The metastatic infection may involve only the choroid and retina (as in localized fungal chorioretinitis), may progress into the vitreous or anterior chamber fluids (fungal endophthalmitis), or may involve all ocular tissues (fungal panophthalmitis). A variety of fungi have been reported to cause endogenous intraocular infection, but by far the most common is Candida species.¹ Candida albicans is the most common yeast isolate and Aspergillus is the second most common in reported series. Other fungi reported to cause intraocular infection are shown in Table 1.^1–12

TABLE 1. Classification of Fungi Recovered in Endogenous Fungal Endophthalmitis

  Yeasts and yeastlike isolates
  Candida species

  C. albicans
  C. parapsilosis
  C. tropicalis
  C. glabrata

  A. fumigatus
  A. niger
  A. glaucus
  A. flavus

  F. solani
  F. oxysporum

A myriad of ocular inflammatory and neoplastic conditions can resemble endogenous fungal endophthalmitis (Table 2). In some cases, differentiation is relatively straightforward; in others, it can be difficult. In most of these conditions a detailed history, careful examination, and appropriate laboratory studies will lead to the correct diagnosis.^13,14

TABLE 2. Differential Diagnosis for Endogenous Fungal Endophthalmitis

This chapter will review the classification of fungi, predisposing factors, signs and symptoms of the systemic and ocular fungal infections, diagnosis, treatment, and complications. Because Candida species is by far the most common cause of endogenous fungal endophthalmitis, most of the chapter will focus on these organisms.

Yeasts or yeastlike fungi (e.g., C. albicans) are single-cell organisms, typically round or oval, that form discrete, smooth, creamy and moist colonies (Fig. 1) within 24 to 72 hours on routine microbiologic media. They reproduce or multiply by budding. The characteristic appearance is shown in Figures 2 and 3. Molds (e.g., Aspergillus fumigatus) are multicellular fungi that contain tubular structures (hyphae) and grow by branching and longitudinal extension. These are identified by their macroscopic (Fig. 4) appearance (e.g., cottony, woolly, powdery) or microscopic structures (conidia, hyphal segmentation), and color (Fig. 5). Some fungi may grow with both yeastlike and hyphal morphology in tissues or culture.

AMPHOTERICIN B

Amphotericin B has traditionally been the drug of choice for treating most fungal infections.¹⁵ Although it still remains an important drug for treating fungal infections, some of the newer azole compounds are gaining increased acceptance for treatment in many situations.

Amphotericin B is one of several polyene antibiotics (Table 3). It was discovered in 1956¹⁶ and first used for the treatment of disseminated Candida infection in 1960.¹⁵ It acts by binding to cell membrane sterols, destroying the cell membrane and leading to cell death. It is effective against most fungi (Table 4). Amphotericin B is not absorbed by the gastrointestinal tract and must be given intravenously for systemic effect. The usual daily dose is 0.5 to 1 mg/kg; the average daily dose is 40 to 50 mg. It must be administered over a period of 4 to 6 hours. For most infections, treatment needs to be continued for at least several weeks.^17–19

TABLE 3. Systemic Antifungal Agents

TABLE 4. Susceptibility Patterns for Common Ocular Fungal Pathogens

Besides the need for intravenous administration, amphotericin B has other disadvantages (Table 5). One of the major disadvantages is its significant toxicity.¹⁷ Renal dysfunction is the most notable toxic effect and occurs in most patients if the drug is administered for a long enough time. The renal toxicity is usually reversible with cessation of the drug, but permanent renal impairment may result. Another limitation of systemically administered amphotericin B for endogenous fungal endophthalmitis is its poor intraocular penetration.^20–23 The nonfenestrated capillaries in the eye do not permit penetration of large and poorly lipid-soluble molecules such as amphotericin B. For this reason, systemic treatment alone is usually not effective for well-established endogenous fungal endophthalmitis with significant vitreous involvement. Although it is usually very effective for many types of fungal chorioretinitis and systemic fungal infections in general, these serious side effects limit the use of amphotericin B for many patients.²⁴

TABLE 5. Disadvantages of Systemic Amphotericin B

  Renal toxicity
  Poor intraocular penetration
  Intravenous administration necessary

Amphotericin B can be injected directly into the vitreous cavity (Table 6). Axelrod and coworkers²⁵ first demonstrated the effectiveness of this technique in 1973 in a rabbit model experiment. Doses of 5 to 10 μg were shown to be nontoxic to the rabbit eye.^26,27 A single amphotericin B injection of up to 20 μg was shown to be nontoxic in the monkey eye.²⁸ Liposomal amphotericin B was tolerated in doses that were at least fourfold higher than that.^27,28 When amphotericin B is injected into the vitreous, it readily reaches the choroid and retinal tissues.²⁹ The drug has a long ocular half-life in nonvitrectomized eyes.^30,31 Concentrations from 0.4 to 1 μg/ml were found in the vitreous 5 weeks after injections of 5 to 20 μg.²⁸ Lens extraction and vitrectomy considerably reduce the half-life to 1.8 days.^30,31 These half-life data are important when considering reinjection of amphotericin B. In nonvitrectomized eyes, reinjection is probably not necessary for at least a week after the initial injection; however, in eyes that have undergone prior vitrectomy, reinjection can be considered at 3 to 4 days if the initial injection fails to achieve a favorable clinical response. The safety of intravitreal amphotericin B in human eyes is well established.³² A near-normal electroretinogram was recorded 1 year after injection of 20 and 30 μg of intravitreal amphotericin B over 48 and 96 hours, respectively, in a patient with postsurgical Candida parapsilosis endophthalmitis.³³ In another case report, 11 separate intravitreal injections of 10 μg amphotericin B over 14 days resulted in a normal electroretinogram 5 months and 5 years after treatment.³⁴

TABLE 6. Intravitreal Antifungal Agents

The efficacy of intravitreal amphotericin B in treating endogenous Candida endophthalmitis has been demonstrated in multiple reports.^35–43 Favorable outcomes have been reported when used in combination with vitrectomy as well as when used as the sole treatment. Strains of C. albicans resistant to amphotericin B have been reported to cause endogenous endophthalmitis, but it is more common to find resistance in the non-albicans strains of Candida.^44–48 Fortunately, they are a much less frequent cause of endogenous fungal endophthalmitis. Pseudallescheria boydii and Aspergillus terreus are also frequently resistant to amphotericin B.

FLUCYTOSINE

Flucytosine was discovered in 1957 and first used to treat Candida in 1968.^49,50 Flucytosine has excellent gastrointestinal absorption. The recommended daily dose is 50 to 150 mg/kg in four divided doses. Peak concentrations occur 2 to 4 hours after a 2-g oral dose. A reduced dose is necessary in patients with impaired kidney function. Side effects are much less common than with amphotericin B (see Table 3).

Flucytosine has reasonably good vitreous penetration after oral administration. Vitreous flucytosine levels as high as 22.2 μg/ml have been documented in humans 18 hours after oral administration in a patient with endophthalmitis.⁵¹

A major drawback to the use of flucytosine in treating Candida infections is the high incidence of organism resistance. Resistance occurs in 7% to 47% of Candida isolates, and additional resistance develops commonly during treatment.^52,53 For this reason, flucytosine is rarely used alone to treat Candida infections. The combination of flucytosine with amphotericin B may improve its in vivo synergism against C. albicans.^47,54–56 The use of intravitreal flucytosine in clinical disease has not been reported, but a 100-μg injection has been found to be nontoxic in the rabbit eye⁵⁷ (Table 6). Flucytosine has no activity against most of the molds recovered from endogenous endophthalmitis.

