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a brown eye up close | | VLS Pharmacy & New Drug Loft ophthalmic compounding

A Focus on Ophthalmic Compounding: Metronidazole

At VLS Pharmacy & New Drug Loft, we are placing increased focus on our ophthalmic compounding offerings. This type of compounding requires specialized facilities and equipment that meet United States Pharmacopeia (USP) guidelines. It may be performed for a variety of reasons, such as to remove an allergenic ingredient in a commercial medication, to provide a patient with medication during drug shortages, or to decrease systemic exposure to a particular medication.

Many FDA-approved drugs are prescribed for off-label ophthalmic indications, but in their commercially-available forms, they are not suitable for ophthalmic administration. A 503A compounding pharmacy like VLS Pharmacy can reformulate these medications so they can be delivered ophthalmically.

One of these medications, metronidazole, is used as an off-label treatment for several ophthalmic indications. Although FDA-approved in 1963 as a gel for treating inflammatory rosacea lesions, metronidazole has since been used off-label to treat various bacterial eye infections. In addition to topical and oral administration routes, metronidazole can also be compounded into an ophthalmic solution or ophthalmic ointment to more directly target ocular bacterial infections.

Benefits of the topical ocular administration of drugs

A topical ophthalmic solution and ointment can directly treat ocular infections while reducing the systemic circulation of a drug. This is particularly beneficial for antibiotics like metronidazole, given the emergence of antibiotic-resistant bacteria due to antibiotic overuse and poor adherence (1). The lower systemic circulation of the antibiotic also helps minimize adverse events related to systemic exposure. Compared with oral administration, topical ocular delivery of metronidazole may:

  • Help preserve the diversity and composition of the gut microbiome, reducing the risk of complications such as opportunistic infections. Topical antibiotics exert selective pressure primarily on the bacteria present at the site of application (i.e. the eye) rather than the entire body. Such localized exposure reduces the likelihood of widespread resistance compared with systemic antibiotics, which impact bacteria throughout the body.
  • Be used as adjunctive therapy with systemic antibiotics, allowing for lower doses of oral antibiotics to be used. This approach can eradicate bacterial infections while minimizing the risk of antibiotic resistance and dysbiosis associated with high-dose systemic monotherapy. Non-systemic medication is especially important for patients with chronic diseases such as ocular rosacea. 

Off-label ophthalmic indications for metronidazole

Ocular Rosacea

More than half of patients with rosacea experience ocular rosacea, which manifests as blepharitis or conjunctivitis. As there is currently no cure for rosacea, patients will require long-term treatment to keep its symptoms under control. In an early study, patients received metronidazole topical gel to the eyelid margin twice daily. The study concluded that metronidazole provided safe and effective treatment for ocular rosacea, with no adverse sequelae (2). Due to the chronic nature of rosacea, topical ocular administration of metronidazole may be preferable to long-term oral administration of this antibiotic to reduce its systemic effects such as gastrointestinal irritation.

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Demodex blepharitis

Demodex mites may cause blepharitis by serving as a vector for bacteria or by inducing hypersensitivity and inflammation. One of the major risk factors for this form of blepharitis is rosacea. Because there is currently no FDA-approved treatment for Demodex blepharitis, prescribers must turn to off-label treatments. Of these, topical metronidazole gel 1 percent was used as adjunctive topical ivermectin 0.1 percent in a recent clinical trial and completely eliminated Demodex in 96.6 percent of treated patients without adverse events. Other reports have similarly demonstrated that metronidazole is effective at resolving symptoms, possibly by killing Demodex (3,4).

Bacterial infections associated with contact lens usage 

It has been suggested that the overnight wearing of orthokeratology contact lenses induces Acanthamoeba keratitis infection (5). Although occurring in only 33 cases per million contact lens wearers, this infection may cause corneal ulceration, ring infiltration, or diffuse stromal infiltration. 

Topical metronidazole solution has been used as an adjunctive for treating Acanthamoeba keratitis (6,7). Three patients with this infection were treated with a mixture of chlorhexidine every hour, and with topical neomycin sulfate 0.5 percent and metronidazole 0.4 percent every 2 hours. Using this treatment, the patient’s ocular inflammation rapidly resolved. 

Although these studies have suggested that metronidazole is effective at treating sclerokeratitis, bacteria culture tests should be performed to confirm the identity of the pathogen to ensure it will respond to metronidazole. For example, sclerokeratitis may also be caused by Pseudomonas aeruginosa, which metronidazole has shown no bactericidal effect on (8).

