PSEUDALLESCHERIA ENDOPHTHALMITIS: FOUR CASES OVER 15 YEARS IN QUEENSLAND, AUSTRALIA, AND A REVIEW OF THE LITERATURE THOMAS P. MOLONEY, MBBS, JOSEPH PARK, FRANZCO Purpose: To describe the clinical features and outcomes of patients with culture-proven Pseudallescheria endophthalmitis in the context of previously published cases. Methods: A multicenter, retrospective, consecutive case series was undertaken. Pathology records were reviewed for all patients with Pseudallescheria endophthalmitis on vitreous/aqueous cultures from June 1998 to June 2013 throughout Queensland, Australia. Results: Three females and 1 male aged 60 to 78 years were identified. All patients had endogenous endophthalmitis, had an underlying malignancy, and were from South East Queensland. Vitreous cultures identified Scedosporium auranticum in two cases and Scedosporium prolificans and Scedosporium apiospermum in one case each. All isolates were sensitive to voriconazole. Enucleation was required in two patients. Two patients had final best-corrected visual acuities of perception of light and no perception of light, respectively. Conclusion: Endophthalmitis caused by species of the P. boydii complex is a devastating condition with poor visual outcomes. It is a condition that is difficult to treat because of its variable antifungal agent resistance. RETINA 34:1683–1701, 2014

P

cases of endogenous Scedosporium auranticum endophthalmitis and the eighth reported case of endogenous Scedosporium prolificans endophthalmitis. We also review the clinical features of previously reported cases of both exogenous and endogenous Pseudallescheria endophthalmitis, the treatment instituted, and the overall outcomes.

seudallescheria fungal infections are caused by species of the Pseudallescheria boydii complex. These infections are difficult to treat because of its resistance to conventional antifungal agents, like amphotericin B, and are associated with a high mortality rate in immunocompromised patients.1 Pseudallescheria species are known causes of ophthalmic infections and are rare causes of both exogenous and endogenous fungal endophthalmitis.1 Recent morphologic and molecular studies have described several new strains of the Pseudallescheria species with potentially differing degrees of human virulence and antifungal agent resistance.2 Scedosporium is the asexual form of the species and usually causes disease in humans. We report 4 cases of Pseudallescheria endophthalmitis over 15 years in public hospitals across Queensland, Australia. Our cases include the first two reported

Methods Queensland public hospital pathology records were reviewed for all patients with endophthalmitis and vitreous/aqueous samples that cultured Pseudallescheria species over a 15-year period from June 1998 to June 2013. Four patients were identified over this period. The medical records of these patients were then retrospectively reviewed for demographic data, background medical history, presenting signs and symptoms, diagnostic testing, results from microbiologic assessment, treatment received, visual outcome, and mortality. This review was conducted in accordance with guidelines set forth by the Declaration of Helsinki and was exempt from institutional review board approval.

From the Department of Ophthalmology, Royal Brisbane and Women’s Hospital, Herston, Brisbane, Queensland, Australia. None of the authors have any financial/conflicting interests to disclose. Reprint requests: Thomas P. Moloney, MBBS, Department of Ophthalmology, Royal Brisbane and Women’s Hospital, Herston, Queensland, Australia 4006; e-mail: [email protected]. gov.au

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1684 RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES

A systematic literature review was undertaken to identify all previously reported cases of endophthalmitis caused by fungal species of the P. boydii complex. Databases searched were MEDLINE/PubMed (National Library of Medicine, Bethesda, MD), Embase, Ovid, Scopus, and Google Scholar. The search was undertaken in August 2013 and used combinations of the following search terms: Pseudallescheria, Pseudallescheria boydii, Scedosporium, Scedosporium apiospermum, Scedosporium prolificans, Scedosporium inflatum, Monosporium, Petriellidium, Allescheria, endophthalmitis, panophthalmitis. Reference sections of the articles obtained from the initial search were reviewed and further articles identified. Non-English-language references were translated professionally. All references identified were then reviewed for demographic data, background medical history, presenting signs and symptoms, diagnostic testing, results from microbiologic assessment, treatment received, visual outcome, and mortality. Results Age, Sex, and Predisposing Factors Three females and 1 male aged 60 to 78 years (mean, 68 years) were identified for our series (Table 1). All patients had endogenous endophthalmitis, had an underlying malignancy, and were from the South East Queensland. One patient had refractory acute myeloid leukemia, one had pancreatic cancer, one had metastatic non–small cell lung cancer, and one patient was currently being investigated for a lung lesion that ultimately proved to be metastatic melanoma. Of the four patients, 3 were immunocompromised and 1 was immunosuppressed from recent systemic corticosteroids. Two patients had an acute pulmonary condition, and two patients had long indwelling lines in situ at the time of diagnosis of endophthalmitis. All four patients had no ophthalmic history, and all had best-corrected visual acuities of better than 20/32 in both eyes before presentation. Presentation and Diagnosis One patient had seen an ophthalmologist before presentation at a hospital ophthalmology department, and one patient was a current inpatient. Three of the four patients had been initially diagnosed with anterior uveitis and treated with topical corticosteroids. The right eye was affected in two cases and the left eye in two cases; no patient had evidence of bilateral disease. Visual acuity was hand movements or worse in the affected eye in three of the four patients. The remaining patient had



2014  VOLUME 34  NUMBER 8

a vision of 20/125 in the affected eye. The major presenting symptom in all cases was decreased visual acuity. One patient reported eye pain, and one patient reported floaters. Two patients had hypopyon, ranging from 0.2 mm to 0.5 mm in height. The two other patients only had mild anterior chamber reaction. All four patients had a degree of vitritis that impaired the view of the fundus. One patient had evidence of retinal exudates. Diagnostic Testing and Microbiology Between the 4 cases, 8 vitreous taps were performed with 4 samples producing positive Pseudallescheria cultures (50%). No anterior chamber taps were performed. Three patients underwent vitrectomy, and all samples taken intraoperatively were positive for Pseudallescheria, two from vitreous washings and one from vitreous cassette. Culture results were initially reported as Scedosporium species in all patients, then the causative strain was identified further. The average length of time for notification of a positive vitreous Scedosporium culture was 4.25 days (range, 3–5 days). Of the four cases, two were ultimately identified as S. auranticum, one was identified as S. prolificans, and one was S. apiospermum. All patients had multiple blood cultures taken, all of which were negative for fungemia. All patients also had sampling of various other specimens including sputum, urine, and bronchial washings—again all of which were negative on fungal culture. Treatment All patients were initially treated with vitreous tap and intravitreal injection of vancomycin and ceftazidime. Three of the four patients also received initial intravitreal injection of an antifungal agent: two were given amphotericin B and one was given voriconazole. Three patients received empirical intravenous antifungal treatment from the day of presentation: one was given amphotericin B, one was given voriconazole, and one was given fluconazole. Once positive culture was obtained, all patients were given systemic voriconazole. This was augmented with intravitreal voriconazole in three patients. A total of 10 intravitreal injections were given between the 4 patients. The average time from the onset of symptoms to first antifungal treatment was 10.25 days (range, 1–34 days). Of the three patients who underwent vitrectomy, one was performed urgently on the day of presentation. The fourth patient’s vitrectomy was aborted as a result of intraoperative findings of a total retinal detachment. The average time from the onset of symptoms to vitrectomy was 16.75 days (range, 1–37 days).