MICONAZOLE

Miconazole is one of four azole drugs used as a systemic agent. It must be given intravenously because of poor gastrointestinal absorption.^58,59 The recommended daily dose for systemic fungal infection is 600 to 3600 mg in three divided doses. It has a relatively broad spectrum of activity for fungi. Much of the experience with this drug has been in treating coccidioidomycosis.^60,61 It is not an ideal drug for Candida infections because of its relatively high minimum inhibitory concentration (MIC) for some Candida species.⁶¹ It may be more effective than amphotericin B for infections due to P. boydii and some Paecilomyces species. The intravitreal penetration of systematically administered miconazole may be subtherapeutic. Because of its fairly significant list of side effects, systemic miconazole is not currently available for the treatment of fungal endophthalmitis (see Table 3).^62–66 An intravitreal (see Table 6) dose of 40 μg has been found to be nontoxic in animal studies.⁶⁶

KETOCONAZOLE

Ketoconazole was approved for systemic use in 1981.⁶⁷ It acts by inhibiting fungal cell membrane sterols.⁶⁸ Because it is well absorbed through the gastrointestinal tract, ketoconazole can be given orally. Gastrointestinal absorption may be variable, however, and depends on gastric acidity. Serum levels peak at about 3 to 6 μg/ml 2 hours after a 200-mg oral dose.⁶⁹ It is a relatively nontoxic drug (see Table 3): its major adverse effect is hepatic dysfunction, ranging from asymptomatic elevation of liver enzymes to fatal hepatic necrosis. Asymptomatic elevations in liver function studies occur in 5% to 10% of patients; serious hepatic injury occurs in about 1 in 15,000 persons treated with the drug. Because of this, it is important to monitor liver function in patients taking ketoconazole.^70–72 It is active against a variety of fungi; however, resistant strains have been reported.^73–76

Conflicting data have been reported regarding the intravitreal penetration and efficacy of orally administered ketoconazole for treating endogenous Candida endophthalmitis.^77–79 In some studies, undetectable vitreous ketoconazole levels were found in healthy rabbit eyes despite adequate serum levels.⁷⁷ The penetration appears to be better in inflamed eyes, however. A vitreous cavity ketoconazole level of 0.92 μg/ml was detected 8 hours after a 600-mg dose in a patient with postoperative Candida endophthalmitis. This eye had undergone a previous vitrectomy.⁷⁹ The safety of intravitreal ketoconazole (see Table 6) has been shown in animal studies, but its use in treating clinical infection in humans has not been reported.⁸⁰

Although when first developed ketoconazole was a significant addition to the available antifungal therapeutic agents, newer and more effective azole compounds, including fluconazole and itraconazole, have now surpassed it.

FLUCONAZOLE

Fluconazole is one of the azole group of antifungal agents.⁸¹ It is highly aqueous-soluble and has excellent absorption properties to the gastrointestinal tract.^82,83 It is the first antifungal agent that can be given both orally and intravenously.⁸¹ Its mode of action is inhibition of ergosterol found in the cell membranes of yeasts and other fungi. It is highly selective for fungal cells. Fluconazole is generally well tolerated, with a low incidence of adverse effects (see Table 3). Because of its long half-life, once-daily dosing is usually adequate. The recommended dose varies depending on the type and severity of infection and ranges from 100 to 400 mg/day. Because it is weakly protein-bound and highly water-soluble, it penetrates well into most body tissues, including the eye and cerebrospinal fluid.^78,84–86 It is excreted primarily by the kidney, and the dose must be adjusted accordingly in patients with impaired creatinine clearance.^82,83

It is active against a large variety of fungi, including most species of Candida. Candida krusei is well known to be resistant to fluconazole. Candida glabrata may develop resistance during therapy, and reports of acquired resistance to azoles by C. albicans have surfaced. This is usually seen in HIV-infected patients with oropharyngeal or esophageal candidiasis.^87,88 Most species of Aspergillus are resistant to fluconazole.

A major advantage of fluconazole in treating endogenous endophthalmitis is its excellent intravitreal penetration. Several studies have confirmed this, both in noninflamed and inflamed animal and human eyes.^78,84,85,89 Two studies looked at the efficacy of treating experimentally induced Candida endophthalmitis in rabbits.^90,91 In both studies, fluconazole was effective in preventing the establishment of ocular infection when administered shortly after inoculation of Candida, but it was not effective when administered 3 to 6 days after inoculation in one study and 7 days after inoculation in the other study. In both studies, the eyes were treated for only a relatively short period, and this may be a major factor in the lack of established efficacy in these studies.

Several clinical case reports have demonstrated the efficacy of oral fluconazole for treating endogenous Candida endophthalmitis.^92–100 These cases include eyes also treated with vitrectomy but without intravitreal amphotericin B, as well as eyes in which no vitrectomy was performed. In most patients, the dosage required to eliminate the intraocular infection was 400 mg/day. These successfully treated eyes include those with only chorioretinitis and minimal to no vitritis, as well as a few eyes with significant vitritis. Postmortem evaluation of eyes from a patient with endogenous Candida endophthalmitis treated for 2 weeks with 200 mg/day fluconazole demonstrated no evidence of organisms in the retina or choroids, but organisms were found in vitreous opacities. This case underscores the need for prolonged treatment with fluconazole when infection involves the vitreous.¹⁰⁰ Although these successfully treated patients are encouraging, there are a few reports of progressive intraocular Candida infection despite ongoing oral fluconazole therapy.^101,102

Intravitreal fluconazole (5 to 10 μg) (see Table 6) has been shown to be safe and effective for treating fungal endophthalmitis in animal and human studies.^103,104 Because of the limited clinical experience and lack of a distinct benefit over intraocular amphotericin B, it is not currently recommended.

ITRACONAZOLE

Itraconazole, like fluconazole, is in the class of triazole compounds. Unlike fluconazole, however, itraconazole is very insoluble in aqueous fluids and is high protein-bound. It does not pass into the cerebrospinal fluid and penetrates into the eye less well than fluconazole. Itraconazole has the edge over fluconazole with respect to direct antifungal activity in vitro. It is well absorbed orally, and its toxicity is relatively low and similar to that of fluconazole^105,106 (see Table 3).

Despite relatively low drug concentrations in the vitreous compared with fluconazole, it appeared to have similar efficacy in a rabbit model of Candida endophthalmitis.⁷⁸ In this model it was also similar to fluconazole in its effectiveness in preventing endophthalmitis, but it was less effective in established cases. In general, itraconazole does not appear to have any significant advantage over fluconazole in treating endogenous Candida endophthalmitis, but it is much more effective than fluconazole for Aspergillus endophthalmitis. It is also more effective than amphotericin B for treating infections caused by P. boydii.

