles and be comprised within a patch / device delivery system, and can also provide sustained release of the active agents (antimicrobial agent and local anesthetic agent).

[0077] 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). injections.III. Exemplary Embodiments

[0078] Drawings are provided to help understand the invention and illustrate specific representative examples. The drawings herein are not necessarily made to scale or actual proportions. For example, the size of components may be adjusted to accommodate the page size.

[0079] FIG. 1 shows the structure of the skin, which is made up of three layers of tissue with different functions and anatomical structures: epidermis 10 (the top layer), dermis 12 (the middle layer), and hypodermis 14 (the bottom or fatty layer, also referred to as the subcutaneous tissue). The epidermis 10 is the topmost layer, which is elastic and constantly regenerating. It provides a waterproof barrier and contributes 5 to skin tone.

[0080] The epidermis 10 also contains keratinocytes, which are the main cells of the epidermis. The dermis 12 is the middle layer, which contains connective tissue, hair follicles, blood vessels, lymphatic vessels, sebaceous glands, and sweat glands. The hypodermis 14 is the deepest layer (also known as subcutaneous tissue), which is made of fat and connective tissue.

[0081] FIG. 1 shows the structure of the skin, which is made up of three layers of tissue with different functions and anatomical structures: epidermis 10 (the top layer), dermis 12 (the middle layer), and hypodermis 14 (the bottom or fatty layer, also referred to as the subcutaneous tissue).224915-3836-0164.1Attorney Docket No. 145105-0106 DSW-31The epidermis 10 is the topmost layer, which is elastic and constantly regenerating. It provides a waterproof barrier and contributes to skin tone. The epidermis 10 also contains keratinocytes, which are the main cells of the epidermis.

[0082] As shown in FIG. 2, the dermis 12 has two sublayers: the papillary layer 16 and the reticular layer 18. The papillary layer 16 is the thin upper layer that contains capillaries, Meissner corpuscles, and lamellar corpuscles. Capillaries help regulate skin temperature and provide nutrients to the epidermis. Meissner corpuscles transmit sensations of delicate touch. Lamellar corpuscles transmit sensations of vibration and pressure. The reticular layer 18 is the lower, thicker layer made of thick collagen fibers that strengthen the skin and provide structure and elasticity. It also supports other components of the skin, such as hair follicles, sweat glands, and sebaceous glands. Also shown in FIG. 2 are the dermal papillae 20, papillary plexus 22, and cutaneous plexus 24.

[0083] As shown in FIG. 3, another aspect of skin anatomy is the various accessory skin structures. Such accessory skin structures are the hair follicles 30, sweat glands 32, and sebaceous glands 34. Hair follicles 30 are tube-like structures (or pores) in the skin that surround a hair’s root and strand. It is a sheath of skin and connective tissue that is located in the top two layers of the skin, and is also connected to a sebaceous gland 34.

[0084] Sweat glands 32 release sweat and can be divided into eccrine and apocrine glands. Eccrine glands are more widespread and are found all over the skin except for the lips and some areas of the genitalia. They are coiled glands that reside in the dermis and open to a pore on the skin’s surface, where the sweat is released. Apocrine glands are larger than eccrine glands and are usually associated with hair follicles in hairy areas like armpits and genital regions.

[0085] Sebaceous glands 34 are mostly found on the scalp, face, upper torso, and anogenital areas. They produce and excrete sebum, a mixture of lipids, onto the skin’s surface. Sebum lubricates and waterproofs the skin and hair. Sebaceous glands 34 are relatively inactive during childhood, but become very active during puberty. Also shown in FIG. 3 are skin pores 36, hair 38, nerve fiber 40, and blood vessels 42.

[0086] Of relevance to this invention, bacteria reside in the hair follicles 30, sweat glands 32, and sebaceous glands 34 of the skin. It is theorized that one possible source of bacteria that causes surgical site infections are the bacteria that reside in these accessory skin structures. That234915-3836-0164.1Attorney Docket No. 145105-0106 DSW-31 is, these accessory skin structures are reservoirs for bacteria that can contaminate a skin incision made during surgery.

[0087] These accessory skin structures are innervated and controlled by the sympathetic nervous system. For example, sympathetic activation of sweat glands 32 causes sweating. When a skin incision is made during surgery, there is stimulation of the sympathetic nervous system that activates these accessory skin structures. Activation of these accessory skin structures by the sympathetic nervous system causes spillage of bacteria out of these accessory skin structures.

[0088] In the present invention, it is believed that the local anesthetic agent (injected into the dermis) 20 has a protective effect against bacterial infection by suppressing the sympathetic activation of the accessory skin structure, thereby preventing the release of bacteria that reside therein. That is, the local anesthetic agent causes an analgesia effect on the sympathetic nerve fibers, thereby suppressing activation of the innervated accessory skin structures and avoiding bacterial spillage therefrom.

[0089] FIG. 4 shows an example of how the invention could be implemented. Shown is a simplified schematic illustration of the various layers of the skin 58. The top layer is the epidermis 52. The middle layer is the dermis 54. The bottom layer is the hypodermis 56. Beneath the hypodermis 56, there is muscle tissue 66. Also shown are accessory skin structures (as simplified block diagrams): is a hair follicle 60, a sebaceous gland 62, and a sweat gland 64.

