Lok Leung

Penetration of Voriconazole, 1%, Eyedrops Into Human Aqueous Humor : A Prospective Open-Label Study

OBJECTIVE To determine the therapeutic efficacy of adjuvant use of voriconazole, 1%, eyedrops in the treatment of refractory fungal keratitis. METHODS A prospective open-label trial was conducted to determine voriconazole levels obtained in human aqueous humor after administration of a 1% solution, preserved with 0.01% benzalkonium chloride, every 6 hours for 3 days, or hourly for 4 doses. Ten participants were selected among patients scheduled to undergo elective anterior segment surgery, and samples were tested using validated high-performance liquid chromatography. RESULTS The mean (SD) voriconazole concentrations after hourly dosing (n = 5) was 1.90 (1.12) microg/mL and after a single dosing every 6 hours (n = 5) was 0.94 (1.21) microg/mL, respectively. The mean (SD) sampling times after the last administration of eyedrops were 1.1 (0.5) hours after hourly dosing and 2.1 (0.6) hours after a single dosing every 6 hours. CONCLUSIONS Voriconazole, 1%, eyedrops are well tolerated and penetrate into human aqueous humor when administered at hourly or 6-hourly intervals. They are effective in treating Candida and Aspergillus keratitis, are substantially more affordable than oral therapy, and have less potential to cause systemic adverse effects.

Stability of extemporaneously prepared voriconazole ophthalmic solution

PURPOSE The stability of extemporaneously prepared voriconazole ophthalmic solution was studied. METHODS Voriconazole solutions (2% and 1%) were reconstituted from the i.v. formulation. After thorough mixing, 3-mL samples of each of the resulting 2% and 1% solutions were filtered into eyedroppers. Three samples for both solutions were analyzed in triplicate at each time point. The 2% voriconazole ophthalmic solutions were stored at 2-8 degrees C, 25 degrees C, and 40 degrees C. The 1% voriconazole eye drops were stored at 2-8 degrees C. The 2% voriconazole solution samples were analyzed at time 0 and at weeks 1, 2, 4, 8, 16, and 32. The 1% solution samples were analyzed at time 0 and at weeks 6 and 14. Stability was measured using high-performance liquid chromatographic analysis. RESULTS The 2% voriconazole ophthalmic solution demonstrated excellent stability at 2-8 degrees C and 25 degrees C for up to 16 weeks. The voriconazole solution displayed no significant change in pH at all time intervals. No change in visual appearance or clarity was observed in the 2% voriconazole eye drops at any point of the study for all study temperatures. Voriconazole 1% solution was stable at 2-8 degrees C for up to 14 weeks. CONCLUSION Voriconazole 2% (20 mg/mL) solution preserved with 0.01% benzalkonium chloride prepared as alternative antifungal eye drops was stable for 16 weeks when stored at 2-8 degrees C and 25 degrees C and for 8 weeks when stored at 40 degrees C, while voriconazole 1% solution was stable at 2-8 degrees C for up to 14 weeks.

Treatment of Alternaria Keratitis with Intrastromal and Topical Caspofungin in Combination with Intrastromal, Topical, and Oral Voriconazole

Objective: To report a case of refractory atypical Alternaria keratitis that was treated with intrastromal and topical caspofungin 0.5% in combination with topical, oral, and intrastromal voriconazole. Case Summary: A 67-year-old female with a history of bilateral intraocular lens exchange and left pseudophakic bullous keratopathy was referred to the emergency department of the Royal Victorian Eye and Ear Hospital, Melbourne, Australia. Visual acuity of her left eye was limited to counting fingers. A fine branching pattern was noted throughout the anterior stroma of her left corneal graft. The anterior chamber was deep and quiet. Hourly topical voriconazole 1% was initiated, with limited response. One week later, Alternaria spp. was cultured from the corneal scraping. Subsequently, topical caspofungin 0.5% was added, with concomitant use of topical, oral, and intrastromal voriconazole. Despite gradual symptomatic improvement, topical voriconazole was increased to 2% and intrastromal caspofungin was added. The patient was discharged after almost 5 weeks of treatment. Topical voriconazole 2% and topical caspofungin 0.5% were continued for an additional 3 weeks and 1 week, respectively, in the outpatient setting. The patient underwent left penetrating keratoplasty 3 weeks postdischarge. Visual acuity was stable at 20/150, with no reported adverse event 15 months postoperative. Discussion: Treatment for Alternaria keratitis remains challenging, as it is refractory to existing antifungal agents. To our knowledge, this is the first reported instance of the use of intrastromal caspofungin to treat Alternaria keratitis in a case in which clinical resolution was not fully achieved despite the use of topical caspofungin in addition to extensive use of topical, intrastromal, and oral voriconazole. This case highlights the importance of intensive pharmacologic management and therapeutic penetrating keratoplasty in preventing evisceration of the patients eye, especially when Alternaria keratitis is involved. Conclusions: Intrastromal and topical caspofungin were employed in combination with voriconazole for the management of refractory Alternaria keratitis, with no observed adverse effects.