NEWER ANTIFUNGAL THERAPIES

New commercially available antifungal agents include the lipid formulations of amphotericin B.²⁶ These include amphotericin B lipid complex, amphotericin B colloidal dispersion, and the small unilamellar vesicle formulation of amphotericin B.^2,107 Studies have demonstrated that these compounds are similar or superior to conventional amphotericin B in antifungal efficacy and are less nephrotoxic at therapeutically equivalent doses.² Data regarding their use in ocular fungal infections are not available, and the poor intraocular penetration will likely limit their potential.¹⁰⁸

Newer antifungal compounds that attack novel targets are being developed. Two agents being investigated are the third-generation broad-spectrum triazoles, voriconazole and SCH-56592. Other drugs being investigated include the echinocandins and pneumocandins. These drugs target cell wall biosynthesis by classic pathogenic fungi. In addition, several measures are being studied to augment the host response in the hopes of treating or preventing invasive fungal infections.¹⁰⁹

CHARACTERISTICS OF CANDIDA SPECIES

Candida species exists in both a yeast and hyphal phase, depending on the environment. Candida grows rapidly on most common culture media at room temperature. Creamy, white colonies begin to appear at 24 to 48 hours after inoculation. C. albicans is a normal inhabitant of the gastrointestinal tract and mucous membranes, including the mouth and vagina.² Immunosuppression, debilitation, or other predisposing factors may allow Candida organisms to become pathogenic. C. albicans is the most frequent species of Candida causing endogenous Candida endophthalmitis, but several other species of Candida have been isolated (see Table 7).

TABLE 7. Candida Species Reported to Cause Endogenous Fungal Endophthalmitis

  Candida albicans
  Candida tropicalis
  Candida parapsilosis
  Candida glabrata
  Candida guillermondi
  Candida krusei

PREDISPOSING FACTORS

The same factors that predispose a person to develop candidemia predispose to endogenous Candida endophthalmitis, because by definition this represents a blood-borne infection. In the 1980s, intravenous drug abuse was the most common predisposing factor,¹² but in the 1990s, reported cases of endogenous Candida endophthalmitis related to intravenous drug abuse declined.¹ The ocular infection usually results from a transient candidemia. Intravenous drug abusers can also develop a distinctive candidiasis syndrome that includes skin and scalp nodules, osteomyelitis, and costochondritis. A published 10-year review (1984 to 1994) of endogenous fungal endophthalmitis demonstrated that 22% of the cases (4 of 18 patients) had a history of intravenous drug abuse.^{1,4–8,110–116}

A more common predisposing factor in cases of endogenous Candida endophthalmitis is use of a long-term intravenous line.^1,117,118 In these cases, it is likely that the Candida organisms enter the blood stream directly from contaminated catheter tips. In a 10-year endogenous fungal endophthalmitis study reported by Essman and coworkers,¹ 67% of the patients has long-term intravenous line placement. Other important predisposing factors are listed in Table 8.^119–135 Persons with diabetes are also predisposed to develop systemic Candida infection, possibly because of increased glucose available for sustaining the Candida organism as well as the patient's relative immune compromise. Persons with diabetes are also predisposed to develop cutaneous ulcers that may be contaminated with Candida. Corticosteroid use may also predispose to Candida infection by increasing available glucose.¹³⁶

TABLE 8. Conditions Predisposing to Candidemia and Endogenous Candida Endophthalmitis

  Long-term intravenous line placement
  Parenteral hyperalimentation
  Prolonged antibiotic therapy
  Systemic corticosteroids
  Immunosuppressive therapy
  Abdominal surgery
  Hemodialysis
  Intravenous drug abuse
  Acquired immunodeficiency syndrome
  Malignancy
  Diabetes mellitus
  Pregnancy
  Massive trauma
  Alcoholism
  Hepatic insufficiency
  Postpartum
  Prematurity
  Genitourinary manipulation

Multiple predisposing factors are often present in patients with systemic Candida infection or endogenous Candida endophthalmitis.^137–149 In rare cases, endogenous Candida endophthalmitis has been reported in otherwise healthy persons with no predisposing factors or events.^126,150,151 The ocular infection can occur weeks or months after the predisposing factor has been eliminated, and a careful history looking for preceding risk factors should be elicited in patients suspected of having an intraocular Candida infection.^{1,135,138,152–156}

RELATION BETWEEN CANDIDEMIA AND ENDOGENOUS CANDIDA ENDOPHTHALMITIS

Several studies have evaluated the relation between candidemia, candidiasis, and ocular Candida infection (Table 9).^{137,157–165} This relation is important in determining which patients are at highest risk for the development of intraocular Candida infection and generating guidelines for screening these high-risk patients. The rate of development of intraocular Candida infection in patients with candidemia or candidiasis has been reported to range from 2.8% to 45%.^158–164 Two prospective studies using more rigid clinical criteria for ocular involvement have been reported.^158,164 The first study examined 118 patients within 72 hours of positive blood cultures for Candida. Only 11 patients (9%) had fungal chorioretinitis, and none had vitreous involvement. All patients in the study were treated with amphotericin B intravenously, and none subsequently developed vitreous involvement.¹⁶¹ In the second study, 214 eyes in 107 patients with a diagnosis of systemic fungal infection were studied. Of the patients examined, 93.4% already were receiving systemic antifungal therapy at the time of ophthalmologic consultation. Only 3 (2.8%) of the 107 patients examined had findings consistent with fungal chorioretinitis. No patient had vitreous involvement, and the ocular findings did not progress during the course of therapy.¹⁶⁴ In these two papers reported in the 1990s, the incidence of Candida endophthalmitis was markedly less than in previously published series in the 1970s and 1980s, in which the incidence of endophthalmitis in patients with candidemia was reported to be in the range of 30% to 40%.^{137,157,159,161,163} The lower incidence in recently reported studies may be related to earlier diagnosis and more aggressive initial treatment of candidemia and candidiasis by primary and intensive care physicians. Systemic antifungal drugs with better ocular penetration may also have contributed to this. Despite the lower incidence, screening ophthalmologic evaluation of hospitalized patients with documented candidemia or disseminated candidiasis is generally recommended, because early detection and treatment are important in reducing the degree of ocular damage.

A 1992 study evaluating the usefulness of screening children at risk for fungal endophthalmitis demonstrated that only patients with deep-tissue fungal infection were at significant risk for developing endogenous fungal endophthalmitis.¹⁶⁶ The authors concluded that ophthalmoscopy with pupillary dilation is necessary for patients with invasive fungal disease and may be useful for at-risk patients with superficial fungal colonization, but this type of examination is not of documented value in immunosuppressed children with negative fungal cultures.

TABLE 9. Reported Rates of Candida Intraocular Infection in Patients With Systemic Candida Infection

The relation between the presence of intraocular Candida infection and systemic Candida infection is important. This relation seems to vary depending on whether the patient with the Candida ocular infection is an inpatient or an outpatient. This relation has also been studied in autopsy series. In hospitalized patients, it appears that the presence of intraocular Candida infection often signifies diffuse systemic involvement. In one study,¹⁶⁰ 4 of 11 patients with Candida chorioretinitis died within 14 days of their ocular examination, and 2 of the 3 patients described by Scherer and Lee¹⁶⁴ died before discharge from the hospital. Previous autopsy series also indicated a very high incidence of coexistent disseminated candidiasis in patients with endogenous Candida endophthalmitis. In a study by Edwards and associates,¹⁶⁷ 77% of 39 autopsy cases of endogenous Candida endophthalmitis had evidence of candidal infection in major organs. These findings are in sharp contrast to outpatients with intraocular Candida infection. In the study by Essman and associates,¹ only 1 of the 16 patients with endogenous Candida intraocular infection had evidence of systemic infection. This patient had a nonhealing foot ulcer that grew Candida. All the patients in this study came to the outpatient eye clinic at an eye institute. Another outpatient series of patients with endogenous Candida endophthalmitis also demonstrated a low incidence of systemic Candida involvement.¹³⁸ These outpatient cases probably result from a transient candidemia with seeding to the eye. Although the immune system often can eliminate the systemic infection when the offending nidus is removed (an indwelling venous catheter), the vitreous cavity is more isolated, and Candida organisms may continue to replicate in the eye, resulting in endophthalmitis. It is therefore important to consider Candida infection in patients with visual complaints or intraocular inflammation who are not acutely ill but may have had previous systemic risk factors or been recently discharged from a hospital.