Table 1. Endogenous Pseudallescheria Endophthalmitis—Queensland Series

Sex, Age

Comorbidities

Site

Antifungal Sensitivity

Compromised

S. prolificans

Voriconazole

Undiagnosed Right eye metastatic melanoma, pneumonia

Compromised

S. auranticum

Voriconazole and natamycin

F, 66

Pancreatic cancer

Compromised

S. apiospermum Voriconazole

F, 60

Left eye Nonsmall cell lung cancer, pneumonia

Suppressed

S. auranticum

Present case 1

2013 M, 68

Present case 2

F, 78

Present case 3

Present case 4

Acute myeloid leukemia

Left eye

Immune Status

Right eye

Voriconazole and natamycin

Antifungal Treatment and Surgery Empirical IVI/systemic amphotericin B. Then systemic voriconazole/IVI voriconazole. Aborted vitrectomy Empirical IVI amphotericin B/systemic fluconazole. Then systemic voriconazole for 6 months. IVI voriconazole. Vitrectomy Empirical systemic voriconazole. Then IVI voriconazole, vitrectomy and systemic voriconazole for 8 weeks Urgent vitrectomy and empirical IVI voriconazole. Then systemic voriconazole long term

Outcome Enucleation after total retinal detachment

VA—no perception of light

Enucleation

VA—perception of light. patient died at 6 months

PSEUDALLESCHERIA ENDOPHTHALMITIS  MOLONEY AND PARK

Year

Microbiology (Vitreous Sample)

F, female; IVI, intravitreal injection; M, male; VA, visual acuity.

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Visual Outcomes and Mortality Enucleation was required in two of the four patients. Average time from the onset of symptoms to enucleation was 29.5 days (range, 19–30 days). One patient avoided enucleation because of long-term systemic voriconazole therapy. This patient had final best-corrected visual acuity of perception of light but eventually died four months later because of other systemic effects of her malignancy—the only mortality of the 4 patients. One other patient avoided enucleation because the endophthalmitis had resolved after a 6-week course of systemic voriconazole. In this patient, the visual outcome was no perception of light.

Discussion Infectious endophthalmitis most commonly occurs exogenously after the introduction of the causative organism into ocular tissues as a result of trauma, surgery, or spread of the organism from a keratitis, scleritis, or adjacent orbital infection. Endogenous endophthalmitis is less common but can have an equally poor visual prognosis.2 Fungi cause endogenous disease more often than gram-positive or gramnegative bacteria.3 Risk factors for endogenous spread to the eye include impaired immune system or systemic immunosuppressive therapy, long-term intravenous line placement, intravenous drug use, abdominal surgery, hemodialysis, human immunodeficiency viral infection, malignancy, diabetes mellitus, and others.1 Endogenous fungal endophthalmitis is of growing importance because of the increasing number of immunocompromised patients. This is as a result of newer antineoplastic agents, immunosuppressive agents, and broad-spectrum antibiotics, all of which allow opportunistic fungi to flourish in the absence of normal flora.2 Although more than 50,000 species of fungi have been described, fewer than 200 of these have been associated with human disease and even fewer have been reported to cause endophthalmitis.2 Of the fungi known to cause endophthalmitis, Pseudallescheria endophthalmitis is a very rare cause, but it has been reported to occur both exogenously and endogenously.1 Species of the P. boydii complex are ubiquitous opportunistic fungi, and although they have a uniform worldwide distribution, they are generally found more commonly in temperate climates.1 Species have been isolated in soil, manure of poultry, cattle and bats, and multiple water sources, including brackish water, saltwater, swamps, sewage, and coastal tidelands.1 The genus Pseudallescheria was first described in the early 1900s, and it has since undergone several