Successful Salvage Treatment of Scedosporium apiospermum Keratitis with Topical Voriconazole After Failure of Natamycin

Objective To report successful management of Scedosporium apiospermum (previously known as Monosporium apiospermum) keratitis with topical voriconazole as monotherapy. Case Summary A 54-year-old previously well woman presented to the emergency department with a painful, injected right eye. There was no history of trauma or use of contact lenses. On examination, the right eye was estimated to have visual acuity of hand movement. Slit lamp examination detected a 2.5 × 3.5 mm dense, central corneal infiltrate with overlying epithelial defect. The eye had mild corneal edema with anterior chamber inflammation. Microbiology testing revealed S. apiospermum as the primary pathogen. Hourly administration of topical natamycin 5% resulted in initial improvement in visual acuity to 20/50, with reduction in the size of the central infiltrate. However, 1 month later, the eye infection relapsed, with recurrence of epithelial defect (3.1 × 3.1 mm) and decline in visual acuity to 20/100. Antifungal therapy was switched to topical voriconazole 1%, administered every 2 hours. Vision improved to 20/30 within 5 days, and the central defect had completely re-epithelialized within 1 week. Discussion Treatment of S. apiospermum keratitis remains inadequate. A high natamycin minimum inhibitory concentration is necessary to treat S. apiospermum infection, which may explain the persistence of central infiltration despite ongoing therapy. The combined use of topical and oral voriconazole for the treatment of S. apiospermum keratitis has been reported. However, this is the first report of a successful clinical experience using topical voriconazole without oral therapy to manage S. apiospermum keratitis. This eliminates some disadvantages associated with oral voriconazole such as high cost, potential significant toxicity, and drug interactions. Conclusions The voriconazole 1% eye drop used alone is a promising, cost-effective, safe option for managing fungal keratitis, even that caused by S. apiospermum. It may have a larger role to play than simply that of adjunctive therapy.

Successful Use of Topical Voriconazole 1% Alone as First-Line Antifungal Therapy Against Candida albicans Keratitis

OBJECTIVE To report the successful use of topical voriconazole 1% given alone as primary therapy against a case of Candida albicans keratitis. CASE SUMMARY A 48-year-old previously well man presented to the emergency department with pain and foreign body sensation in the left eye following exposure to dust while driving a forklift. He wore weekly disposable soft contact lenses. Anterior stromal scar and dense infiltrate were detected in the left eye. The anterior chamber remained deep, with flare and copious white cells. Intraocular pressure was 12 mm Hg and visual acuity was 20/200. The epithelial defect persisted, with progressive thinning despite topical fluorometholone and ofloxacin 0.3% therapy for 2 days. Microbiology testing revealed C. albicans as the affecting pathogen. Hourly administration of voriconazole 1% eye drops was initiated as antifungal therapy. The corneal infiltrate began to resolve and the epithelial defect decreased in size within 2 days. Visual acuity improved to 20/120. After 4 days of voriconazole use, the epithelial defect was completely healed and visual acuity was 20/30 in the affected eye. No fungi were isolated from a second eye scrape. DISCUSSION Topical voriconazole as salvage monotherapy to manage fungal keratitis has been previously reported. It can be argued, however, that the primary therapy has facilitated the positive response to subsequent topical voriconazole. To date, there has been no solid evidence to suggest that topical voriconazole is effective when used as primary therapy. The current report provides evidence of topical voriconazole demonstrating clinical success when used as first-line therapy to treat C. albicans keratitis. The use of topical voriconazole can reduce the costs, toxicity, and drug interactions associated with common antifungal therapies. CONCLUSIONS Topical voriconazole 1% eye drops administered alone demonstrated success as first-line therapy against the most common fungal keratitis, C. albicans keratitis.

Penetration of 1% voriconazole eye drops into human vitreous humour: a prospective, open‐label study

Purpose:  Although there have been reports describing the use of 1% voriconazole eye drops in the treatment of fungal infections, little is known about the penetration of voriconazole eye drops into the vitreous humour. The aim of this study was to elucidate if topical application of 1% voriconazole eye drops could reach therapeutic levels in the vitreous humour.

Rapid and Sensitive Liquid Chromatography/Mass Spectrometry Assay for Caspofungin in Human Aqueous Humor

ABSTRACT A rapid, precise, and sensitive liquid chromatography/mass spectrometry (LC/MS) method to quantify the caspofungin concentration in human aqueous humor was developed and validated. Sample preparation involved simple dilution of aqueous humor samples with acetonitrile. Azithromycin was the internal standard. Good linearity over 10 to 5,000 ng/ml was observed. The lower limit of quantification was 10 ng/ml. The intra- and interday accuracies (percent bias) were within 11%, while the intra- and interday precisions were within 6%.

Prospective Open-Label Study of the Administration of Two-Percent Voriconazole Eye Drops

ABSTRACT Thirteen human subjects scheduled for elective anterior segment eye surgery received hourly 2% voriconazole eye drops 4 hours presurgery. No side effects were reported. Significantly, the voriconazole concentration in the aqueous humor of the eye was similar to that reported for the 1% voriconazole solution, suggestive of concentration-independent absorption.

Stability of Extemporaneously Prepared 0.5-Percent Caspofungin Eye Drops: a Potential Cost-Savings Exercise

ABSTRACT While the successful use of topical caspofungin for patients has been reported, topical caspofungin is not commercially available and its stability is unknown, limiting its usefulness in treating fungal keratitis. Caspofungin (0.5%) eye drops were aseptically prepared, and the concentrations were measured using a validated high-performance liquid chromatography (HPLC) analysis. The preparations remained stable for 28 days under refrigerated condition but not at 25.0°C. Our study supports the cost-saving use of caspofungin eye drops in the clinical setting.

Penetration of Topically Administered 0.5-Percent Caspofungin Eye Drops into Human Aqueous Humor

ABSTRACT Ten participants attending elective anterior segment eye surgery received 0.5% caspofungin eye drops either 1 drop hourly for 4 h or 1 drop an hour before surgery. The eye drops were generally well tolerated. In the absence of inflammation or corneal abrasion, topical caspofungin does not achieve clinically relevant concentrations.