CLINICAL FINDINGS

The most common presenting symptoms (Table 10) of Candida endophthalmitis are blurred vision, pain, photophobia, and ocular redness. Patients may also complain of floaters, cobwebs, or veils across their vision. Severely ill or debilitated patients may be unaware of or unable to express visual symptoms. The two most characteristic clinical signs (Table 11) are creamy white, well-circumscribed chorioretinal lesions (Fig. 6), most common in the posterior pole, and yellow or white fluffy vitreous opacities. They may be connected by strands of inflammatory material, producing what has been called a string-of-pearls appearance (Fig. 7). These focal vitreous opacities have been shown to evolve from the chorioretinal inflammatory lesions after they have broken through into the vitreous. These vitreous opacities are composed of inflammatory cells and often contain Candida organisms. Less specific posterior findings include vitritis, vasculitis, papillitis, and retinal hemorrhages. These retinal hemorrhages sometimes surround the white chorioretinal lesions, mimicking a Roth spot.^{1,3,12,152,153,167,168}

TABLE 10. Symptoms of Endogenous Candida Endophthalmitis

  Blurred vision
  Floaters
  Pain
  Photophobia
  Ocular redness

TABLE 11. Signs of Endogenous Candida Endophthalmitis

  Anterior Segment
  Conjunction injection
  Corneal edema
  Anterior chamber cell and flare
  Hypopyon
  Fibrin
  Posterior Segment
  White chorioretinal lesions
  White fluffy vitreous opacities (“string of pearls”)
  Vitritis
  Vasculitis
  Papillitis
  Retinal hemorrhages

Anterior segment findings are relatively nonspecific and include conjunctival discharge and injection, keratic precipitates, anterior chamber cell, and flare, usually without a hypopyon. When a hypopyon is present it is usually small. Episcleritis and scleritis are uncommon. After treatment, depigmented chorioretinal scars develop in areas of previously active chorioretinitis (Fig. 8). Choroidal neovascular membranes can develop in these scars, particularly when they are in the macular area.^169,170

Late findings and complications of the infection include epiretinal membrane formation causing macular distortion as well as tractional and rhegmatogenous retinal detachment.^171–174 Cyclitic membranes can lead to hypotony and finally phthisis bulbi. The latter finding is usually seen in chronic cases where there was a delay in initiation of specific treatment. Parenteral drug abusers with Candida endophthalmitis often have a more severe inflammatory response than immunosuppressed or debilitated patients with Candida endophthalmitis. The potential reasons for this difference include a delay in presentation or diagnosis, as well as the lack of an associated immunosuppressive condition contributing to a reduced inflammatory response.

DIAGNOSIS

An important aspect in the diagnosis is maintaining a high index of suspicion for endogenous Candida ocular infection. In patients with known systemic Candida infection and ocular inflammatory findings consistent with intraocular Candida infection, a clinical diagnosis can often be made without the need for intraocular specimens. When systemic Candida infection is not clinically apparent or is undiagnosed in a patient suspected of having intraocular Candida infection, a definitive diagnosis often requires analysis of intraocular specimens (aqueous, vitreous, or both). The fresh specimens should be processed for specific stains and culture (Table 12). The presence of the characteristic mixture of yeast and mycelial phase organisms on stained smears is useful for diagnosis. Candida grows rapidly on most common culture media, but Sabouraud's agar without cyclohexamide at room temperature is recommended when Candida is clinically suspected (Fig. 9). More rapid and specific diagnostic tests are being evaluated by polymerase chain reaction and by detection of fragment length polymorphism.^12,175

TABLE 12. Laboratory Techniques for Isolation or Identification of Fungi

  Direct Detection
  Stains

  Calcofluor white stain
  Giemsa stain
  Gram stain
  Methenamine silver staining
  Potassium hydroxide
  Periodic acid-Schiff stain
  India Ink

  DNA probes
  Polymerase chain reaction
  DNA subtyping (RAPD, REA)

  Sabouraud's dextrose agar
  Blood agar
  Brain-heart infusion agar

  Brain-heart infusion agar broth/blood
  Culture media

MANAGEMENT

The management of patients with endogenous Candida endophthalmitis must be individualized and depends on the degree of ocular involvement and presence of systemic infection (Table 13). Patients without evidence of systemic Candida infection who have ocular infection localized to the choroid and retina can usually be successfully treated with oral fluconazole at a dose of 100 to 200 mg/day. Treatment usually needs to be continued for 2 months or more, depending on the clinical response. Oral therapy with fluconazole can usually be administered on an outpatient basis and is generally successful. When mild to moderate vitritis complicates the chorioretinitis, oral fluconazole treatment alone can be considered, but the success rate is not as high and frequent follow-up visits are important to detect progressive vitreous infection.

TABLE 13. Management of Endogenous Candida Endophthalmitis

  Document characteristic clinical findings.
  Make presumed diagnosis in presence of known systemic Candida infection.
  Initiate systemic workup when systemic Candida infection not already known.
  When vitreous is involved, obtain specimen for stains and culture.
  Consider newer rapid and specific diagnostic tests (polymerase chain reaction) if available.
  Consider pars plana vitrectomy and injection of intravitreal amphotericin B.

When there is a more severe vitritis manifested by vitreous infiltrates, systemic therapy with fluconazole is usually not adequate and vitrectomy combined with intravitreal amphotericin B (5 to 10 μg) is often recommended. Oral fluconazole can be used to supplement the local ocular treatment. One series reported that early vitrectomy might be superior to a delay in these more severely involved eyes.¹

The use of intraocular corticosteroids (dexamethasone 400 μg) can be considered as an adjunctive treatment at the time of vitrectomy and intravitreal amphotericin B. This has been shown to reduce more rapidly the intraocular inflammatory response without promoting fungal replication.^176,177 It is important to use steroids only when specific antifungal therapy has been administered.

Every patient suspected of having endogenous Candida endophthalmitis should have a thorough workup for evidence of systemic infection. The presence of active systemic Candida infection can sometimes be treated with oral or intravenous fluconazole; however, amphotericin B may be recommended in more severe cases and in immunosuppressed patients. Specific recommendations are usually made in conjunction with an internist or infectious disease specialist.

