Abstract
Abstract
Purpose:
To investigate the penetration of micafungin, a new class of echinocandin antifungal agent, into the aqueous humor and vitreous after an intravenous administration.
Methods:
Endogenous endophthalmitis caused by Candida albicans developed bilaterally in a 67-year-old man. Three hours before vitrectomy, the patient received an intravenous injection of 300 mg micafungin. Samples of aqueous and vitreous were collected during the vitrectomy approximately 60 min after the intravenous injection. The concentration of micafungin in both bodies was determined by high-performance liquid chromatography.
Results:
The concentration of micafungin was 25.36 μg/mL in the serum, 0.026 μg/mL in the aqueous, and 0.043 μg/mL in the vitreous. The micafungin minimum inhibitory concentration (MIC) against the C. albicans strain isolated from our patient was 0.03 μg/mL. Thus, the micafungin reached the MIC in the vitreous.
Conclusion:
We suggest that intravenous micafungin should be considered in mild cases of endogenous fungal endophthalmitis, or be given in combination with other intravitreal antifungal agents with vitrectomy in more severe cases.
Introduction
Micafungin is a water-soluble echinocandin antifungal agent that inhibits the synthesis of beta (1,3)-D-glucan, an essential component of the cell wall of Candida spp. and Aspergillus spp., with little or no toxicity in vivo. 3 Despite the increasing use of micafungin in patients with endogenous fungal endophthalmitis, little is known about the ocular penetration of echinocandin antifungals in humans. Therefore, we administered micafungin intravenously to a patient with bilateral endogenous endophthalmitis caused by Candida albicans who was scheduled to undergo vitrectomy. The ocular distribution of micafungin was determined in samples of the aqueous humor and vitreous collected during the vitrectomy.
Case Report
A 67-year-old man with myelodysplastic syndrome had undergone major abdominal surgery for a perforated gastric ulcer on October 31, 2008, at another hospital, and he was given broad spectrum antibiotics postoperatively. A central venous catheter was inserted during the postsurgical period, and the next day, the patient developed fever and the catheter was removed. He was treated with 1 g of cefmetazole intravenously. Systemic cultures were not made, and a fungal infection was not considered. Two weeks later, he was examined at another eye clinic complaining of blurred vision in both eyes. The doctors suspected bilateral uveitis, and the patient was referred to the Department of Ophthalmology, Gifu University Graduate School of Medicine, for further evaluation and treatment on January 22, 2009.
Our examination showed that his best-corrected visual acuity (BCVA) was 6/20 right eye (OD) and 12/20 left eye (OS). His intraocular pressures were 13 mmHg OD and 9 mmHg OS. There was mild conjunctival injection, cells in the anterior chamber, and diffuse haze and cells in the vitreous of both eyes. Fundus examination revealed multiple subretinal infiltrates with a large lesion temporal to the fovea of right eye and severe vitreous opacification that prevented a detailed examination of the posterior pole of the left eye (Fig 1: A, B).
Fundus photographs and optical coherence tomographic image of a patient with endogenous fungal endophthalmitis.
Laboratory tests showed normal white blood cell count, decreased red blood cell count, decreased hemoglobin level, and elevated C-reactive protein. The sedimentation rate was 45.0 mm/h, and the serum level of β-D-glucan was 21.0 pg/mL. The Aspergillus antigen titer was 0.6. Chest roentgenogram and computed tomography (CT) scan demonstrated pneumonia-like infiltrative shadows with air space consolidation in the right lower lobe.
On the basis of his surgery, laboratory data, and fundus lesions, a tentative diagnosis of fungal endophthalmitis was made. Fluconazole (400 mg/day) was intravenously initiated according to the Guidelines for Management of Deep-seated Mycoses 2007 of Japan. Three weeks later, there was an improvement and resolution of the ocular signs, however the titer of Aspergillus antigen and C-reactive protein in the serum increased. X-rays showed that the infiltrative shadows of the chest increased in both lower lobes.
Fluconazole was discontinued and replaced by 300 mg/day of intravenous micafungin. A remarkable resolution of the vitreous inflammation was observed in both eyes, however an active macular lesion was observed in the right eye, and the vision in the left eye remained depressed. Pars plana vitrectomy with phacoemulsification and intraocular lens implantation was performed after 12 days in the right eye and after 19 days in the left eye.
The study was approved by the ethics committees of Gifu University Hospital, and the patient provided written informed consent to participate in this study.
Three hours before the vitrectomy, 300 mg micafungin was injected intravenously, and samples of aqueous humor and vitreous were collected during the surgery approximately 60 min after the intravenous injection of micafungin. The intravenous infusion of micafungin continued for 5 days after surgery, and the treatment was switched to oral itraconazole (100 mg).