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reclassifications and nomenclature changes as fungal taxonomy has been revised. Until recently, Pseudallescheria comprised seven morphologically similar species: Pseudallescheria africana, Pseudallescheria angusta, P. boydii, Pseudallescheria desertorum, Pseudallescheria ellipsoidea, Pseudallescheria fimeti, and Pseudallescheria fusoidea.4 These species were known as the P. boydii complex. However, with improvements in genetic techniques and studies in molecular phylogeny, new strains of this species have recently been identified.5,6 In humans, it is the anamorph (asexual form) of P. boydii that usually causes infection, and for many years, this was thought to be S. apiospermum. However, recently, Gilgado et al7 showed that high genetic variation exists within the Scedosporium species and proposed that a separate strain called Scedosporium boydii is actually the anamorph of P. boydii with S. apiospermum making up another separate strain of the species. In the same study, Gilgado et al5,6 also identified and proposed three new strains: Pseudallescheria minutispora, S. auranticum, and Scedosporium dehoogii. These new strains are in addition to a more distantly related Scedosporium strain—S. prolificans (ex inflatum)—which was identified in 1984 by Malloch and Salkin.8 Worryingly, reports of S. prolificans infections have been increasing, especially in Spain9 and Australia,10 and the strain usually shows resistance to all systemically active antifungal agents, including the new echinocandins and second-generation azoles. More recent research has shown that along with S. prolificans, the strains P. minutispora, S. auranticum, and S. dehoogii display different degrees of human virulence and variable susceptibility to common antifungal agents.7 Pseudallescheria species have been most commonly associated with localized skin and subcutaneous infections of the lower extremities after trauma and subsequent inoculation of the organism (Madura foot).1 However, Pseudallescheria has also been implicated in opportunistic pulmonary infections, sinusitis, central nervous system infections, and osteomyelitis.1 Disseminated pseudallescheriasis has been predominantly reported in immunocompromised patients, in whom the respiratory tract has been identified as the main portal of entry. In the eye, reported infections include keratitis, scleritis, retinitis, chorioretinitis, palpebral infection, orbital infection, and endophthalmitis.1 To our knowledge, and now including our current series, there have been a total of 52 reported cases of endophthalmitis caused by species of the P. boydii complex (Tables 1–3). This represents a considerable increase in the number of reported cases compared with the 22 cases previously described in recent

Table 2. Endogenous Pseudallescheria Endophthalmitis, Previously Reported Cases

Lutwick et al11

1976

F, 32

Systemic lupus erythematosus

Right eye

Suppressed

S. apiospermum

Miconazole

Davis et al4

1980

F, 62

Pacemaker endocarditis

Left eye

Suppressed

S. apiospermum (postmortem)

Not performed

Meadow et al12

1981

F, 15

Left eye

Competent

S. apiospermum

Not reported

Stern et al13

1986

M, 31

Right eye

Compromised S. apiospermum

Miconazole

Caya et al14

1988

M, 49

Epilepsy, drowning, aspiration pneumonia Endocarditis, tracheostomy, diaphragmatic paralysis Renal transplant

Bilateral

Suppressed

S. apiospermum

Miconazole

Pfeifer et al15 1991

M, 45

Heart transplant

Left eye

Suppressed

S. apiospermum

Not reported

M, 52

Pulmonary fibrosis, Left eye pneumonia

Suppressed

S. apiospermum

Not reported

M, 66

Acute myeloid leukemia, neutropenia

Reference

Marin et al16 1991

Comorbidities

Site

Left eye

Microbiology Immune Status (Vitreous Sample)

Compromised S. prolificans (postmortem)

Antifungal Sensitivity

Econazole

Antifungal Treatment and Surgery

Outcome

Evisceration Empirical amphotericin B; vitrectomy and IVI amphotericin B; IV miconazole Nil antifungal Patient died 7 treatment days after admission Patient died at Empirical 4 weeks amphotericin B; vitrectomy; IV miconazole Patient died at Nil empirical; 4 weeks vitrectomy and lensectomy; IV/ IVI miconazole Left enucleation; Empirical patient died at amphotericin B 3 months and urgent left vitrectomy; right vitrectomy/IVI amphotericin B; IV/IVI (RE) miconazole Enucleation at 6 Empirical weeks; patient amphotericin B; died at 7 weeks urgent vitrectomy; IV/ IVI miconazole; PO fluconazole Nil empirical; IV/ Evisceration at 4 weeks; patient IVI died at 10 amphotericin B; weeks IV fluconazole Empirical Patient died at amphotericin B 2 weeks