TABLE 14. Aspergillus Species Reported to Cause Endogenous Aspergillus Endophthalmitis

  Aspergillus fumigatus
  Aspergillus flavus
  Aspergillus niger
  Aspergillus terreus
  Aspergillus candidus

Aspergillus species are ubiquitous in nature and occur worldwide. Aspergillus conidia are frequently airborne both indoors and outdoors; thus, inhalation is a common route of contamination and infection. The organism is also found in soil, water, plants, and dust and is particularly common in agricultural environments.¹⁸⁰

PREDISPOSING CONDITIONS

In a 1998 summary of 10 patients (12 eyes) with culture-proven endogenous Aspergillus endophthalmitis, the most common predisposing factors (Table 15) were chronic obstructive pulmonary disease and intravenous drug abuse.¹⁷⁹ The ocular infection can be associated with disseminated aspergillosis, but it is also seen in patients without definitive clinical or laboratory evidence of systemic infection. Most patients are immunocompromised either by their underlying disease or iatrogenically. Endogenous Aspergillus endophthalmitis has been reported in association with cardiac transplantation, endocarditis, lung, liver, and kidney transplants, leukemia, and periodontitis.^181–202 Patients with no apparent predisposing conditions may also develop aspergillosis and endogenous Aspergillus endophthalmitis. In 15% to 20% of patients with invasive pulmonary aspergillosis, the chest radiographs are normal. Drug abuse appears to be a more common risk factor than recognized in the earlier literature. Another more recently recognized high-risk group are patients undergoing orthotopic liver transplants.^203,204

TABLE 15. Predisposing Conditions for Endogenous Aspergillus Endophthalmitis

  Chronic obstructive pulmonary disease
  Intravenous drug abuse
  Organ transplantation
  Endocarditis
  Leukemia
  Periodontitis

OCULAR MANIFESTATIONS

Most patients with endogenous Aspergillus endophthalmitis have acute or subacute ocular symptoms.¹⁷⁹ The most common presenting symptom is blurred vision, sometimes associated with ocular pain, redness, and lid swelling. Most patients have anterior segment inflammatory signs, including anterior chamber cells and keratic precipitates. A hypopyon may be present. In most cases the organism initially affects the posterior segment, forming a yellowish macular infiltrate (Fig. 10). This begins in the choroid and progresses through the subretinal space into the retina. It frequently involves the macula, and this probably accounts for the rapid onset of visual loss in many cases. A frequent clinical feature is the gravitational layering of inflammatory exudates (pseudohypopyon) in either the preretinal (subhyaloid) or subretinal space (Fig. 11). Although this finding is not pathognomonic of Aspergillus infection, when seen it should prompt a high suspicion for Aspergillus. This is usually associated with a vitritis. Other features include occlusive vasculitis and retinal hemorrhages. Orbital involvement can also occur, but this usually results from contiguous spread from an adjacent sinus infected with Aspergillus. After treatment the area of chorioretinitis progresses to formation of a subretinal scar. Because of the predilection for macular involvement, the visual outcome is generally poor.

TREATMENT

Visual outcomes after treatment for endogenous Aspergillus endophthalmitis are generally worse than Candida cases but have improved in recent years. This is most likely due to earlier detection of the infection, leading to more rapid initiation of specific treatment. Previously reported cases were often diagnosed at the time of enucleation or after death.

Although there are significant phenotypic differences in susceptibility between different Aspergillus isolates, the antifungal agent of choice for Aspergillus infection is usually amphotericin B. In vitro sensitivities to amphotericin B are not always reliable and do not necessarily correspond to in vivo response to treatment. To help reduce the toxicity and enhance the effectiveness of intravenous amphotericin B, combinations with 5-fluorouracil and azole compounds have been used. Ketoconazole, clotrimazole, and miconazole have inconsistent efficacy for Aspergillus and are not recommended. Despite fluconazole's excellent vitreous penetration, it shows a relatively high MIC against Aspergillus and is not usually recommended. In one study using in vitro testing, fluconazole did not inhibit any of 45 pathogenic strains of A. fumigatus.²⁰⁵

Itraconazole exhibits a favorably low MIC for many species of Aspergillus, and in selected reports it has shown a favorable response for the treatment of invasive aspergillosis. The vitreous penetration of itraconazole is better than amphotericin but remains only a fraction of the serum level.^144,206

Most patients with endogenous Aspergillus endophthalmitis have significant vitreous involvement at the time of diagnosis. For this reason, vitrectomy is recommended in most cases. This is combined with intravitreal injection of amphotericin B, 5 to 10 μg. The goal should be to perform a fairly complete vitrectomy in the hopes of removing as many organisms as possible. The use of intravitreal corticosteroids can be considered to reduce the potentially destructive associated inflammatory response associated with endogenous Aspergillus endophthalmitis. Its role is still unproven, but successfully treated cases using a combination of vitrectomy, amphotericin B, and intravitreal dexamethasone have been reported.¹⁷⁹ Intravenous amphotericin B may be used to supplement local ocular treatment, although the poor intraocular penetration may not warrant the potential systemic toxicity of amphotericin B in cases where there is no evidence of disseminated or invasive aspergillosis, such as in intravenous drug abusers. A better choice to supplement the local ocular treatment is itraconazole. At least two reports of successfully treated endogenous Aspergillus endophthalmitis without the use of systemic antifungal therapy have been reported.^183,207

When there is evidence of active systemic Aspergillus infection, intravenous amphotericin B is usually indicated, either alone or in combination with other antifungal agents.^205,208 The role of itraconazole in this situation is controversial. The presence of a localized Aspergillus chorioretinitis without significant vitreous involvement is rare, and one can only speculate on the optimal treatment in this situation. Systemic treatment with amphotericin B or itraconazole may be effective in these relatively rare cases. There are previously reported cases in which one eye had significant vitreous involvement and was treated with vitrectomy and intravitreal amphotericin B, and the fellow eye had only a chorioretinitis and responded to systemic amphotericin B alone.¹⁷⁹ All patients suspected of having endogenous Aspergillus endophthalmitis should be thoroughly evaluated for evidence of systemic aspergillosis in cooperation with an internist or infectious disease subspecialist.

C. neoformans can be identified by direct examination using a wet-mount preparation mixed with a drop of India ink. This technique clearly outlines the characteristic mucoid capsule surrounding the organism. The organism can also be identified in stained histopathologic specimens. The most reliable test for identifying the organism is culture. The organism grows well on Sabouraud's glucose agar within 24 to 48 hours of inoculation.^209,210 Rapid tests for detection from sterile fluid include latex agglutination and various serologic tests.

C. neoformans has been isolated from milk, fruit, and the atmosphere. The primary mode of human infection is through the respiratory tract. This can result in an asymptomatic pneumonitis or can lead to a severe disseminated infection involving any part of the body, with a predilection for the brain and meninges. Intraocular infection may occur by direct extension from the central nervous system (CNS) along the meningeal sheath of the optic nerve or by hematogenous spread from either a localized or disseminated cryptococcal infection.

Associated systemic conditions include lymphoma, systemic lupus erythematosus in addition to other collagen vascular diseases, sarcoidosis, tuberculosis, diabetes mellitus, drug abuse, Cushing syndrome, and pregnancy. Organ transplant recipients have a 2% to 3% infection rate, and approximately 10% of patients with AIDS are reported to have some form of cryptococcal infection.^211–216 Many patients with ocular cryptococcal infection have evidence of cryptococcal infection elsewhere in the body, although cases without extraocular involvement have been reported.^217,218 In many patients, no known predisposing systemic risk factors can be identified.^219–225

OCULAR MANIFESTATIONS

Up to 40% of patients with CNS involvement have ophthalmic complications, including papilledema, optic atrophy, extraocular muscle paresis, chorioretinitis and endophthalmitis.