[0090] FIG. 4 further shows a needle 50 puncturing through the skin 58. Needle 50 penetrates through the epidermis 52 and the distal tip of needle 50 is positioned in the dermis 54 of the skin 58. The aqueous injection mixture, comprising at least one antimicrobial agent and at least one local anesthetic agent, is injected into the dermis 54. Note that the aqueous injection mixture is not injected into the hypodermis 56 (i.e., the fatty layer or subcutaneous layer). Also note that the injection mixture is not injected into muscle tissue 66. The at least one local anesthetic agent anesthetizes the hair follicle 60, sebaceous gland 62, and sweat gland 64. Thus, when a surgical incision is made into skin 58, sympathetic activation of these accessory skin structures is suppressed, thereby preventing spillage of bacteria out of these accessory structures of the skin. Thus, in combination with the at least one antimicrobial agent, the at least one local anesthetic agent causes a synergistic effect in protecting the site of the skin incision against bacterial infection.244915-3836-0164.1Attorney Docket No. 145105-0106DSW-31

[0091] Compositions and methods of the disclosure provide global benefits, including for example, higher local tissue drug levels, reduced systemic toxicity, lower antimicrobial resistance (AMR) contribution, increased patient compliance (single injection vs systemic course), improved surgical outcomes with reduced SSI (surgical site infections), and cost savings for hospitals and payers through reduced complications.

[0092] An exemplary embodiment comprises a combination of the antimicrobial agent clindamycin phosphate (CAS 24729-96-2) co-formulated with the local anesthetic agent lidocaine hydrochloride, designed for Surgical Antibiotic Prophylaxis (SAP) and localized infection. The addition of lidocaine improves patient comfort and injection tolerability, enabling wider adoption in dermatologic, orthopedic, oncologic, and emergency surgical settings. The dosage form can be, for example, an injectable solution in a prefdled syringe. Target indications can be, for example, Surgical Antibiotic Prophylaxis (SAP), Dermatologic and minor surgical infection prevention, and Orthopedic, OB / Gyn, oncology, and emergency surgery prophylaxis. Surgical Antibiotic Prophylaxis (SAP): Affects -312 million surgeries annually worldwide, and accounts for 15% of global antibiotic use.

[0093] The appearance of the composition is clear, colorless to slightly yellow solution. An exemplary concentration can be 6 mg / mL clindamycin phosphate + 10 mg / mL lidocaine, with a pH: 4.2-4.8 (stability + injection comfort). Osmolality: 270-320 mOsm / kg (isotonic to minimize irritation). Stability: 24 months at room temperature (20-25°C). Sterility: SAL < 106. Endotoxin: < 0.5 EU / mL.

[0094] Clindamycin injection is commercially available as a pale yellow sterile solution, containing clindamycin phosphate, a water soluble ester of clindamycin and phosphoric acid. Each mL contains the equivalent of 150 mg of clindamycin, 0.5 mg of disodium edetate, and 9.45 mg benzyl alcohol added as preservative. Sodium hydroxide and / or hydrochloric acid may be added to adjust pH.

[0095] An exemplary formulation composition can comprise clindamycin phosphate (antibiotic), Lidocaine hydrochloride (local anesthetic), Buffering agent (citrate / phosphate system), Water for Injection (WFI), and Preservative-free (single-use only). The container closure system can comprise a 3 mL prefilled syringe (ISO 11040 compliant), Material: Borosilicate glass or Cyclic Olefin Polymer (COP), and Amber protective packaging for photostability. Regarding clinical254915-3836-0164.1Attorney Docket No. 145105-0106 DSW-31 compatibility, lidocaine Co-admini strati on: Stable with no precipitation; injection Site Tolerance: Buffered, isotonic solution minimizes irritation; and patient Experience: Improved due to pain reduction and reduced systemic antibiotic side effects.IV. Antimicrobial Agents

[0096] Any pharmaceutically acceptable antimicrobial agent can be utilized in the compositions, 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.

[0097] Examples of antimicrobial agents include but are not limited to clindamycin, ceftriaxone, nafcillin, ofloxacin, vancomycin, gentamicin, doxycycline, trimethoprim / sulfa, daptomycin, ciprofloxacin, cephalexin, cefdinir, cefuroxime, and cefaclor. 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).

[0098] Other exemplary antimicrobial agents, or antibiotics, that can be utilized in the compositions, kits and methods of the invention include, but are not limited to, 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®), .

[0099] Additional examples of antibiotic agents include, but are not limited to, metronidazole and ciprofloxacin aminoglycosides, Ansamycins, Carbacephems, Carbapenems, Cephalosporins, Glycopeptides, Macrolides, Monobactams, Penicillins, Polypeptides, Polymyxin, Quinolones, Sulfonamides, Tetracyclines, and others (e.g., Arsphenamine, Chloramphenicol, Clindamycin,264915-3836-0164.1Attorney Docket No. 145105-0106DSW-31Lincomycin, Ethambutol, Fosfomycin, Fusidic acid, Furazolidone, Isoniazid, Linezolid, Metronidazole, Mupirocin, Nitrofurantoin, Platensimycin, Pyrazinamide, Quinupristin / Dalfopristin, Rifampicin (Rifampin in US), Thi amphenicol, Tinidazole, Dapsone, and 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®, Cioxacillin®, 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.

[0100] 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, Podofdox, Remdesivir, Paxlovid (nirmatrelvir + ritonavir), Molnupiravir, Tecovirimat, and any combination thereof.