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PSEUDALLESCHERIA ENDOPHTHALMITIS  MOLONEY AND PARK

Year

Sex, Age (Years)

Reference 17

Wood et al

(Continued )

Year

Sex, Age (Years)

1992

M, 52

Acute myeloid leukemia

Right eye

Compromised S. prolificans

M, 31

Intravenous drug use

Left eye

Competent

S. prolificans

Comorbidities

Site

Microbiology Immune Status (Vitreous Sample)

F, 79

Nil

Right eye

Competent

S. apiospermum

Luu et al19

2001

M, 46

Liver transplant

Left eye

Suppressed

S. apiospermum

McKelvie et al20

2001

F, 38

Acute myeloid leukemia, neutropenia

Bilateral

Compromised S. apiospermum

Fortún et al21 2003

M, 59

Renal transplant

Left eye

Suppressed

S. apiospermum

Vagefi et al22 2005

F, 56

Lung transplants

Bilateral

Suppressed

S. prolificans

Schiedler et al23

2004

M, 52

Liver transplant

Left eye

Suppressed

S. apiospermum

Figueroa et al24

2004

M, 44

Renal transplant

Left eye

Suppressed

S. apiospermum

Nil empirical; IV amphotericin B and flucytosine Not reported Enucleation; no antifungals given Not reported Empirical amphotericin B; lensectomy; vitrectomy Itraconazole and Empirical ketoconazole amphotericin B; vitrectomy/IVI amphotericin B; PO itraconazole Not performed Empirical amphotericin B; IVI amphotericin B Voriconazole Empirical amphotericin B; vitrectomy; PO voriconazole for 3 months Fully resistant Empirical voriconazole/ terbinafine; IVI amphotericin B/ voriconazole Not reported Empirical amphotericin B; IVI amphotericin B; vitrectomy Voriconazole and Empirical amphotericin B amphotericin B; PO voriconazole for 3 months

Outcome Patient died of sepsis at 4 weeks Enucleation Enucleation as a result of retinal detachment Patient died

Patient died

VA: 30% of vision returned

Patient died at 4 weeks

Patient died at 8 weeks

VA: counting fingers

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1993

Not reported

Antifungal Treatment and Surgery



Orr et al18

Antifungal Sensitivity

1688 RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES

Table 2.

Table 2.

Reference

Year

Sex, Age (Years)

Comorbidities

Site

(Continued )

Microbiology Immune Status (Vitreous Sample)

Antifungal Sensitivity

F, 28

Bronchiectasis

Right eye

Competent

S. apiospermum

Itraconazole

Symoens et al26

2006

F, 26

Lung transplants

Bilateral

Suppressed

S. apiospermum

Voriconazole

Sen et al27

2006

M, 62

Not given

Not reported Not given

S. apiospermum (aqueous tap only)

Voriconazole

Musk et al28 2006

M, 63

Lung transplant

Left eye

Suppressed

S. apiospermum

Not reported

M, 57

Lung transplant

Left eye

Suppressed

S. apiospermum

Voriconazole

Urgent vitrectomy and empirical/ IVI amphotericin B; PO/IVI itraconazole Empirical amphotericin B; systemic voriconazole; IVI miconazole; long-term voriconazole IVI amphotericin B; empirical fluconazole; ICI/IVI voriconazole; systemic voriconazole Empirical amphotericin B; systemic voriconazole/ terbinafine; IVI voriconazole Urgent vitrectomy, terbinafine/PO voriconazole long term

Outcome Evisceration

Patient died at 3 months

VA: 20/125

VA: no perception of light

VA: no perception of light

(continued on next page)