The symptoms of intraocular cryptococcal infection are nonspecific and most commonly include blurred vision, pain, photophobia, floaters, and redness. The ocular findings may also be nonspecific and vary with the severity and location of the intraocular infection. They are frequently confined to the fundus. There may be a mild anterior segment inflammatory reaction, including conjunctival and episcleral injection and anterior chamber cells with large “mutton fat” keratic precipitates. A patient who had an isolated iris mass has been reported.²²⁶ There is often a vitritis that may range from a few cells to marked inflammation sufficient to obscure fundus detail. Fundus findings include intraretinal hemorrhage, vascular sheathing, nerve fiber layer infarcts, optic nerve edema, optic atrophy, glistening retinal and preretinal lesions, and a yellow-white chorioretinal mass or scarlike lesion. Retinal detachment may complicate the infection. The symptoms and signs may be present for only a few weeks or for several years. The infection has been misdiagnosed as sterile uveitis.²¹⁶

DIAGNOSIS

In addition to observing the organism directly on stained smears and culturing it, various serologic tests, including complement fixation, tube agglutination, immunodiffusion, and an indirect immunofluorescent test, can be used. The most commonly used test for detecting the disease in body fluids is the latex agglutination for antigen detection of polysaccharides on cryptococcal capsules. A titer of greater than 1:8 is significant.²²⁷

The diagnosis of endogenous cryptococcal endophthalmitis can be difficult to make in the presence of nonspecific ocular inflammatory signs. Any patient with known predisposing conditions with ocular inflammatory disease of unknown etiology not responding to local anti-inflammatory therapy should be considered suspect for cryptococcal infection. Suspicion of infection should be greater in the presence of a yellow or white chorioretinal abscess. When cryptococcal infection is known to be present elsewhere in the body, a presumptive diagnosis of ocular involvement may cautiously be made. In the absence of known systemic infection or if the ocular infection does not respond to ongoing therapy for systemic cryptococcal infection, more specific ocular diagnostic techniques should be considered, including diagnostic vitrectomy and in some cases biopsy of the chorioretinal abscess using needle-aspiration techniques previously described.²²⁸

TREATMENT

Because of the relative rarity of ocular cryptococcal infection, there are no well-established guidelines for treatment. The treatment of systemic infection has evolved during the past several years with the addition of new antifungal agents. A previously described treatment for systemic cryptococcal infection includes amphotericin B with or without flucytosine.^229–232 Results from clinical trials indicate that both fluconazole and itraconazole may be as effective as amphotericin B.^217,233 They both have the advantage of reduced systemic toxicity and better intraocular penetration. Fluconazole has the overall best intraocular penetration and for this reason may be the ideal systemic drug when there is intraocular infection. The cure rate for cryptococcal meningitis using itraconazole is 65%. There is a 25% partial cure rate (persistent positive cultures but symptoms improve) and a 10% failure rate. The systemic treatment is required for several months. The median time required for cerebrospinal fluid cultures to become negative in cryptococcal meningitis in AIDS patients was 42 days for patients treated with amphotericin B and 64 days for patients treated with fluconazole.²³³

There is limited experience using intravitreal amphotericin for the treatment of endogenous cryptococcal endophthalmitis.^{222–224,228,229} In one well-documented case, a 5-μg intravitreal amphotericin B injection resulted in clearing of the vitreous. The patient developed an epiretinal membrane and cataract. Persistent organisms were identified in the epiretinal membrane at the time of removal of the membrane. A second intravitreal amphotericin B injection was administered, and 4 months later the eye was free of inflammation and intraocular cultures were negative.²²⁹

The saprophytic mold fungus grows well on most routine culture media at room temperature. Definitive identification requires documenting the production of spherules at 40°C in liquid culture or in experimentally infected animals.²³⁴

The infection results from inhalation of arthroconidia. The arthroconidia are easily detached from the hyphae and released into the atmosphere. The organism is commonly found in dust. For this reason, agricultural and construction workers are particularly prone to infection. C. immitis is one of the most virulent of all fungi, and inhalation of only a few conidia in an immunocompetent host will produce infection. After exposure of the organism to the respiratory tract, the infection may result in a subclinical pneumonitis or mild to severe respiratory disease. In the immunocompetent person, it is usually self-limited and resolves in 2 to 3 weeks without significant sequelae. In unusual cases it can lead to chronic pulmonary disease and pulmonary scarring. Disseminated infection may occur in immunosuppressed patients, including AIDS patients and patients receiving steroids. The disseminated infection may result in a chronic cutaneous disease, a widespread lymphatic disease, bone involvement, visceral organ involvement, or meningitis.^235–237

Coccidioidomycosis is highly endemic in the southwestern United States, northern Mexico, Central America, and several South American countries. The San Joaquin Valley is the most endemic area in the world. Since 1990, there has been a dramatic increase in cases of coccidioidomycosis documented in California. This recent increase in reported cases was related to cycles of severe aridity followed by intense rainfall. In addition, increases in construction with associated soil turnover in the area may have played a factor.^238,239

DIAGNOSIS

Culture of the organism from body tissues or direct identification histopathologically is the only way to make a definitive diagnosis. In addition, a skin test using extract from the saprophytic phase of the fungus may be helpful. Serologic tests, including the tube precipitin test, latex agglutination test, immunodiffusion test, and complement fixation test, may be used.^{234,237,240–242}

OCULAR MANIFESTATIONS

The first histologically proven case of endophthalmitis secondary to C. immitis was reported in 1948.²⁴³ Since then, several culture-positive and histopathologically proven cases have been reported.^244–260 A prospective study found that 50% of patients with chronic pulmonary or disseminated coccidioidomycosis had ocular involvement.²⁵⁴ Because of this high incidence of ocular involvement, any patient with chronic pulmonary or systemic coccidioidomycosis should have a screening ocular examination.

The ocular involvement can range from lid lesions to panophthalmitis. The anterior segment involvement may be extraocular and include conjunctivitis, episcleritis, scleritis, or keratoconjunctivitis. Intraocular involvement may range from a chronic granulomatous iridocyclitis to a fulminant acute anterior segment inflammatory response. Posterior segment involvement includes vitritis, choroiditis, and retinitis. There is a predilection for the peripapillary choroid to be involved, and patients may have peripheral punched-out scars similar to those seen in ocular histoplasmosis. Active choroidal lesions are often white and elevated and may involve the overlying retina. Subretinal fluid and exudate may be present. Scars may be seen in asymptomatic patients with a prior history of systemic coccidioidomycosis. In one study, 5 of 54 patients with documented systemic coccidioidomycosis had inactive peripheral chorioretinal scars.²⁵⁷

TREATMENT

There is limited information regarding the treatment of ocular C. immitis infection.^258–260 The organism usually responds to amphotericin B, although failures have occurred, both in the treatment of systemic infection and ocular infection.^{234,237,258–260} Intravenous miconazole has been used in cases of systemic coccidioidomycosis with ocular involvement, but the recurrence rate is high, and in one case the chorioretinitis developed while the patient was receiving the drug; in this case the infection subsequently responded to intravenous amphotericin B.²⁵⁵ Ketoconazole has been used in the treatment of systemic infection, but recurrence rates as high as 25% have been reported.^261,262 In one study of 112 patients with nonmeningeal coccidioidomycosis, a success rate of 23% was obtained using 400 mg ketoconazole daily and 32% using 800 mg daily.²⁶² Fluconazole and itraconazole appear to be effective for systemic coccidioidomycosis; however, their efficacy for ocular involvement is unproven.^263,264

It is important to maintain a high index of suspicion for C. immitis infection in any patient with ocular inflammation of unknown etiology living in or traveling to an endemic area. This is particularly true for patients who have previous exposure to the organism. Ocular involvement has been reported as late as 22 years after primary systemic infection.²⁵⁸

Demonstration of S. schenckii is necessary for definitive diagnosis of this infection. Culture recovery is the best way of identifying the organism, but it can also be found using periodic acid-Schiff and Gomori stains of biopsy tissue. Immunochemical staining of biopsy specimens may be useful when other stains and cultures are negative and a definitive diagnosis is necessary for treatment. Identification of the antibodies to the organism is helpful when there is systemic involvement.²⁶⁵

Sporotrichosis can be either a subacute or chronic fungal disease. It occurs in four major forms: cutaneous or lymphocutaneous (most common), pulmonary disease, osteoarticular disease, and disseminated infection. Disseminated infection usually occurs in immunocompromised persons, including AIDS patients. Infection usually results from a skin puncture by material containing the organism. The organism is most commonly found in soil and decaying vegetation introduced into the body by pricks of thorns or barbs and can be initially manifested as a skin nodule. A less common means of acquiring the organism is by inhalation.^266–273 It is an occupational hazard for farmers, gardeners, and horticulturists.