[0101] 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),274915-3836-0164.1Attorney Docket No. 145105-0106DSW-31Metronidazole, Tinidazole, Miltefosine, Fexinidazole; (3) for Trypanosomes: Melarsoprol, Eflornithine, Fexinidazole; (4) for Leishmania / Amoebae: Miltefosine.

[0102] 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.V. Microdose of Antimicrobial Agent

[0103] 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.

[0104] 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 5 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.284915-3836-0164.1Attorney Docket No. 145105-0106DSW-31

[0105] 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 > 0.01 mg / ml up to about 10 mg / ml, from > 0.01 mg / ml up to about < 5 mg / ml, from > 0.01 mg / ml up to about < 2.5 mg / ml, and from > 0.01 mg / ml up to about < 1.0 mg / ml.

[0106] 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.

[0107] The injectable composition for intradermal delivery can comprises a mixture of the at least one antimicrobial agent and at least one local anesthetic, or two separate injectable compositions can be sequentially administered, a first injectable composition comprising at least one antimicrobial agent and a second injectable composition comprising at least one local anesthetic agent.

[0108] 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.

[0109] 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.

[0110] In an exemplary aspect, the table below provides proposed dosing ranges for several exemplary antimicrobial agents that can be utilized in the intradermal delivery methods of the disclosure.294915-3836-0164.1Attorney Docket No. 145105-0106DSW-31

[0111] 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 29 to 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, 75S(7):718-726 (Jul. 1, 2023). These concentrations of clindamycin are substantially lower than the concentrations used in the prior art.

[0112] Currently, there are no commercially available formulations of clindamycin phosphate at concentrations between about 300- about 600 pg / mL, nor are there any prefilled 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).

[0113] 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.

[0114] In some embodiments, the antimicrobial agent is flucloxacillin. The flucioxacillin in the injection solution may be at any suitable dilute concentration for microdosing. In some304915-3836-0164.1Attorney Docket No. 145105-0106 DSW-31 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, / 55(7):718-726 (Jul. 1, 2023). These concentrations of flucloxacillin are substantially lower than the concentrations used in the prior art.

[0115] 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. Jenita et al., Ir J Acad Med Pharm., 5(4): 1024-1028 (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.

[0116] 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.

[0117] In some embodiments, the antimicrobial agent is gentamicin. The gentamicin in the injection solution may be at any suitable dilute concentration for microdosing. In some314915-3836-0164.1Attorney Docket No. 145105-0106 DSW-31 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 700 pg / ml. These concentrations of gentamicin are substantially lower than the concentrations used in the prior art.

[0118] 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.

[0119] 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 in-between 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.324915-3836-0164.1Attorney Docket No. 145105-0106DSW-31V. Anesthetic Agents

[0120] Any pharmaceutically acceptable local anesthetic can be utilized in the compositions, kits and methods of the invention. The at least one anesthetic is present in an injectable composition, such as an aqueous, non-aqueous, or saline formulation. The volume of local anesthetic agent injected is expected to be between about 0.1 ml to about 30ml.

[0121] In another aspect of the disclosure, the local anesthetic agent is administered at a dosage which is less than the dosage required for the same anesthetic to be given systemically.

[0122] In a further aspect, the local anesthetic agent can be present at a concentration of about 0.1% up to about 10%, and administered at a total volume of about 0.1 mb up to about 50 mL, depending upon the size of the administration field. In another aspect, the local anesthetic is administered in a volume of about 0.5 mL up to about 50 mL, or from about 1 mL up to about 10 mL. In yet other aspects, the local anesthetic agent is present at a concentration of about 0.1% up to about 5%, about 0.5%, about 1.0%, about 1.5%, or about 2.0%.334915-3836-0164.1Attorney Docket No. 145105-0106DSW-31

[0123] Examples of local anesthetics include, but are not limited to, a nonsteroidal antiinflammatory drugs (NSAIDs) (e.g., meloxicam, diclofenac, toralac (Tordol®, naproxen, ketorolac, ibuprofen), morphine, benzocaine, lidocaine, bupivacaine, tetracaine, ropivacaine (with or without mepivacaine). Additional local anesthetic agents include, but are not limited to, acetaminophen, articaine, bupivacaine, carbocaine, chloroprocaine, cocaine, dibucaine, etidocaine, lidocaine, lidocaine / tetracaine, marcaine, mepivacaine, moxicaine, procaine, ropivacaine, septocaine, tetracaine, tetracine, topicaine, vivacaine, xylocaine, zorcaine, or any combination thereof. In a further aspect, epinephrine can be combined with any of these anesthetics.

[0124] The local anesthetic agent can also comprise a narcotic class of drug, such as an opioid. Examples of such drugs include, but are not limited to, buprenorphine, butorphanol (Stadol®) carfentanil, codeine, fentanyl, hydrocodone, hydromorphone (Dilaudid®), methodone, morphine, oxycodone, oxymorphone (Opana®), tramadol, thebaine, or any combination thereof. In one aspect, the local, intradermal administration of the opioid anesthetic enables the use of a dose significantly less than that required for systemic administration. This significantly lower dose is correlated with fewer side effects and a reduced or minimized risk of abuse and addiction, and can also significantly minimize the risk of Opioid Use Disorder (OUD).

[0125] Another example of a local anesthetic is a nerve block injection. For example, lidocaine and bupivacaine are commonly employed in nerve blocks.

