Download Intravitreal Amphotericin B

Fungal endophthalmitis
Leila Rezaei, vitreoretinal surgeon
Assistant professor of Kermanshah university of medical science
 Fungal Endophthalmitis, a serious,
sight-threatening infection, is
often a complication of
intraocular surgery, systemic
infection, and ocular trauma.
 Endogenous,
Follows Fungemia, with
Hematogenous seeding of eye.
 Exogenous,
Follows Eye surgery,
or Fungal Keratitis.

The most common organisms in fungal
endophthalmitis are:
Candida spp,
Aspergillus spp,
Coccidioides spp,
Blastomyces spp,
Cryptococcus spp,
Histoplasmosis spp.
The common causes for:
 Endogenous FE:
 Post-traumatic FE:
 FE secondary to keratitis:
Candida albicans
Aspergillus niger
Fusarium solani
 The causative species is often difficult to diagnose
because of poor growth in culture.
 The diagnosis is usually based on clinical history and
presence of characteristic features in posterior segment.
 Choice of drugs is not routinely based on laboratory
susceptibility testing of fungal isolates.
Treatment of Fungal Endophthalmitis
• Treatment is also difficult, resulting from:
Drug resistance,
Antifungal drug toxicity,
Poor bioavailability of systemically administered drugs.
• Intravitreal antibiotics are a mainstay of treatment for
fungal endophthalmitis.
Systemic Antifungal Agents
 Amphotericin B
 Flucytosine
 Azole compounds
Fluconazole
Itraconazole
Voriconazole
Posaconazole
 Echinocandins
Caspofungin
Micafungin
Anidulafungin
0.6–1 mg/kg/day IV
50 to 150 mg/kg/day oral
400–1600 mg/day oral or IV
400–800 mg/day oral or IV
6 mg/kg/day oral or IV
400–800 mg/day oral or IV
50 mg/day IV
50–150 mg/day IV
50–100 mg/day
Intravitreal Antifungal Agents
Amphotericin B
5–10 μg/0.1 ml
Voriconazole
0.1 mg/0.1 ml
Caspofungin
0.1 mg/0.1 ml
Fluconazole
(experimental)
Flucytosine
(experimental)
• The drug should be given slowly in the central vitreous space, as
a bolus of even very small doses near the retina may result in
retinal necrosis.
• The drug has been found to reach the retinal surface in a few
hours.
• The frequency with which intravitreous injections can be given
safely has not been determined and is different for each agent.
• The elimination half-life of a drug in a vitreus cavity
depends on 2 pathways:
1)
Anterior route passage into aqueous,
2)
Posterior route by active transport across retina.
• In inflamed eye, mechanism of active transport across
retina is compromised, resulting in increased half-lives
of drugs eliminated primarily through a posterior route.
 Increased retinal toxicity to routinely used doses of intravitreal
antibiotics was demonstrated in eyes filled with silicone oil.
 This was possibly due to reduction of the preretinal space.
 Using one quarter of the nontoxic dose could prevent retinal
toxicity.
 Animal studies indicate that drug clearance is more rapid after
vitrectomy.
Intravitreal Amphotericin B
 Intravitreal Amphotericin B: 5–10 μg, is
generally nontoxic.
 Intraocular toxicity from highly concentrated
amphotericin B:
Severe Noninfectious Panophthalmitis and
Retinal Necrosis.
Intraocular Injection of Amphotericin-B
 After intraocular injection, half-life : 9.1 days.
 Repeat injection:
every 1 week
 The half-life is further decreased by vitreous removal.
(only 1.8 days in vitrectomized eyes)
Intraocular Injection of Amphotericin-B
a. 50mg vial in 10cc Aqua (=5mg/cc)
b. take 0,1cc (=0,5mg) and dilute with 9,9cc Aqua (=0,05mg/cc)
c. draw in tuberculin syringe for intravitreal injection
d. inject 0,1cc (=0,005mg=5μg) into the vitreous cavity.
 Physicians should examine the color of Amphotericin B
solution prior to intraocular administration.
 If the solution appears to be Yellow,
the medication should not be injected.
Liposomal Amphotericin B
• Liposomal Amphotericin B is a lipid-associated
formulation of the Amphotericin B.
• Liposome incorporation reduces the toxicity of
Amphotericin B by at least fourfold.
•route in the rhesus monk
Intravitreal Fluconazole
• Fluconazole penetrates ocular tissues well, achieving levels
in the retina/choroid that are equal to serum levels, and
aqueous and vitreous humor levels ≥ 70% of serum levels.
• Intravitreous injection of Fluconazole is probably not
necessary because of its good intraocular penetration.
• Intravitreal Fluconazole has been tested in animal models,
but does not appear to be any more effective than
intravitreal Amphotericin B and is thus rarely used
clinically.
Intravitreal Voriconazole
 Broad spectrum of action.
 Intravitreal Voriconazole has been shown to be less
toxic to the retina than intravitreal Amphotericin B.
 Based on animal models, intravitreal Voriconazole
(VCZ) appears to be nontoxic up to doses of 100 μg.
Dosage: 50 – 100 μg/0.1 cc
a. 200mg vial in 20 cc Aqua (=10mg/cc)
b. take 1cc (=10mg) and dilute with 19cc Aqua
(=0,5mg/cc)
c. draw in tuberculin syringe for intravitreal
injection
d. inject 0,1cc (=0,05mg) into the vitreous
cavity.
The half-life:
2.5 hours.
Supplementation of intraocular Voriconazole to
maintain therapeutic levels is required in clinical
settings.
Voriconazole is eliminated primarily through the retina,
thus half-life of drug is increased in fungal
endophthalmitis.
Intravitreally Implantable
Voriconazole Delivery System
 The therapeutic effect of intravitreal VCZ DDS on
fungal endophthalmitis appears to be significantly
better than intravitreal injection of VCZ.
 The optimal dose of VCZ in the DDS in studies was
1.2 mg.
Combination therapy with intravitreal Amphotericin
B and Voriconazole could be a novel treatment
strategy in the management of Endophthalmitis
caused by Filamentous fungus.
Intravitreal Miconazole
• Intravitreous injection of Miconazole has
been used to treat endogenous
Pseudallescheria boydii infection of the eye
that was resistant to Amphotericin B.
Intravitreal Ketoconazole
• Intravitreal Ketoconazole has been reported
safe in a rabbit model, but its use has not
been reported in humans.
Intravitreal Micafungin
• In rabbits, intravitreal injection of 15 μg
Micafungin was nontoxic, but its use has not
been reported in humans.
Intravitreal Corticosteroids
• Intravitreal corticosteroids (e.g., Dexamethasone
400 μg) may be a helpful adjunct in some patients
with fungal endophthalmitis, by reducing
inflammation.
• Generally, corticosteroids should be withheld
until proper antimicrobials have been initiated,
especially in patients with suspected fungal
disease.
Conclusion
For the treatment of fungal endophthalmitis, intravitreal
injection of Amphotericin B is the therapy of choice.
The recommended dose ranges from 5 to 10 μg/0.1ml
and may be repeated weekly.
In vitrectomised patients, the dosing regimen should be
reduce to every 3 or 4 days.
The length of treatment and the total dosage are based
on the extent of disease and its response to therapy.
THE END