OCULAR MANIFESTATIONS

The first case of intraocular S. schenckii was reported in 1909.²⁷⁴ There are fewer than 20 reported cases of endogenous S. schenckii endophthalmitis in the literature.^274–280 The ocular infection has been reported in immunocompromised patients with disseminated sporotrichosis as well as in otherwise healthy persons with no evidence of extraocular involvement. Any patient with known extraocular S. schenckii infection and ocular inflammatory disease should be suspected of having endogenous S. schenckii infection. Ocular involvement in sporotrichosis includes orbital, eyelid or lacrimal apparatus lesions, keratitis, scleritis, and endophthalmitis. The ocular findings vary depending on whether the anterior segment or posterior segment is primarily involved. Most of the reported patients had primarily anterior segment inflammation initially, which often progressed to endophthalmitis or panophthalmitis. The presenting ocular symptoms are nonspecific and include decreased vision, redness, and pain. The anterior segment inflammation may vary in severity and occasionally is present as a hypopyon. The uveitis may appear granulomatous or nongranulomatous. White iris nodules have been observed clinically. Posterior synechiae, glaucoma, and cataracts may develop as a result of chronic uveitis. Posterior segment involvement includes vitritis as well as chorioretinitis. The posterior segment lesion has been reported to be a fluffy white necrotic retinal lesion with overlying vitreous haze. This lesion can rapidly progress to panophthalmitis. It is important to recognize the ocular inflammatory disease as a potential infectious process and not treat solely with corticosteroid therapy, because this can cause a rapid exacerbation.

TREATMENT

In previously reported cases of endogenous S. schenckii endophthalmitis, treatment results have been disappointing and salvage of useful vision has not been reported. An AIDS patient with disseminated S. schenckii infection developed a rapidly progressive endophthalmitis. This progressed despite intravenous amphotericin B therapy, and the patient was subsequently treated with intravitreal amphotericin B injections (total of 25 μg). Despite treatment, the ocular inflammatory response persisted and the eye was enucleated. The vitreous culture obtained before enucleation was negative, and electron microscope examination of the anterior chamber demonstrated disorganization of the organisms, suggesting the treatment was effective in killing the organism.²⁷⁹

Antifungal agents used to treat sporotrichosis include saturated solution of potassium iodide (SSKI), 5-fluorocytosine, amphotericin B, ketoconazole, fluconazole, and itraconazole. There are no comparative studies of treatment with various agents available to determine the antifungal agent of choice. SSKI is effective, but unfortunately it is poorly accepted by most patients because of side effects, including increased lacrimation, increased salivation, salivary gland swelling, gastrointestinal upset, and rash. Ketoconazole (200 to 800 mg/day) has been used for lymphocutaneous and systemic sporotrichosis but has largely been replaced by itraconazole. This remains the drug of choice at a recommended dose of 200 mg orally twice a day. In patients whose disease is unresponsive to itraconazole, or in the presence of meningitis, amphotericin B is recommended at a total dose of 2 g. There is no reported clinical experience using itraconazole for intraocular sporothrix infection. After systemic administration, itraconazole has an advantage over amphotericin B of better intraocular penetration.^281–284

The treatment of choice for endogenous S. schenckii endophthalmitis, particularly when there is significant vitreous involvement, is a combination of vitrectomy and intravitreal amphotericin B injection.

The organism is endemic to parts of the midwestern and south-central United States and Canada, but blastomycosis has been reported worldwide. In the United States the disease is concentrated in an area along the Mississippi and Ohio River basins and around the Great Lakes.^2,286

Because the organism usually obtains access to the body through inhalation, the most common form of clinical infection is pulmonary. This can range from an asymptomatic or self-limited flulike illness to a chronic pneumonia characterized by cough, chest pain, hemoptysis, weight loss, and low-grade fever. Hematogenous dissemination from the lung can occur, resulting in extrapulmonary infection, including skin infection in 40% to 80% of cases and multiple organ involvement, including the eye in approximately 50% to 60% of cases. After the lung and skin, other sites of involvement include bones and joints as well as the male genitourinary system. CNS involvement is uncommon. It is an uncommon opportunistic pathogen but may cause severe disseminated infection in the immunocompromised host.^286–289

OCULAR MANIFESTATIONS

The spectrum of ocular disease includes eyelid lesions, keratitis, choroiditis, endophthalmitis, and panophthalmitis.^290–299 Orbital blastomycoses has also been reported.^299,300 In most cases, the ocular involvement is associated with obvious systemic disease, but cases of ocular involvement with no evidence of systemic disease have been reported.

There are at least 11 reported cases of intraocular blastomycosis in the literature.^290–300 Six of these cases were verified by histologic examination of the enucleated globe and three were presumed diagnoses based on the presence of systemic blastomycosis.

Ocular symptoms are nonspecific and depend on the site of ocular involvement. They include pain, redness, photophobia, and blurred vision. The onset may be subacute or acute. A pale-yellow elevated choroidal lesion appears to be characteristic of B. dermatitidis choroiditis. The choroidal lesions may be multiple or solitary and associated with hemorrhage and periphlebitis. Lesions can be unilateral or bilateral.

TREATMENT

The three drugs approved for the treatment of blastomycoses are amphotericin B, itraconazole, and ketoconazole.^{288,289,301,302} Previously reported treatment for systemic disease has been amphotericin B, and this continues to be the preferred treatment when there is CNS involvement. Itraconazole has been gaining increased acceptance for non-CNS disease.³⁰² Its efficacy approximates that of amphotericin B. Ketoconazole is less efficacious but was shown to be effective in approximately 80% of cases in one series.³⁰¹ Ketoconazole has the advantage of being less expensive, and because treatment needs to be continued with either oral agent for at least 6 months, this may be an important consideration in infections that are responsive to ketoconazole. Amphotericin B is generally reserved for patients with disseminated life-threatening disease, particularly in immunocompromised patients, patients with CNS disease, or patients in whom oral therapy has failed. The total recommended dose of amphotericin B is 1.5 to 2.5 g. Itraconazole can be started at 200 mg/day and advanced by 100-mg increments at monthly intervals to a maximum of 400 mg/day. Ketoconazole can be initiated at 400 mg/day and advanced by 200-mg increments monthly to 800 mg/day as needed.

Patients with systemic disease associated with an isolated choroiditis can probably be successfully treated with an oral agent, preferably itraconazole. When there is significant vitreous involvement, pars plana vitrectomy combined with intravitreal amphotericin B should be considered. This should be supplemented with oral itraconazole for either documented or presumed systemic infection.