[0126] As noted above, any suitable dosage of the local anesthetic can be utilized in the methods and compositions of the invention. The suitable dosage is less than that required for systemic administration.

[0127] As an example, lidocaine hydrochloride for injection without epinephrine is approved in four different strengths, and all four strengths can be utilized in the methods and compositions of the disclosure: about 0.5%, about 1.0%, about 1.5%, and about 2.0%. The volume of lidocaine injection is expected to be between about 0.1 ml to about 20ml. Note that this is not the total volume of lidocaine but rather the volume of lidocaine needed when it is mixed with an antimicrobial agent.344915-3836-0164.1Attorney Docket No. 145105-0106 DSW-31

[0128] In one embodiment, the antimicrobial agent is ceftriaxone and the local anesthetic agent is lidocaine. In another embodiment, the antimicrobial agent is vancomycin and the local anesthetic agent is bupivacaine.VI. Additional Active Agents & Injection Solution Components / Parameters

[0129] Other active agents that can be administered along with the at least one antimicrobial agent and at least one local anesthetic include, for example, clotting agents (e.g., tranexamic acid), agents that improve blood flow (pentoxifylline), Vitamin D3, a steroid or corticosteroid (e g., betamethasone, clobetasol, triamcinolone, dexamethasone, flucinolone), epinephrine, or any combination thereof.

[0130] In one aspect, the at least one local anesthetic is administered along with epinephrine and / or at least one steroid, which can improve safety and prolong the activity of the local anesthetic.

[0131] A liquid diluent for the injection solution comprising the at least one antimicrobial agent and / or the at least one anesthetic 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 compositions 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 nonaqueous 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.

[0132] The pH of the injection solution comprising the at least one antimicrobial agent and / or the at least one anesthetic agent is selected on the basis of various considerations such as patient354915-3836-0164.1Attorney Docket No. 145105-0106DSW-31 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 up to about 7.5.

[0133] The pH of the injection solution comprising the at least one antimicrobial agent and / or the at least one anesthetic 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 0- cyclodextrin, hydroxypropyl-0-cyclodextrin, etc.). Another example is using chelating agents (such as EDTA, citric acid, etc.), which prevent metal-ion-induced instability at higher pH levels. Another example is adjusting the ionic strength (such as using sodium chloride, mannitol, etc.).

[0134] 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, increase solubility, 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.364915-3836-0164.1Attorney Docket No. 145105-0106DSW-31VII. Kits

[0135] In one aspect of the disclosure, encompassed is a kit for use in the methods described herein. The kit can comprise at least one antimicrobial agent, at least one local anesthetic 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, sideport needle, multi-dose, etc.

[0136] The antimicrobial agent and / or local anesthetic 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 light-sensitive drugs. In particular, the syringe may be darkened to avoid light exposure to the antimicrobial agent and / or local anesthetic agent. 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.

[0137] In one aspect of the disclosure, encompassed are pre-filled, single-use syringes for use in methods of the disclosure. The pre-filled syringes can comprise a mixture of a therapeutically effective microdose of at least one antimicrobial agent and at least one local anesthetic, or a first pre-filled syringe with a therapeutically effective microdose of at least one antimicrobial agent and a second pre-filled syringe with at least one local anesthetic agent can be utilized in the methods of the disclosure.

[0138] 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.

[0139] 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, high374915-3836-0164.1Attorney Docket No. 145105-0106DSW-31 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.

[0140] 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.

[0141] In another aspect, the kits are designed for self-administration, or administration by nonmedical 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.

[0142] In another aspect, the kits are designed to be incorporated in a first-aid kit.

[0143] In an exemplary embodiment, lidocaine is utilized as a diluent for the antimicrobial agent. Lidocaine is approved as a diluent to reconstitute clindamycin. An example of this embodiment in a kit comprises the following components: (1) a clindamycin phosphate solution in an aseptically filled, single-use vial; (2) a 5 ml, single-use, vial of 1% lidocaine hydrochloride; (3) a closed system transfer device to assist with the mixture of the lidocaine and the clindamycin phosphate; (4) a 3ml sterile, single-use, plastic, glass, or polymer syringe used to withdraw 3ml of solution from the final mixture; (5) a 21 -gauge needle for delivering the lidocaine into the clindamycin phosphate vial; and (6) a 30-gauge needle attached to the 3 ml syringe to deliver intradermally into the skin of the patient's surgical / wound site. In an alternative aspect, a kit can comprise, for example, prefilled 1-3 ml single-use, disposable, plastic, glass, or polymer syringe comprising two active ingredients. The first component would be clindamycin phosphate at a concentration of about 500ug / ml, and the second component would be lidocaine hydrochloride at a concentration between about 0.5% to about 2.0%. The most common concentration would be 1%; e.g., a combination of clindamycin phosphate 500ug / ml and 1% lidocaine hydrochloride.VIII. Methods of Treatment

[0144] The present disclosure encompasses methods of preventing, minimizing the risk of, or treating microbial infections associated with surgical sites or wounds.384915-3836-0164.1Attorney Docket No. 145105-0106DSW-31

[0145] In a first aspect, the present disclosure is directed to a method for treating, reducing the risk of, or preventing a microbial infection at a surgical site of the skin or mucosa of a subject. The method comprises, prior to initiation of a surgical incision, (1) identifying a surgical site that will require an incision into the subject’s mucosa or skin, and (2) intradermally administering to the surgical site a therapeutically effective microdose of at least one antimicrobial agent in combination with at least one local anesthetic agent. In a further aspect, a surgical incision is made within about 12 hours following the intradermal administration. In other aspects, the 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. The therapeutically effective microdose of the at least one antimicrobial agent can be combined with the at least one local anesthetic in a single injection composition, or the two active agents can be administered sequentially.

