INTRAVITREAL INJECTION OF
`THERAPEUTIC AGENTS
`
`GHOLAM A. PEYMAN, MD,*† ELEONORA M. LAD, MD, PHD,†
`DARIUS M. MOSHFEGHI, MD†
`
`Background:
`Intravitreal injection (IVI) with administration of various pharmacological
`agents is a mainstay of treatment in ophthalmology for endopthalmitis, viral retinitis,
`age-related macular degeneration, cystoid macular edema, diabetic retinopathy, uveitis,
`vascular occlusions, and retinal detachment. The indications and therapeutic agents are
`reviewed in this study.
`Methods: A search of the English, German, and Spanish language MEDLINE database
`was conducted. A total of 654 references spanning the period through early 2008 were
`individually evaluated.
`Results: The advantage of the IVI technique is the ability to maximize intraocular levels
`of medications and to avoid the toxicities associated with systemic treatment. Intravitreal
`injection has been used to deliver several types of pharmacological agents into the vitreous
`cavity: antiinfective and antiinflammatory medications, immunomodulators, anticancer
`agents, gas, antivascular endothelial growth factor, and several others. The goal of this
`review is to provide a detailed description of the properties of numerous therapeutic agents
`that can be delivered through IVI, potential complications of the technique, and recom-
`mendations to avoid side effects.
`Conclusion: The IVI technique is a valuable tool that can be tailored to the disease
`process of interest based on the pharmacological agent selected. This review provides the
`reader with a comprehensive summary of the IVI technique and its multitude of uses.
`RETINA 29:875–912, 2009
`
`Intravitreal injection (IVI) was initially performed
`
`for treatment of retinal detachment (RD) and vit-
`reous hemorrhage. In 1895, Deutschmann1 injected
`transplanted rabbit vitreous, and Ohm2 injected air
`in the vitreous cavity for the repair of RD. During
`subsequent decades, the use of IVI was limited to
`administration of saline3–7 and air.8 In the 1960s
`and 1970s, long-lasting gases were developed for
`the repair of complex RD.9 Intravitreal penicillin
`for treatment of endophthalmitis was attempted in
`the late 1940s,10 –12 but was subsequently aban-
`doned by the same authors in favor of systemic and
`subconjunctival injection.
`
`From the *Department of Ophthalmology and Vision Science,
`College of Medicine, University of Arizona, Tucson, Arizona;
`Attending Physician, Maricopa Health System, Phoenix, Arizona;
`Department of Ophthalmology, Tulane University, New Orleans,
`Louisiana; and †Department of Ophthalmology, Stanford Univer-
`sity, Stanford, California.
`The authors have no proprietary interest in any of the materials
`discussed in this article.
`Reprint requests: Gholam A. Peyman, MD, Department of Oph-
`thalmology and Vision Science, College of Medicine, University of
`Arizona, 10650 Tropicana Circle, Sun City, AZ 85351; e-mail:
`gpeyman1@ yahoo.com
`
`The modern era of IVI began in the early 1970s
`with the investigation of the blood ocular barri-
`ers.13,14 The results of these investigations stimu-
`lated the use of IVI of antibiotics for treatment of
`endophthalmitis and steroids for treatment of in-
`traocular inflammation to bypass anatomical barri-
`ers in the eye.15–17 This concept heralded the advent
`of IVI of antiinflammatory and antineoplastic com-
`pounds in the 1970s to 1980s, antivirals in the
`1980s to 1990s, triamcinolone acetonide (TA), and
`vascular endothelial growth factor (VEGF) inhibi-
`tors in the 2000s, setting the stage for a paradigm
`shift in how therapeutic agents are delivered to the
`eye.18 Medicare claims data indicated that 325,000
`IVIs (CPT 67028) codes had been filed in 2006
`alone,19 and the number is likely in excess of a
`million today. Intravitreal injection has been used to
`deliver many types of medications into the vitreous
`cavity: antiinfective (antibiotic, antifungal, and an-
`tiviral), antiinflammatory (nonsteroidal antiinflam-
`matory, steroids, and immunomodulators), antican-
`cer agents, gas, anti-VEGF, etc. With numerous
`novel therapies currently being investigated in clin-
`
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`RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES ● 2009 ● VOLUME 29 ● NUMBER 7
`
`ical trials, it is likely that the number of drugs under
`development for IVI will continue to increase.