Postoperatively, a significant decrease of inflammation and improvement of vision were observed in both eyes. However, the foveal scar in the right eye remained. At the 1-year follow-up examination, there was no evidence of a recurrence, and his BCVA had recovered to 20/20 in both eyes (Fig 1: C, D, E). The infiltrative shadow in both lower lobes on the chest roentgenograms and CT scan and the titer of the Aspergillus antigen also decreased.
Subsequent cultures from vitreous biopsy specimens in the left eye grew C. albicans, which was sequenced after polymerase chain reaction. The bacterial culture was negative in both eyes. The susceptibilities of C. albicans to amphotericin B, flucytosine, fluconazole, itraconazole, miconazole, micafungin, and voriconazole were 0.5, 0.25, 1, 0.25, 0.25, 0.03, and 8 μg/mL, respectively.
The micafungin concentrations in the serum and tissues were determined by high-performance liquid chromatography as reported.4,5 The concentration of micafungin was 25.94 μg/mL in the serum, 0.030 μg/mL in the aqueous, and 0.025 μg/mL in the vitreous of the right eye. In the left eye, the concentration was 24.77 μg/mL in the serum, 0.022 μg/mL in the aqueous, and 0.061 μg/mL in the vitreous.
Discussion
The effectiveness of antifungal agents depends on the concentration achieved in the ocular tissues, for example, aqueous humor and vitreous. It has been reported that intravenously administered echinocandins do not penetrate into the vitreous,6,7 because they do not easily cross the blood-ocular barrier owing to their size. The molecular weight of micafungin is 1292.26 Da. 7 A pharmacokinetic study on rabbits showed that the micafungin levels were low or undetectable in the aqueous humor and vitreous after an intravenously injection of micafugin. 4 Suzuki et al. 5 demonstrated that the concentration of micafugin in the retina-choroid and plasma exceeded the minimum inhibitory concentrations (MICs) for fungal pathogens after systemic administration in a rabbit model, although micafungin was not detected in the vitreous humor in the noninflamed eye. In our case, the concentration of micafungin was measured in the vitreous of a patient with fungal endophthalmitis. The infection may be produced by proinflammatory cytokines that could have altered the capillary permeability and disrupted the blood–ocular barrier. 8
Our results showed that the concentration of micafugin in the vitreous was 0.10%–0.25% and that in the aqueous, it was 0.09%–0.12% of the serum concentration. For voriconazole, the percentage concentration in the aqueous and vitreous to that in the serum in humans was 38.1% (0.81 μg/mL) and 53.0% (1.13 μg/mL), 2 and for fluconazole, the concentration in the vitreous was 69.5% (12.1 μg/mL) and in the aqueous, it was 73.6% (12.8 μg/mL). 9 Both voriconazole and fluconazole readily penetrate into ocular tissues in comparison to micafungin. The concentration of voriconazole would not have exceeded the MIC for our isolated C. albicans (8 μg/mL). The fluconazole levels would have achieved the MIC level of the fungus (1 μg/mL) and should have improved the ocular condition, although the Aspergillus antigen and C-reactive protein increased in our case. Although the concentration of micafungin in the vitreous (mean; 0.043 μg/mL) was low, it was sufficient to reach the MIC against the C. albicans (0.03 μg/mL) strain that was isolated from our patient and to resolve the ocular inflammation.
Repeated doses should lead to a gradual increase in the concentration of the antimicrobials. 10 After multiple doses of intravenous micafungin, the vitreal micafungin levels might be higher and attain effective levels. In our case, the vitreous micafungin concentration in the left eye after 19 repeated doses over a 24-h period was slightly higher than that in the right eye after 12 days of therapy.
Although further pharmacokinetic and clinical studies are needed, our data suggest that micafungin should be considered for patients with mild endogenous fungal endophthalmitis as a systemic treatment without vitrectomy (fungal infection only in the ocular tissues such as the retina-choroid and not in the vitreous). Micafungin should also be considered to be used in combination with an intravitreal antifungal agent (e.g., amphotericin-B 1 or voriconazole 2 ) with vitrectomy in more severe cases (fungal invasion in the vitreous).
In conclusion, we report the ocular concentration of micafungin in a patient with bilateral endogenous endophthalmitis caused by C. albicans after intravenous administration. Our results showed that the concentration of micafugin in the vitreous attained the MIC for C. albicans, although micafungin as a systemic treatment for severe endogenous fungal endophthalmitis may be considered in combination with an intravitreal antifungal agent with vitrectomy.
Author Disclosure Statement
The authors have no proprietary or financial interest in any products used in this study. None to declare.