[0146] Prophylactic treatment and / or prevention of SSIs using the methods of the invention is anticipated to significantly reduce the incidence of an SSI. In one aspect, following intradermal administration of the combination of a therapeutically effective microdose of at least one antimicrobial agent and at least one local anesthetic at a surgical site for the subject, the subject undergoes surgery which comprises a surgical incision into the subject’s skin, and subsequently, the subject does not contract an SSI.

[0147] In another aspect, the overall incidence of SSIs for a patient population that receives prophylactic intradermal administration of a combination of a therapeutically effective microdose of at least one antimicrobial agent and at least one local anesthetic agent to the surgical site of the subject is expected to decrease by about 100%, about 90%, 80%, about 70%, about 60%, or about 50%, as compared to a patient population that does not receive the prophylactic treatment and undergoes a surgery that comprises a surgical incision into the subject’s skin.

[0148] The time period for measuring whether the subject contracts an SSI can be about 30 days, about 60 days, about 90 days, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months or about 1 year.394915-3836-0164.1Attorney Docket No. 145105-0106DSW-31

[0149] 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.

[0150] In another aspect, the disclosure encompasses methods of preventing, reducing the risk of, or treating a microbial infection of a wound or lesion in a subject’s skin or mucosa. Examples of mucosal sites include, for example, oral, nasal, anal, vaginal, anogenital, 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.

[0151] The method comprises intradermally injecting into the site of the subject’s wound or lesion a combination of a therapeutically effective microdose of at least one antimicrobial agent and at least one local anesthetic agent as described herein. The composition can be administered by medical personnel, non-clinical personnel, a caregiver, a bystander, a first responder, military personnel, self-administered, buddy-administered, administered via remote guidance (e.g., teletriage), or any combination thereof.

[0152] Treatment and / or prevention of microbial infections of a wound or lesion in a subject’s skin or mucosa using the methods of the invention is anticipated to significantly reduce the incidence of microbial infection, as well as speed recovery of existing microbial infections. In one aspect, following intradermal administration of the combination of a therapeutically effective microdose of at least one antimicrobial agent and at least one local anesthetic at a wound or lesion in a subject’s skin or mucosa, the subject does not contract a microbial infection at the wound or lesion site.

[0153] Administration of the combination according to the disclosure can be before or after wound irrigation / debridement. Additionally, administration can also comprise peri-wound ring dosing (multiple intradermal administration sites).404915-3836-0164.1Attorney Docket No. 145105-0106DSW-31

[0154] The time period for measuring whether the subject contracts a microbial infection at the wound or lesion site can be about 30 days, about 60 days, about 90 days, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months or about 1 year.

[0155] In another aspect, the overall incidence of microbial infection of a wound for a patient population that receives intradermal administration of a combination of a therapeutically effective microdose of at least one antimicrobial agent and at least one local anesthetic agent to the wound site of the subject is expected to decrease by about 100%, about 90%, 80%, about 70%, about 60%, or about 50%, as compared to a patient population with a wound in the dermis or mucosa that does not receive the treatment.

[0156] In one aspect of the methods of the disclosure, the surgical site or wound is evaluated for signs of microbial infection following intradermal administration of a combination of at least one antimicrobial agent and at least one local anesthetic. Typically, an infection can be first identified doing a wound assessment within about 3 to about 7 days following treatment. Skin and soft tissue infections (SSTIs) are clinical entities of variable presentation, etiology and severity that involve microbial invasion of the layers of the skin and underlying soft tissues. SSTIs range from mild infections, such as pyoderma, to serious life-threatening infections, such as necrotizing fasciitis. The minimum diagnostic criteria are erythema, edema, warmth, and pain or tenderness. The affected area may also become dysfunctional (e g., hands and legs) depending on the severity of the infection. A patient’s comorbidities (e.g., diabetes mellitus and AIDS) can easily transform a normally mild infection into a rapidly advancing threat to life. Any medically acceptable wound assessment scale or metric can be used to assess a wound for microbial infection following treatment, including for example, the Bates-Jensen Wound Assessment Tool (BWAT), Pressure Ulcer Scale for Healing (PUSH), Sessing Scale, Sussman Wound Healing Tool (SWHT), Wound Healing Scale (WHS), Photographic Wound Healing Tool (PWHT), and the Japanese Pressure Ulcer Healing Process (PUHP).

[0157] The volume amount of the injection solution the at least one antimicrobial agent and / or the at least one anesthetic agent that is injected may be about 1 up to about 20 ml.

[0158] For all methods described herein, the intradermal injection may be administered into both the papillary and the reticular sublayers of the dermal layer.414915-3836-0164.1Attorney Docket No. 145105-0106DSW-31

[0159] Patient populations: In one aspect, a patient population to be treated are patients anticipated to undergo a surgical procedure requiring a surgical incision into the patients’ dermis or mucosa. In another aspect, a patient population to be treated are patients having a wound in the patients’ dermis or mucosa. In a further aspect, a patient population to be treated are first responders, military personnel, frontline workers etc., either as a prophylactic treatment or as a treatment following a wound to the subject’s dermis or mucosa. Further examples of patient populations are those at high risk for microbial infection following a wound or surgical incision in the skin or mucosa, including for example pediatric subjects, geriatric subjects, diabetic subjects, and immunocompromised subjects.