`
`Intravitreal Injection Technique
`
`The use of preoperative topical antibiotics is not
`widespread despite evidence that this method can re-
`duce the conjunctival bacterial flora.20 –26 A recent
`report of a large series of IVI without preoperative use
`of antibiotics showed a low rate of endophthalmitis,
`indicating that the preoperative antibiotic may not be
`needed in each case.27 Another study involving more
`than 16,000 patients receiving office-based IVIs of anti-
`VEGF demonstrated a low rate of endophthalmitis
`(0.02%) despite variable preoperative prophylaxis.28
`Intravitreal injection is performed under topical an-
`esthesia, usually in an office-based setting. Clinicians
`should use aseptic techniques and use povidone–iod-
`ine to minimize the conjunctival bacterial flora.20 –24
`The type of anesthesia used with IVI varies between
`retinal specialists. Although 98% of retinal physicians
`surveyed in 2006 reported the use of anesthesia before
`IVI, the mode of anesthesia administration was divided
`between topical anesthesia (66.6%) and subconjunctival
`(33.3%).29 Anesthesia is usually accomplished with ei-
`ther cotton-tip applicators soaked in lidocaine or subcon-
`junctival injection of 2% lidocaine or 4% lidocaine jelly.
`Other options include topical anesthetics (lidocaine, pro-
`paracaine, or tetracaine) or the application of tetracaine
`jelly. Typically, a povidone–iodine (5%) solution is ap-
`plied to the eye either in solution form or povidone
`followed by thorough cleaning of the eyelashes, with
`subsequent application of a lid speculum. The anes-
`thetics used (proparacaine, lidocaine, or bupivacaine)
`have been shown to be nontoxic to intraocular struc-
`tures in rabbits. Intraocular application of lidocaine up
`to 2%, bupivacaine up to 0.75%, and a combination of
`the two anesthetics induced reversible electroretino-
`gram changes in the rabbit retina but did not result in
`any adverse clinical reactions or histologic retinal
`abnormalities.30
`After anesthesia, the pharmacological agent for IVI
`(either prepared by the manufacturer, such as ranibi-
`zumab, or prepared by the compounding pharmacist,
`such as bevacizumab) is drawn into a 1-mL tuberculin
`syringe from a sterile bottle, usually with a filter needle
`in place for the IVI itself. Thirty- to 32-gauge needles are
`most commonly used, whereas larger bore needles (27
`or 28.5 gauge) are less frequently used.31
`The injection site is usually the infero-temporal
`quadrant to avoid drug deposition in front of the visual
`axis. The pars plana is 3 mm to 4 mm posterior to the
`limbus. The needle should be aimed at the midvitreous
`with the bevel upward, and the injection should be
`
`done slowly to avoid jet formation or cavitary flow.
`The needle should not be introduced all the way to the
`hub. Using a single smooth continuous maneuver, the
`pharmacological agent is injected into the eye. The vol-
`ume of the administered compound is relatively con-
`sistent between studies, with the most commonly used
`volume being 50 ␮L to 100 ␮L. However, the studies
`using standard volumes do not account for the reduc-
`tion in size of the human vitreous that occurs with
`age.32 Generally, most clinicians believe that 100 ␮L
`is the largest safe volume, and larger volumes are
`reserved mainly for administration of gas for pneu-
`matic retinopexy (PR).31,33 The needle is removed si-
`multaneously with the application of a cotton-tipped
`applicator over the sclerotomy site to minimize reflux of
`material (particularly if the injected volume exceeded
`0.05 mL).
`The use of postoperative antibiotics is routine, re-
`ported in approximately 59% of the studies.31 A
`postinjection course of topical antibiotics typically
`lasts for 3 days to 7 days.
`
`Delivery of Antiinfective Agents
`
`Antibacterial Drugs
`
`Administration of antibiotics directly into the vitre-
`ous body through IVI is the standard of care for the
`treatment of bacterial endophthalmitis. Table 1 shows
`the recommended dosage of antibiotic for IVI, the
`half-life of each antibiotic in the vitreous body, and
`the maximum nontoxic dosage for IVI. Selection of an
`appropriate antibiotic depends on prevailing organ-
`isms in the geographic area, mechanism of endoph-
`thalmitis, strain of bacteria, sensitivity and resistance,
`as well as patient factors (e.g., allergies and sensitiv-
`ities). In the setting of acute postsurgical endoph-
`thalmitis, vancomycin in combination with either a
`third-generation cephalosporin or amikacin is typi-
`cally injected as initial empirical therapy.