Emerging research for other potential indications

While the above indications of metronidazole have significant literature and clinical support, it is currently being investigated for other ophthalmological indications. However, research is emerging in this area, and clinicians should rely on their own expertise to determine whether metronidazole is appropriate to prescribe.

Extragenital Trichomoniasis vaginalis

As metronidazole is an antibiotic, it may be effective at treating a variety of ocular bacterial infections, but the evidence is limited. Trichomoniasis vaginalis infections are generally treated with metronidazole, but extragenital infections are also possible. A case study reported that metronidazole resolved a patient’s residual conjunctivitis, with both eyes showing satisfactory resolution (9).

Corneal neovascularization

In a murine model, both 0.1 percent and 0.5 percent metronidazole significantly inhibited corneal neovascularization in chemical burns (10). Although these are promising results, no in vivo human studies have been reported yet.

Ophthalmological compounding expertise at VLS Pharmacy and New Drug Loft

As mandated by USP, ophthalmic compounding requires specialized equipment and a sterile environment. Our expertise in this niche area of compounding allows us to supply adult and pediatric patients with ophthalmic compounds – whether in a hospital/surgical setting, the office, or at home. Our compounding pharmacists are skilled in advanced aseptic techniques, and all compounds have been independently tested by third-party facilities. Our multi-state licensure and quick turnaround allow you to predictably plan patient protocols to create a safe, individualized ophthalmic treatment regimen.

 

Please comment below with any thoughts or questions.

Reach out to our team to learn about best practices and to partner with our experts on custom compounded medications for your patients. All medications from VLS Pharmacy and New Drug Loft are prepared in a lab that follows safety and quality standards per our status as a 503A pharmacy.

 

References

  1. Smith A. Metronidazole resistance: a hidden epidemic? Br Dent J. 2018;224(6):403-404. doi:10.1038/sj.bdj.2018.221
  2. Barnhorst DA, Foster JA, Chern KC, Meisler DM. The efficacy of topical metronidazole in the treatment of ocular rosacea. Ophthalmology. 1996;103(11):1880-1883. doi:10.1016/s0161-6420(96)30412-0
  3. Junk AK, Lukacs A, Kampik A. [Topical administration of metronidazole gel as an effective therapy alternative in chronic Demodex blepharitis–a case report]. Klin Monbl Augenheilkd. 1998;213(1):48-50. doi:10.1055/s-2008-1034943
  4. Paichitrojjana A, Chalermchai T. Comparison of in vitro Killing Effect of Thai Herbal Essential Oils, Tea Tree Oil, and Metronidazole 0.75% versus Ivermectin 1% on <em>Demodex folliculorum</em>. CCID. 2023;16:1279-1286. doi:10.2147/CCID.S414737
  5. Xuguang S, Lin C, Yan Z, et al. Acanthamoeba keratitis as a complication of orthokeratology. American Journal of Ophthalmology. 2003;136(6):1159-1161. doi:10.1016/S0002-9394(03)00635-4
  6. Sun X, Zhang Y, Li R, et al. Acanthamoeba keratitis: clinical characteristics and management. Ophthalmology. 2006;113(3):412-416. doi:10.1016/j.ophtha.2005.10.041
  7. van der Bijl P, van Eyk AD, Seifart HI, Rer Nat D, Meyer D. In Vitro Transcorneal Penetration of Metronidazole and Its Potential Use as Adjunct Therapy in Acanthamoeba Keratitis. Cornea. 2004;23(4):386.
  8. Radford R, Brahma A, Armstrong M, Tullo AB. Severe sclerokeratitis due to Pseudomonas aeruginosa in non-contact-lens wearers. Eye. 2000;14(1):3-7. doi:10.1038/eye.2000.2
  9. Abdolrasouli A, Croucher A, Roushan A, Gaydos CA. Bilateral Conjunctivitis Due to Trichomonas vaginalis without Genital Infection: an Unusual Presentation in an Adult Man. J Clin Microbiol. 2013;51(9):3157-3159. doi:10.1128/JCM.01425-13
  10. Claros-Chacaltana FDY, Aldrovani M, Kobashigawa KK, et al. Effect of metronidazole ophthalmic solution on corneal neovascularization in a rat model. Int Ophthalmol. 2019;39(5):1123-1135. doi:10.1007/s10792-018-0922-2

 

 


 

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