[0160] In another aspect, a patient population to be treated includes patients at risk for a surgical site infection. Patients deemed at risk for an SSI may have 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.

[0161] In another aspect, patient populations may include those present in an emergency site, natural disaster site (flood, wildfire, hurricane, earthquake, hurricane, tornado, tsunami-struck areas), battlefield site, austere or contaminated environment, mass-casualty environment, terrorism / CBN environment, and other conditions where skin abrasions / soft tissue wounds / wounds are prevalent and the risk of microbial infection is high. Examples of microbial contamination sources in disaster / emergency environments include, for example, flood / seawater, sewage / gray water, soil / debris / ash, smoke / dust, etc.

[0162] The methods of the disclosure can be practiced in both clinical settings as well as in field hospitals, shelters, point-of-injury sites, ambulance / MEDEVAC, etc.IX. Definitions

[0163] The following definitions are provided to facilitate understanding of certain terms used throughout this specification.

[0164] 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 / or424915-3836-0164.1Attorney Docket No. 145105-0106DSW-31 methodologies known to those of ordinary skill in the art can be utilized in carrying out the methods described herein.

[0165] 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 expression “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.

[0166] 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.

[0167] 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.

[0168] “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.434915-3836-0164.1Attorney Docket No. 145105-0106DSW-31

[0169] “Pharmaceutically acceptable excipient or carrier” refers to an excipient that may optionally be included in the compositions of the disclosure and that causes no significant adverse toxicological effects to the patient.

[0170] 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)).

[0171] “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%.

[0172] 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”).

[0173] 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.

[0174] 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.

[0175] The foregoing description and following example 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 may perceive444915-3836-0164.1Attorney Docket No. 145105-0106DSW-31 modifications to these embodiments that incorporate the spirit and substance of the invention. Such modifications are within the scope of the invention.X. ExamplesExample 1

[0176] This example demonstrates an exemplary method according to the disclosure for surgical antibiotic prophylaxis. The purpose of this example is to demonstrate a clindamycin formulation that can be administered via intradermal injection employing a 3 ml syringe and a 4 mm, 30- gauge needle.

[0177] 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.

[0178] The antimicrobial agent comprises a stable solution of clindamycin phosphate at 500 pg / mL and a target pH of 7.0.

[0179] 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). 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. 9A shows the first injection, FIG. 9B shows a second injection, and FIG. 9C depicts the needle length of 4 mm.454915-3836-0164.1Attorney Docket No. 145105-0106DSW-31

[0180] The volume of injectable composition required has been calculated as about 0.6 - about 1.0 ml per centimeter.Example 2

[0181] The purpose of this example is to detail a method according to the present disclosure using a combination of the antimicrobial agent ceftriaxone and the local anesthetic lidocaine.

[0182] Ceftriaxone can be reconstituted in a diluted concentration of 10 mg / ml, and provided in a vial.

[0183] A syringe, such as a BD 3 ml luer-lok (SKU 309577), is provided. The local anesthetic lidocaine is provided as an aqueous or non-aqueous solution and is drawn into the syringe. Next, the lidocaine solution in the syringe is instilled into the vial comprising the ceftriaxone. The lidocaine solution and the ceftriaxone solution are mixed together within the vial to produce the injection mixture. The injection mixture is then drawn up into the syringe.

[0184] A 4 mm, 30-32g, needle is attached to the syringe. The injection mixture 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.

[0185] Within about 90 minutes following intradermal injection of the combination of ceftriaxone and lidocaine, a surgical incision is made at the surgical site. The surgical incision is then followed by a surgical procedure.

[0186] It is anticipated that the intradermal injection of the combination of ceftriaxone and lidocaine at the surgical site prior to a surgical incision will prevent or minimize the risk of the subject contracting an SSI.Example 3

[0187] The purpose of this example is to detail application of intradermal injections of an antibiotic (Clindamycin phosphate) combined with a local anesthetic (lidocaine) at surgical sites for prevention of microbial infection in a dermatology clinic.

[0188] Patients at risk for surgical site infections were deemed candidates for clindamycin phosphate solution, administered in a combined mixture with 1% lidocaine hydrochloride.464915-3836-0164.1Attorney Docket No. 145105-0106 DSW-31

[0189] 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 cell carcinoma. 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.

[0190] The skin was prepared with a standard surgical scrub using chlorhexidine gluconate at the proposed surgical site. The anesthetic / antibiotic solution was prepared on the same day as use by the following method.

[0191] A sterile, multi-use 50 mL 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 mL sterile, single-use vial. Exactly 0.15 mL 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.

[0192] 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.

[0193] 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.474915-3836-0164.1Attorney Docket No. 145105-0106 DSW-31

[0194] The patients received the anesthetic / antibiotic mixture through injection with a 30-gauge, 4-mm needle, administered circumferentially around the skin cancer to be removed. The volume of anesthetic / antibiotic 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.

[0195] No allergic reactions to this mixture were reported, and no cases of colitis were observed.

[0196] 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.

[0197] 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.* * * *

[0198] 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.