`Aminoglycosides. Aminoglycosides have potent ac-
`tivity against gram-negative bacteria but are limited
`by their potential toxicity. The aminoglycoside anti-
`biotic family—streptomycin, gentamicin, kanamycin,
`tobramycin, amikacin, and netilmicin— has a chemi-
`cal composition of an organic base with amino
`sugars and are synthesized from numerous species
`of fungal organisms. Their wide spectrum of anti-
`biotic activity against both gram-positive and gram-
`negative bacteria is due to the ability to interfere
`with synthesis of ribosomal proteins. Amikacin is
`often the aminoglycoside of choice for human en-
`dophthalmitis,18 whereas gentamicin and clindamy-
`cin were shown to be effective in the prevention of
`
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`INTRAVITREAL INJECTION OF THERAPEUTIC AGENTS ● PEYMAN ET AL
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`877
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`Table 1. Recommended Dose and Pharmacologic
`Profile of Intravitreal Antibiotics
`
`Antibiotic
`
`Aminoglycosides
`Amikacin
`Gentamicin
`Kanamycin
`Netilmicin
`Streptomycin
`Tobramycin
`Penicillins
`Ampicillin
`Azlocillin
`Carbenicillin
`Cloxacillin
`Dicloxacillin
`Methicillin
`Mezlocillin
`Oxacillin
`Penicillin G
`Piperacillin
`Ticarcillin
`Cephalosporins
`Cefamandole
`Cefazolin
`Cefotaxime
`Cefotetan
`Cefoxitin
`Ceftazidime
`Ceftriaxone
`Cephalexin
`Cephaloridine
`Cephalothin
`Moxolactam
`Fluoroquinolones
`Ciprofloxacin
`Garenoxacin
`Gatifloxacin
`Levofloxacin
`Moxifloxacin
`Norfloxacin
`Ofloxacin
`Pefloxacin
`Travofloxacin
`Macrolides
`Erythromycin
`Clarithromycin
`Lincosamides
`Lincomycin
`Clindamycin
`Carbapenems
`Imipenem
`Meropenem
`Glycopeptides
`Vancomycin
`Teicoplanin
`Miscellaneous
`Aztreonam
`Chloramphenicol
`Cotrimoxazole
`Doxycycline
`Chloramphenicol
`
`Intravitreal
`Dose (mg)
`
`Vitreous
`Half-Life (h)
`
`0.4
`0.2
`
`0.25
`
`0.2
`
`5
`
`24
`12–35
`
`24
`
`16
`
`6
`
`0.5–2
`
`10–20
`
`3–5
`
`3
`
`0.5
`7
`
`16
`12
`3
`
`2.4
`20
`
`5
`
`1.72
`
`5.65
`3
`
`30
`2
`
`7–8
`
`30
`
`7.5
`10
`
`2
`
`0.5
`0.2–0.3
`1.5
`3
`
`0.08
`0.5–2.0
`0.4
`1
`
`2
`2
`
`2.5
`2
`1.25–2.0
`
`0.1
`0.1–2
`0.4
`0.625
`0.05–0.16
`
`0.05
`0.2
`0.025
`
`0.5
`1
`
`1
`0.5–1
`
`0.5
`
`1
`0.75
`
`0.1
`2
`1.6
`0.125
`1
`
`Antibiotic
`
`Antifungals
`Polyene antimycotics
`Amphotericin B
`Natamycin
`Nystatin
`Azoles
`Fluconazole
`Itraconazole
`Ketoconazole
`Miconazole
`Oxiconazole
`Terconazole
`Voriconazole
`Echinocandins
`Caspofungin
`Miscellaneous
`Faeriefungin
`Flucytosine
`Cilofungin
`
`Table 1.