When the spores are disturbed, they become airborne. Human infection results from inhalation of these infectious particles. When they reach the alveoli, they convert to small yeast, which represents the tissue-invasive form. Once the organism gains access to the pulmonary alveoli, it travels to organs rich in cells of the reticuloendothelial system before immunity to the organism develops. After development of adequate cell-mediated immunity, macrophages kill the fungi in most immunocompetent persons. Greater than 90% of infected persons are asymptomatic, and the only evidence of previous infection is conversion of the histoplasmin skin test to positive. A few patients who inhale the infecting particles become acutely ill. In immunocompetent persons, this is usually an influenza-like illness with fever, chills, and nonproductive cough. It may be associated with erythema multiforme or erythema nodosum. If the infective dose is extremely high, patients may experience a fulminant pneumonitis with secondary respiratory compromise. Most immunocompetent patients with pulmonary histoplasmosis recover completely, but they are often left with pulmonary scars. The characteristic scar is a round fibrotic lesion with associated calcification (coin lesions). These pulmonary scars can often be found in patients living in areas endemic for histoplasmosis.³⁰³

A progressive, disseminated form of histoplasmosis can develop in patients with deficient cell-mediated immunity. This usually leads to a rapidly progressive wasting systemic illness. HIV-infected persons living in endemic areas are at greatest risk for this form of histoplasmosis.^{2,234,304,305}

OCULAR MANIFESTATIONS

Three main forms of ocular involvement by H. capsulatum have been identified in humans^306–315: disseminated histoplasmosis with uveal, retinal, or optic nerve involvement; solitary histoplasmic chorioretinal granuloma; and the presumed ocular histoplasmosis syndrome. The latter syndrome is presumably due to histoplasmosis, although no organisms have been convincingly identified in the eye in most of these patients.³¹⁴ The classic features of the presumed ocular histoplasmosis syndrome include peripapillary scars in combination with macular and peripheral pigmented or atrophic punctate scars. The major significance of these lesions is the later development of choroidal neovascularization resulting from macular scars. The findings are often picked up on routine fundus examination, and these patients are usually asymptomatic until they develop choroidal neovascularization.³¹⁴ Occasionally these patients also develop what appears to be an active focal choroiditis that in some cases can be difficult to distinguish from a choroidal neovascular membrane clinically or on fluorescein angiography. The histoplasmin skin test is often positive in these patients. The scars in these patients are presumed to be due to an acute choroidal infection with the organism, but this is rarely identified.^314,315 One report of an acute histoplasmosis choroiditis in two immunocompetent brothers enabled a rare opportunity to observe the acute form of what is believed to result in the typical presumed ocular histoplasmosis syndrome lesions.³¹⁵

Endogenous histoplasmic endophthalmitis has been reported in several patients with disseminated systemic histoplasmosis.^306–309 Most of the previously reported cases were in patients with AIDS.^306,307 The ocular infection may result in a granulomatous anterior uveitis. Vitritis may be mild to severe. The classic fundus lesion is a cream-colored or gray-white chorioretinal infiltrate, often surrounded by hemorrhage. There may be associated retinal pigment epithelial alteration, indicating partial spontaneous healing. The lesions may be solitary or multiple and can range from less than a disc diameter to several disc diameters. Histoplasmic optic neuritis has also been reported in association with the chorioretinitis. The ocular findings are not specific for histoplasmic endophthalmitis, and the diagnosis should be suspected in any immunosuppressed patient living in an area endemic for histoplasmosis. Most patients have clinical and laboratory evidence of disseminated infection, in which case the ocular infection can be presumed to be due to histoplasmosis based on the known systemic infection. When the ocular infection is uncertain and there is significant vitreous involvement, a diagnostic vitrectomy should be considered. When there is no significant vitritis in a patient with choroidal infiltrates of unknown cause, chorioretinal biopsy can be considered, although this can be associated with significant risk. This is probably not indicated when the diagnosis is suspected based on known systemic histoplasmosis.

Because culturing the organism can be difficult, the diagnosis of histoplasmosis is often made by pseudodiagnosis. A complement fixation test becomes positive 3 weeks after the onset of infection, and by 6 weeks a diagnostic titer may be obtained in up to 75% of patients. A Histoplasma polysaccharide antigen test is useful in the diagnosis of histoplasmosis in HIV-infected patients where the complement of organisms is high. The test is not sensitive for patients with low organism counts. The histoplasmin skin test is useful for determining whether immunocompetent patients have been exposed to the organism.³¹⁶

TREATMENT

As with other intraocular fungal infections, the systemic antifungal therapy is determined by the presence and extent of systemic involvement. Most acutely infected immunocompetent patients with histoplasmosis require no treatment. In the unusual situation where there is severe pulmonary infection, intravenous amphotericin B is initiated at a dose of 500 mg in 50-mg daily doses. Once the patient is stable, this can be switched to itraconazole 200 mg twice daily.³¹⁷ Chronic pulmonary histoplasmosis in immunocompetent patients can be treated with either ketoconazole 400 to 800 mg/day³¹⁸ or itraconazole 200 to 400 mg twice daily. In the case of failure to respond to this oral therapy, intravenous amphotericin B can be considered. For progressive disseminated infection, amphotericin B is the initial treatment of choice.³¹⁹ Once stable, the patient can be switched to itraconazole 200 to 400 mg twice daily.

There is limited clinical experience in the treatment of endogenous ocular histoplasmic infection. When the infection is limited to the choroid or retina, systemic therapy alone with amphotericin B, ketoconazole, or itraconazole may be curative. If there is significant vitreous involvement, local ocular therapy, including vitrectomy and intravitreal amphotericin B, can be considered. This local ocular therapy should probably be combined with systemic antifungal therapy, depending on the presence and extent of systemic infection.

Because Nocardia asteroides can clinically and histopathologically resemble endogenous fungal eye infection, it should be considered in the differential diagnosis of endogenous fungal endophthalmitis.^336–340 The organisms resemble fungi microscopically and appear as delicate intertwining, branched hyphae. Nocardia are slow-growing soil-borne filamentous bacteria. They usually enter the human body through the respiratory tract. Clinical infection is usually seen in immunosuppressed patients, particularly when cell-mediated immunity is impaired. Hematogenous dissemination occurs after the initial pneumonitis in about half of patients. The infection can spread to virtually every organ in the body, but the CNS is the most common site. Ocular infection is uncommon, but at least 14 cases have been reported.^336–341 The characteristic fundus lesion is a discrete white subretinal mass with overlying subretinal fluid and hemorrhage. A subretinal pseudohypopyon similar to that seen in patients with Aspergillus endophthalmitis has been reported.³³⁶

Nocardia responds well to sulfonamides, and sulfadiazine 6 to 8 g/day is typically used in adults. Trimethoprim-sulfamethoxazole may be substituted as an alternative first-line agent. Minocycline, amikacin, and ampicillin have also been successful in treating patients without brain abscess or patients who fail to respond to the sulfonamides. Treatment usually needs to be continued for several months.³⁴⁰

In some cases of endogenous fungal endophthalmitis, the diagnosis is made based on the presence of known systemic infection; in other cases, the diagnosis can be determined only by evaluating intraocular fluids. The eye may be the organ most accessible to obtaining infected material, which may be useful in determining the cause of an unknown systemic infection.

In many cases, the treatment of endogenous fungal endophthalmitis depends on the extent of ocular involvement. When the infection is isolated to the choroid and retina, systemic treatment alone may be curative. When there is vitreous involvement, a vitrectomy and injection of amphotericin B can be considered. In these cases, the systemic treatment is guided by the extent of systemic disease, and treatment should be initiated in conjunction with an infectious disease specialist. Newer, less toxic antifungal medications may improve the outcomes of treatment and reduce potential treatment complications.

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