[0199] 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 described or portions thereof, but it is recognized that various modifications are possible within the scope of the claimed484915-3836-0164.1Attorney Docket No. 145105-0106DSW-31 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.

[0200] 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 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.

[0201] 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.

[0202] 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.

[0203] All publications, patent applications, issued patents, and other documents referred to in this specification are herein incorporated by reference as if each individual publication, patent494915-3836-0164.1Attorney Docket No. 145105-0106DSW-31 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.

[0204] Other embodiments are set forth in the following claims.504915-3836-0164.1

Claims

Attorney Docket No. 145105-0106DSW-31CLAIMS1. A composition for intradermal administration comprising a combination of:(a) a therapeutically effective microdose of at least one antimicrobial agent; and(b) a therapeutically effective amount of at least one local anesthetic agent.

2. The composition of claim 1, wherein:(a) the therapeutically effective microdose of the antimicrobial agent ranges from > 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.

3. The composition of claim 1 or 2, wherein the volume of the composition for intradermal injection ranges from about 1 ml up to about 20 ml.

4. The composition of any one of claims 1-3, wherein the local anesthetic agent is administered at a dosage which is less than the dosage required for the same anesthetic to be given systemically.

5. The composition of any one of claims 1-4, wherein the local anesthetic agent is present at a concentration of:(a) about 0.1% up to about 10%;(b) about 0.1% up to about 5%;(c) about 0.5%,(d) about 1.0%,(e) about 1.5%, or(f) about 2.0%.

6. The composition of any one of claims 1-5, wherein the at least one antimicrobial agent and at least one local anesthetic agent are present:(a) in an injectable dosage form; or(b) in a sterile powder for reconstitution as an injectable dosage form.514915-3836-0164.1Attorney Docket No. 145105-0106 DSW-317. The composition of any one of claims 1-6, wherein the at least one antimicrobial agent is selected from the group consisting of an antibacterial agent, an antiviral agent, an antiparasitic agent, and an antifungal agent.

8. The composition of any one of claims 1-7, wherein:(a) the at least one antimicrobial agent is selected from the group consisting of 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, and any combination thereof;(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, Foscamet, Cidofovir, Ribavirin, monoclonal antibodies, Imiquimod, Sinecatechins, Podofilox, Remdesivir, Paxlovid (nirmatrelvir + ritonavir), Molnupiravir, Tecovirimat, and any combination thereof;(c) the at least one antimicrobial agent is an antiparasitic agent, which is selected from the group consisting ofAlbendazole, Mebendazole, Ivermectin, Pyrantel pamoate, Praziquantel, Triclabendazole, Moxidectin, Nitazoxanide, Pyrimethamine, Metronidazole, Tinidazole, Miltefosine, Fexinidazole, Melarsoprol, Eflornithine, Fexinidazole, Miltefosine, and any combination thereof; and / or524915-3836-0164.1Attorney Docket No. 145105-0106 DSW-31(d) the at least one antimicrobial agent is an antifungal agents, which is selected from the group consisting of Polyene Antifungals, Azole Antifungals, Echinocandins, Allylamines, Pyrimidine (Nucleic Acid) Analogs, and Glucan Synthase (Novel) Inhibitors, and any combination thereof.

9. The composition of any one of claims 1-8, wherein the at least one local anesthetic agent is selected from the group consisting of a nonsteroidal anti-inflammatory drug (NSAID), acetaminophen, articaine, articaine / epinephrine, benzocaine, bupivacaine, bupivacaine / epinephrine, buprenorphine, butorphanol, carbocaine, carfentanil, chloroprocaine, cocaine, codeine, dibucaine, diclofenac, etidocaine, fentanyl, hydrocodone, hydromorphone ibuprofen, ketorolac, lidocaine, lidocaine / epinephrine, lidocaine / tetracaine, marcaine, meloxicam, mepivacaine, methodone, morphine, moxicaine, naproxen, an opioid, oxycodone, oxymorphone, procaine, ropivacaine, tetracaine, toralac, xylocaine / epinephrine, septocaine, tetracaine, tetracine, thebaine, topicaine, tramadol, xylocaine, vivacaine, zorcaine, and any combination thereof.

10. The composition of any one of claims 1-9 wherein:(a) the antimicrobial agent is ceftriaxone and the local anesthetic agent is lidocaine; or(b) the antimicrobial agent is vancomycin and the local anesthetic agent is bupivacaine.

11. The composition of any one of claims 1-10 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; or534915-3836-0164.1Attorney Docket No. 145105-0106DSW-31(d) 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; 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; or(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.

12. The composition of any one of claims 1-11, further comprising a diluent.

13. The composition of claim 12, wherein the diluent is aqueous or non-aqueous.

14. The composition of claim 12 or 13, wherein:(a) the diluent is aqueous and is selected from the group consisting of sterile water, bacteriostatic water, saline, dextrose in water, and lactated Ringer’s solution; 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. A kit comprising:(a) a container or syringe comprising a therapeutically effective microdose of at least one antimicrobial agent;(b) a therapeutically effective amount of at least one local anesthetic; and(c) a needle having a length of about 2 mm to about 15 mm and a gauge of about 24 up to about 35.

16. The kit of claim 15, wherein the needle length is about 4 mm17. The kit of claim 15 or 16, wherein:(a) the at least one antimicrobial agent and the at least one local anesthetic agent are544915-3836-0164.1Attorney Docket No. 145105-0106DSW-31 present in the same container or syringe; or(b) the at least one antimicrobial agent and the at least one local anesthetic agent are present in different containers or syringes.