`
`Intravitreal
`Dose (mg)
`
`Vitreous
`Half-Life (h)
`
`6.9–15.1
`
`3.1
`
`2
`
`2.5
`
`0.005–0.01
`3 X 0.025
`200 U
`
`0.1
`0.01
`0.54
`0.025–0.05
`0.1
`10
`0.05–0.1
`
`0.1
`
`0.1
`0.1
`0.32
`
`acute posttraumatic bacterial endophthalmitis.34,35
`Side effects of parenteral aminoglycosides include
`ototoxicity and neprotoxicity.18
`Toxicity of intravitreal aminoglycosides, which can
`occur with doses as low as 10 ␮g to 200 ␮g of
`gentamicin, includes the following: 1) formation of
`lysosomal cellular inclusions, resulting in ocular cell
`toxicity and loss of function; 2) cataracts following a
`dose greater than 200 ␮g of gentamicin; and 3) retinal
`infarction due to gentamicin and tobramycin.36,37 For
`this reason, some advocate the use of low-dose gen-
`tamicin (4 – 8 ␮g) in the infusion fluid.34,35 Current
`recommendations emphasize administration of IVI
`into the anterior vitreous with the needle bevel facing
`the lens, slow injection of the medication, and avoid-
`ance of repeated IVI in short intervals (less than 1
`week, except for the negative sensitivity results for the
`antibiotic used), especially in combination at
`low
`doses with vancomycin or clindamycin to limit the
`possibility of toxicity.18,34
`Cephalosporin. The third-generation cephalosporins,
`which include ceftriaxone, ceftazidime, and moxolac-
`tam, are a mainstay in the initial management of IVI.
`They have increased activity against gram-negative
`organisms but are less active against gram-positive
`organisms.38 The cephalosporins were first isolated
`from the fungus Cephalosporium acremonium. These
`semisynthetic antibiotics have a similar chemical
`structure and mechanism of action to the penicillin
`family. The first generation of cephalosporins, which
`includes cefazolin, cephalexin, and cephalothin, has a
`wide spectrum of activity against gram-positive bac-
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`RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES ● 2009 ● VOLUME 29 ● NUMBER 7
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`teria and some activity against gram-negative bacteria.
`The second generation, represented by cefotetan, ce-
`foxitin, and cefamandole, has more activity against
`gram-negative organisms but are less active against
`gram-positive bacteria, especially Staphylococcus. Other
`members of this family—cephaloridine, cephalothin,
`ceftazidime, and cefotaxime—have demonstrated effi-
`cacy and safety in experimental models of progression of
`endophthalmitis without toxicity to intraocular structures
`in rabbit eyes.39 – 44 Cefazolin is currently not recom-
`mended for treatment of endophthalmitis due to increase
`in resistant organisms.39,42 Intravitreal injection of moxa-
`lactam inhibited experimental Staphylococcus aureus
`endophthalmitis but resulted in retinal abnormalities in
`rabbits at doses of 2.5 mg or higher.45,46
`
`Glycopeptides
`Vancomycin.—Vancomycin is the preeminent choice
`for initial treatment of acute postoperative endoph-
`thalmitis due to gram-positive organisms. Vancomy-
`cin is an antibiotic produced by Streptomyces asianis
`and has a unique chemical structure that lends it high
`activity against gram-positive cocci.47 Vancomycin
`inhibits bacterial cell wall synthesis. Vancomycin,
`first developed in 1958, has become an extremely
`effective drug in treatment of severe gram-positive
`ocular infections (keratitis, endophthalmitis, orbital
`cellulitis) in the setting of antibiotic-resistant bacteria
`or antibiotic allergy. However, in recent years, a con-
`troversy arose over the use of this agent in ophthalmol-
`ogy, especially as a prophylaxis in elective cataract sur-
`gery.18 The identification of vancomycin resistance in
`coagulase-negative Staphylococci in 1987, followed by
`cases of resistant Enterococci in 1988, has led to calls for
`the judicious use of this agent in ophthalmology.48,49
`Intravitreal vancomycin is the drug of choice for
`endophthalmitis caused by gram-positive organisms.18
`Intravitreal injection of vancomycin was nontoxic to
`ocular structures in the clinically recommended dose
`of 1 mg/0.1 mL; added to infusion fluid for intraocular
`surgery, the nontoxic dose is 8 mg/mL to 32 mg/mL.50
`A dose of 1 mg/0.1 mL halted progression of methi-
`cillin-resistant S. aureus endophthalmitis.47 We urge
`caution in patients with silicone oil, because nontoxic
`concentrations of this drug may become toxic after
`IVI in postvitrectomy, silicone-filled rabbit eyes.51
`The threshold for ocular toxicity in rabbits decreased
`to one quarter of the nontoxic dosage in an unoperated
`eye compared with silicone-filled eyes.51 In the En-
`dophthalmitis Vitrectomy Study,52 all gram-positive