18. The kit of any one of claims 15-17, wherein the kit is multi-dose or single use.

19. The kit of any one of claims 15-18, further comprising a guide for needle depth and / or angle insertion.

20. 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 combination of a therapeutically effective microdose of at least one antimicrobial agent and a therapeutically effective amount of at least one local anesthetic agent.

21. The method of claim 20, wherein a surgical incision is made within about 12 hrs following the intradermal injection.

22. The method of claim 21, 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.

23. The method of any one of claims 20-22, further comprising performing a surgical procedure after making the surgical incision.

24. A method of preventing, minimizing the risk of, and / or treating a microbial infection of a skin or mucosal wound site of a subject, comprising: intradermally injecting into a subject’s dermis layer of the skin or mucosa at the wound site a combination of a therapeutically effective microdose of at least one antimicrobial agent and a therapeutically effective amount of at least one local anesthetic agent.554915-3836-0164.1Attorney Docket No. 145105-0106DSW-3125. The method of claim 24, wherein the combination is administered by medical personnel, non-medical personnel, a caregiver, a first responder, military personnel, self-administered, or any combination thereof.

26. The method of any one of claims 20-25, wherein:(a) the intradermal injection does not comprise injection of the antimicrobial agent or the local anesthetic agent into a muscle tissue of the subject; and / or(b) the intradermal injection does not comprise injection of the antimicrobial agent or the local anesthetic agent into a hypodermis layer of the skin of the subject.

27. The method of any one of claims 20-26, wherein the antimicrobial agent is selected from the group consisting of an antibacterial agent, an antiviral agent, an antiparasitic agent, and an antifungal agent.

28. The method of any one of claims 20-27, wherein:(a) the at least one antimicrobial agent is selected from the group consisting of 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, thi amphenicol, tigecycline, tinidazole, trimethoprim / sulfa, trimethoprim-sulfamethoxazole, vancomycin, 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),564915-3836-0164.1Attorney Docket No. 145105-0106DSW-31 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, Podofdox, 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 ofAlbendazole, 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, Allylamines, Pyrimidine (Nucleic Acid) Analogs, and Glucan Synthase (Novel) Inhibitors, and any combination thereof; and / or(e) the at least one local anesthetic is selected from the group consisting of a nonsteroidal anti-inflammatory drug (NS AID), mel oxicam, diclofenac, morphine, benzocaine, lidocaine, bupivacaine, tetracaine, ropivacaine, marcaine, mepivacaine, cocaine, articaine / epinephrine, carbocaine, lidocaine / epinephrine, bupivacaine / epinephrine, lidocaine / tetracaine, xylocaine / epinephrine, septocaine, tetracine, chloroprocaine, dibucaine, moxicaine, topicaine, xylocaine, vivacaine, zorcaine, and any combination thereof.

29. The method of any one of claims 20-28 wherein:(a) the local anesthetic agent suppresses sympathetic activation of an accessory skin structure; and(b) suppression of sympathetic activation of the accessory skin structure prevents and / or minimizes release of bacteria and / or microbes from the accessory skin structure.

30. The method of claim 29, wherein the accessory skin structure is a hair follicle, sweat gland, sebaceous gland, or any combination thereof.

31. The method of any one of claims 20-30, wherein the method comprises intradermally injecting a mixture of the antimicrobial agent and the local anesthetic agent.574915-3836-0164.1Attorney Docket No. 145105-0106DSW-3132. The method of any one of claims 20-31 , wherein the method comprises sequentially intradermally administering:(a) a first injection comprising the antimicrobial agent and a second injection comprising the local anesthetic agent; or(b) a first injection comprising the local anesthetic agent and a second injection comprising the antimicrobial agent.

33. The method of any one of claims 20-32, wherein the volume of the intradermal injection comprising a combination of a microdose of at least one antimicrobial agent and at least one local anesthetic agent, administered either as a single composition comprising a combination of the antimicrobial agent and the local anesthetic, or administered as two separate compositions, a first composition comprising the antimicrobial agent and a second composition comprising the local anesthetic, is about 1 to about 50 ml.

34. The method of claim 33, wherein the volume is less than or equal to about 10 ml.

35. The method of any one of claims 20-34, wherein the combination of a therapeutically effective microdose of at least one antimicrobial agent and at least one local anesthetic agent is formulated into an injection composition comprising a diluent.

36. The method of claim 35, wherein the diluent is aqueous or non-aqueous.

37. The method of claim 35 or 36, wherein:(a) the diluent is aqueous and is selected from the group consisting of sterile water, bacteriostatic water, saline, dextrose in water, and lactated Ringer’s solution; 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.

38. The method of any one of claims 35-37, wherein the injection composition has a pH of about 7.0 to about 7.8.

39. The method of any one of claims 20-38, wherein 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.584915-3836-0164.1Attorney Docket No. 145105-0106DSW-3140. The method of any one of claims 20-39, wherein the method is used to treat a patient population having a soft tissue injury due to active conflict.

41. The composition according to any one of claims 1-14 for use in prophylaxis against surgical site infection (SSI).

42. The composition according to any one of claims 1-14 for use in preventing, minimizing the risk of, and / or treating a microbial infection of a skin or mucosal wound site of a subject.594915-3836-0164.1

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