`bacteria including methicillin-resistant S. aureus were
`susceptible to vancomycin.53
`In cases of endophthalmitis due to gram-positive
`organisms, resistance to vancomycin is still rare, at
`
`only 2.1% of a reported 8,500 strains of bacteria.54
`However, ophthalmologists should use caution when
`using vancomycin, because the incidence of vanco-
`mycin-resistant S. aureus and Enterococci isolates
`continues to rise.49 New antibiotics such as quinu-
`pristin-dalfopristin, linezolid, and daptomycin may
`show promise in the treatment of vancomycin-re-
`sistant infections.55– 65 Vancomycin showed syner-
`gism with aminoglycoside antibiotics against vari-
`ous organisms, especially Enterococcus, and with
`␤-lactams against gram-positive bacteria and some
`gram-negative bacteria.54,55
`Teicoplanin.—Teicoplanin is a relatively new glyco-
`peptide antibiotic that is isolated from Actinoplanes
`teichomyceticus. It is active against most gram-posi-
`tive bacteria, especially Staphylococci. Teicoplanin in
`combination with gentamicin is effective against En-
`terococci. Intravitreal injection of teicoplanin is non-
`toxic in rabbit retinas at doses up to 750 g/0.1 mL.66,67
`Penicillins. The penicillins are rarely used for treat-
`ment of endophthalmitis because of widespread resis-
`tance. Penicillins are a group of antibiotics derived from
`6-aminopenicillic acid. They work by inhibiting bacterial
`cell wall synthesis. Intravitreal injection administration is
`currently reserved for methicillin, cloxacillin, dicloxacil-
`lin, and ampicillin. Methicillin, oxacillin, and ampicillin
`are penicillinase-resistant, semisynthetic penicillins that
`can be delivered by IVI and do not cause toxicity at
`recommended dosages.68 –70 The number of Staphylo-
`cocci species resistant to methicillin and other peni-
`cillinase-resistant penicillins has increased.18 The tox-
`icity, clearance, and efficacy of IVI cloxacillin and
`dicloxacillin for endophthalmitis management have
`not been studied.18
`Extended-spectrum penicillins are alphacarboxypeni-
`cillins (e.g., carbenicillin and ticarcillin) and acylamin-
`openicillins (e.g., azlocillin, mezlocillin, and piperacil-
`lin). Although these antibiotics are effective against
`gram-negative aerobic organisms that cause endoph-
`thalmitis, such as Enterobacteriaceae and Pseudomo-
`nas, which are currently resistant to many penicillins,
`their use is not widespread. Similarly, experimental
`evidence suggests that
`intravitreal piperacillin/ta-
`zobactam, carbenicillin,
`ticarcillin, and piperacillin
`have demonstrated efficacy and lack of toxicity in
`experimental models.71–73
`are not
`Fluoroquinolones. The fluoroquinolones
`widely used via IVI for treatment of endophthalmitis.
`The fluoroquinolones are derived from nalidixic acid
`and have a potent activity against gram-negative bac-
`teria. Ciprofloxacin is considered effective for prophy-
`laxis and treatment of intraocular infections74 and is
`not toxic to the rabbit retina.75
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`Norfloxacin, ofloxacin, and pefloxacin are only ad-
`ministered orally for prevention or management of
`endophthalmitis76 but have not been used for IVI.
`Despite their initial efficacy, resistance to first- and
`second-generation quinolones in bacterial keratitis and
`other ophthalmologic infections is increasing.76,77
`This prompted the development of third- (levofloxa-
`cin) and fourth-generation quinolones (gatifloxacin,
`garenonoxacin, and moxifloxacin) during the past de-
`cade. New quinolones achieved an increased efficacy
`against gram-positive organisms while maintaining
`activity against gram-negative bacteria.78 – 80
`The third- and fourth-generation fluoroquinolones
`represent a good first-line antibiotic treatment for
`many ocular infections. Intravitreal injection of these
`antibiotics did not
`result
`in electroretinographic
`changes or retinal toxicity in rabbits when adminis-
`tered in doses up to 625 ␮g for levofloxacin,78 400 ␮g
`for gatifloxacin,78 4,000 ␮g for garenonoxacin,79 and
`160 ␮g for moxifloxacin.80
`Macrolides. Due to increasing resistance, erythromy-
`cin has rarely been used for IVI therapy of endoph-
`thalmitis. Erythromycin, which was first synthesized
`from Streptomyces erytheus in 1952, has activity
`against gram-positive cocci and Neisseria species. Its
`mechanism of action is inhibition of protein synthesis
`by binding the 23S rRNA molecule of the 50S subunit
`of bacterial ribosome, inhibiting peptide growth.81 De-
`spite effectiveness against experimental S. aureus en-
`dophthalmitis and a lack of ocular toxicity,82 erythro-
`mycin is not used due to widespread resistance.
`Intravitreal clarithromycin was also nontoxic to rabbit
`eyes in a dose of up to 1.0 mg.83
`Lincosamides. The lincosamides are rarely used for
`IVI therapy of endophthalmitis.
`Lincomycin.—Lincomycin is derived from the acti-
`nomycete Streptomyces lincolnensis and has a mech-
`anism of action similar to that of erythromycin.81,84 It
`is effective against Group A Streptococci, Pneumo-
`cocci, penicillinase-producing S. aureus, Corynebac-
`teria, Clostridia, and Bacteroides species.
`Clindamycin.—Clindamycin, a semisynthetic deriv-
`ative of lincomycin, has the same antibiotic activity
`and mechanism of action as lincomycin but with
`higher potency.18 Intravitreal injection of clindamycin
`has demonstrated efficacy for prophylaxis against en-
`dophthalmitis and is nontoxic to the retina.34,68 Intra-
`vitreal injection or intracameral injection of clindamy-
`cin (45 ␮g) in conjunction with IVI or intracameral
`gentamicin (40 ␮g) was superior to balanced salt
`solution IVI/intracameral injections in the prevention
`of endophthalmitis after penetrating eye injury (2.3%
`vs. 0.3%, P ⫽ 0.04).34 Additionally, it was found that
`
`IVI antibiotic administration was superior to intracam-
`eral administration.34 These data strongly suggested
`that intraocular and especially intravitreal gentamicin
`and clindamycin were effective in preventing acute
`posttraumatic bacterial endophthalmitis. Intravitreal
`injection of 1.0 mg clindamycin in 0.1 mL and 1.0 mg
`of dexamethasone in 0.1 mL was also well tolerated in
`patients with toxoplasmic retinochoroiditis.85 This
`treatment resulted in a favorable response after 2
`weeks; specifically, there was improvement in visual
`acuity and preservation of the disk and macula, sug-
`gesting that this regimen may be an additional tool in
`treatment of toxoplasmic retinochoroiditis.85 Further
`research into IVI clindamycin is warranted because
`the reported adverse drug reaction rate to clindamycin
`for ocular toxoplasmosis is 22.5%.86
`Carbapenems. Imipenem/cilastatin is a combination
`of two antibiotics, cilastatin and the ␤-lactam theina-
`mycin, and works by inhibiting cell wall synthesis. It
`has a wide spectrum of activity against gram-positive
`and gram-negative aerobic and anaerobic bacteria.
`Systemic imipenem has good ocular penetration, with
`aqueous concentration of 2.99 ␮g/mL and vitreous
`concentration of 2.53 ␮g/mL 2 hours after adminis-
`tration of 1 g ofimipenem in 25 patients undergoing
`routine cataract extraction.87 Although rarely used in
`IVI therapy, imipenem has demonstrated efficacy in
`one case of Pseudomonas endophthalmitis and was
`nontoxic to ocular structures.88 Experimental IVI of
`imipenem for
`treatment of experimental Bacillus
`cereus and Pseudomonas endophthalmitis in pigs
`demonstrated safety and efficacy.89,90 The combina-
`tion of amikacin and vancomycin was superior to IVI
`of imipenem for treatment of experimental S. aureus
`endophthalmitis in rabbits.91
`is an antibiotic
`Chloramphenicol. Chloramphenicol
`first isolated from Streptomyces venezuelae in 1947.18 It
`has a wide spectrum of action that includes many gram-
`positive and gram-negative baceria but excludes P.
`aeruginosa.18 Systemic use of this antibiotic should be
`carefully monitored, because it may result in serious
`toxic reactions such as fatal blood dyscrasias.92 Intravit-
`real injection of chloramphenicol (1 mg), in contrast, is
`nontoxic to all intraocular structures and is effective
`against experimental endophthalmitis.93 The lack of cov-
`erage of P. aeruginosa has limited the use of IVI chlor-
`amphenicol for treatment of endophthalmitis.18
`
`Antifungal Agents
`
`Fungal endophthalmitis, representing only 3% to
`13% of all reported cases of endophthalmitis, can be a
`difficult diagnosis due to the long onset of symptoms
`and the prolonged time necessary for organism iden-
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`RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES ● 2009 ● VOLUME 29 ● NUMBER 7
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`tification.18 McDonnell et al94 suggested that ophthal-
`mologic screening is important in patients at high risk
`for development of systemic fungal infections, be-
`cause the eye is commonly affected in fungemia.
`Empirical treatment is given based on clinical presen-
`tation and presence of associated risk factors for fun-
`gal infection. Fungal endophthalmitis is associated with
`the use of hyperalimentation, broad-spectrum antibiotics,
`indwelling catheters, hemodialysis, cancer, intravenous
`drug use, acquired immunodeficiency syndrome (AIDS),
`or other immunocompromised state.18 Premature infants
`are more prone to development of endogenous Can-
`dida endophthalmitis, especially during treatment
`with broad-spectrum antibiotics and hyperalimenta-
`tion.95–97 Finally, geographic area may play a role,
`because postoperative fungal endophthalmitis is more
`common in the Far East than in Western societies.18
`Fungal endophthalmitis is most commonly caused by
`Candida (56% of cases) and Aspergillus (24% of
`cases).98 Endogenous Candida endophthalmitis has
`slower progression but better prognosis compared
`with other fungal endophthalmitis.99,100 One study re-
`ported a mean of 61 days from onset of symptoms to
`treatment for Candida versus 5 days for Aspergil-
`lus.100 Aspergillus endophthalmitis, which occurs in
`association with pulmonary disease and intravenous
`drug use, has a more acute presentation and a more
`rapid progression than Candida endophthalmitis.100
`Aspergillus also has an increased tendency to result in
`macular scarring, which potentially can lead to visual
`loss.101 Endophthalmitis caused by other fungal or-
`ganisms is rare.102–106 There are many treatment
`options for fungal endophthalmitis including IVI
`amphotericin B (which has significantly better in-
`traocular penetration compared with the intrave-
`nous route),107,108 systemic fluoconazole,109 sys-
`temic fluocytosine for all fungal infections except
`resistant Candida species,107,108 systemic or intravit-
`real voriconazole,98,110 –112 and caspofungin.98,113–115
`
`Polyene Antimycotics
`Amphotericin B.—Amphotericin B, a fungistatic and
`fungicidal antibiotic synthesized from Streptomyces
`nodosus strains, is currently the most effective anti-
`fungal drug available. This agent acts by binding a
`sterol on the cell membrane, resulting in permeabili-
`zation and outflow of intracellular components. How-
`ever, amphotericin B can have significant side effects
`that include severe constitutional symptoms, thrombo-
`phlebitis, hepatoxicity, nephrotoxicity, neurotoxicity,
`allergic reactions, and cardiac arrest with rapid intra-
`venous infusion.116 Intravitreal injection of amphoter-
`icin B reversed experimental Candida endophthalmi-
`tis and was nontoxic in doses up to 10 ␮g.117–124
`
`Amphotericin B was effective against zygomycetes
`endophthalmitis when 10 ␮g was administered in the
`vitreous and 10 ␮g between the iris and posterior
`capsule.122 Early vitrectomy and IVI of amphotericin
`B demonstrated efficacy in treatment of fungal en-
`dophthalmitis123,124 and in a case of Aspergillus ne-
`crotizing retinitis.125 Currently, IVI of amphotericin B
`(5 ␮g in 0.05 mL) is the drug of choice for suspected
`fungal endophthalmitis. Care must be taken while
`performing IVI of amphotericin B because apposition
`to the retina can result in retinal necrosis.18,120 The
`finding that amphotericin B is synergistic with ri-
`fampin against some Candida, Aspergillus, Penicil-
`lium, and Rhizopus strains may lead to future clinical
`applications in ophthalmology.126
`Nystatin.—Nystatin is an antifungal isolated from
`Streptomyces noursei that has a similar mechanism of
`action as amphotericin B. It is fungistatic and fungi-
`cidal against Candida, Cryptococcus, Histoplasma,
`and Blastomyces species.18 Nystatin was successful
`against experimental Aspergillus endophthalmitis if
`administered 24 hours after inoculation.127 At thera-
`peutic doses (200 U or 57.14 ␮g), a transient inflam-
`matory reaction occurs, and this may explain the rel-
`ative lack of use of IVI nystatin.127
`Natamycin.—Natamycin (pimaricin) belongs to the
`same class of polyene antifungal antibiotics as ampho-
`tericin B and nystatin. It has a wide spectrum of
`activity but its clinical utility is limited by poor ocular
`penetration.128,129 Intravitreal natamycin was thera-
`peutic in rabbits with Aspergillus endophthalmitis
`only when administered in doses that resulted in irre-
`versible retinal toxicity. Some clinicians suggest that a
`useful regimen of intravitreal natamycin may use
`25-␮g doses given at 72-hour intervals130; however,
`the practicality of such a divided dose in the face of
`known retinal toxicity has severely limited the use of
`IVI natamycin. Presently, we do not recommend that
`IVI natamycin be used except in the most extraordi-
`nary situations where other IVI antifungals have failed
`to halt the progression of fungal endophthalmitis.
`Azoles. The antibiotic agents from the azole family
`are active against dermatophytes, yeasts, fungi, some
`bacteria, and protozoa and are generally less toxic
`than amphotericin B.18 These qualities rendered them
`useful in treatment of systemic and ocular fungal
`infections.
`The imidazoles (miconazole, ketoconazole, and
`oxiconazole) have a broad spectrum of activity that
`includes Candida, Cryptococcus, and Coccidioides.
`Miconazole is fungistatic at low dosages and fungi-
`cidal at higher dosages. Intravenous miconazole has
`good penetration of the vitreous body.116 Intravitreal
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`injection of miconozale demonstrated that it may not
`be as effective as its systemic adminstration.131,132
`Ketoconazole has a lower incidence of systemic side
`effects than miconazole, can result in hepatotoxicity,
`and has poor vitreous penetration.133 Ketoconazole is
`only available as an oral tablet or powder dissolved in
`dimethyl sulfoxide. There is a paucity of literature on
`use of intravitreal ketoconazole for treatment of fungal
`endophthalmitis. Intravitreal injection of ketoconazole
`has been mainly administered after intravitreal am-
`photericin B. In 2 patients with postoperative Candida
`parapsilosis endophthalmitis treated with a combina-
`tion of intravitreal amphotericin B, removal of the
`pseudophakos, and oral ketoconazole (800 mg/day for
`12 weeks), the efficacy of oral ketoconazole could not
`be ascertained.134 Intravitreal ketoconazole in doses
`up to 540 mg was nontoxic to ocular structures.135
`Oxiconazole has a broad spectrum of activity and is
`more effective against Candida than other imida-
`zoles.18 The use of oxiconazole is currently limited
`mainly to superficial mycoses; oxiconazole was non-
`toxic to rabbit ocular structures.136
`Triazoles (itraconazole, fluconazole, and voricon-
`azole) are newer azole antifungals that contain a third
`nitrogen on the azole ring. Their mechanism of action
`is via inhibition of ergosterol biosynthesis and damage
`of phospholipid membranes at higher dosages.137 Itra-
`conazole has a broad spectrum of activity and low
`systemic toxicity. It was successful even at low doses
`when administered early in a rabbit model of endog-
`enous Candida endophthalmitis but not when admin-
`istered 7 days after the infection.138 In a mouse model,
`itraconazole or fluconazole was synergistic when given
`in combination with flucytosine in the management of
`Candida and Aspergillus infections.139 Fluconazole is
`active against a wide variety of fungal organisms and has
`one of the best pharmacokinetic properties of all antifun-
`gal drugs.139 Although fluconazole was nontoxic to rab-
`bit eyes in doses up to 100 ␮g,138,140 it was not effective
`in a rabbit model of endogenous Candida endoph-
`thalmitis when administered in high doses at 7 days
`after infection.138 Voriconazole is a second-generation
`synthetic derivative of fluconazole that is a promising
`new modality in the treatment of fungal endophthalmi-
`tis.111 This agent has a greater ability to inhibit biosyn-
`thesis of fungal cell membranes than other antifungal
`drugs. The minimal inhibitory concentration for Candida
`species, Aspergillus fumigatus, Histoplasma capsulatum,
`and Fusarium organisms is much lower than those of
`amphotericin B, fluconazole, itraconazole, ketocon-
`azole, and 5-flucytosine.112 Intravitreal injection of
`voriconazole was effective against experimental Can-
`dida albicans endophthalmitis in a rabbit model98 and
`has demonstrated efficacy against endogenous Scedos-
`
`porium apios