PSEUDALLESCHERIA ENDOPHTHALMITIS  MOLONEY AND PARK

Larocco and 2005 Barron25

Antifungal Treatment and Surgery

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Reference 29

Jain et al

Chen et al30

2007

F, 21

Wegener’s granulomatosis

Bilateral

Compromised S. apiospermum

Itraconazole

F, 37

Acute lymphoid leukemia

Left eye

Compromised S. apiospermum

Voriconazole

F, 59

Acute lymphoid leukemia

Left eye

Compromised S. apiospermum

Voriconazole

M, 56

Lung transplant

Left eye

Suppressed

S. apiospermum

Not reported

M, 62

Lung transplant

Left eye

Suppressed

S. apiospermum

Not reported

M, 61

Diabetes, hypertension

Right eye

Competent

S. apiospermum (aqueous tap only)

Voriconazole

2007

2007

Comorbidities

Site

Microbiology Immune Status (Vitreous Sample)

Antifungal Sensitivity

Antifungal Treatment and Surgery Empirical amphotericin B/ bilateral IVI amphotericin B; left vitrectomy; IVI itraconazole Empirical amphotericin B; systemic voriconazole; vitrectomy. IVI voriconazole Empirical amphotericin B; systemic/IVI voriconazole. vitrectomy No empirical; urgent vitrectomy; PO/ IVI voriconazole; vitrectomy/ lensectomy Urgent vitrectomy, empirical/IVI voriconazole Empirical ketoconazole, topical natamycin. IVI/ topical amphotericin B; AC washout; topical/ICI/IVI voriconazole

Outcome Patient died of sepsis

Inferior retinal detachment; patient died

Exenteration; patient died at 6 months Enucleation after 12 weeks

Enucleation after 11 weeks VA: complete resolution

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Year

Sex, Age (Years)



Shankar et al31

(Continued )

1690 RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES

Table 2.

Table 2.

(Continued )

Year

32

2007

F, 19

Lung transplant

Not reported Suppressed

S. apiospermum

O’Hearn et al33

2010

F, 38

Heart transplant

Right eye

Suppressed

S. prolificans

Tarabishy et al34

2011

Not Lung transplant reported

Right eye

Suppressed

S. apiospermum

Vergoulidou et al35

2011

M, 36

Acute leukemia, pneumonia

Bilateral

Compromised S. apiospermum

Fernandez Guerrero et al36

2011

F, 29

Acute lymphoid leukemia, endocarditis

Bilateral

Compromised S. prolificans

Belenitsky et al37

2012

M, 83

Diabetes, previous Bilateral endophthalmitis

Reinoso et al38

2013

F, 35

Hodgkin’s lymphoma, acute myeloid leukemia

Sahi et al

Comorbidities

Site

Left eye

Microbiology Immune Status (Vitreous Sample)

Compromised S. apiospermum Compromised S. prolificans

Antifungal Sensitivity Voriconazole

Antifungal Treatment and Surgery

Empirical voriconazole; systemic caspofungin/ terbinafine; IVI voriconazole Voriconazole and Empirical terbinafine amphotericin B; urgent vitrectomy; systemic/IVI voriconazole; terbinafine Not reported Empirical amphotericin B and IVI voriconazole, vitrectomy Voriconazole Nil empirical; systemic voriconazole. vitrectomy Fully resistant Empirical voriconazole and amphotericin B; mitral valve replacement Not reported Empirical/IVI voriconazole; vitrectomy Voriconazole Empirical voriconazole and amphotericin B

Outcome Enucleation. patient died

VA: perception of light

Evisceration; patient died

Patient died

Patient died at 6 weeks

VA: RE 20/40, LE no perception of light Patient died

PSEUDALLESCHERIA ENDOPHTHALMITIS  MOLONEY AND PARK

Reference

Sex, Age (Years)

AC, anterior chamber; F, female; IV, intravenous; ICI, intracameral injection; IVI, intravitreal injection; LE, left eye; M, male; PO, oral; RE, right eye; VA, visual acuity.

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1972

M, 26

Ocular burn/keratitis

Left eye

S. apiospermum

Not given

Glassman et al40 Bloom et al41

1973

F, 49

Left eye

S. apiospermum

Amphotericin B

1991

M, 57

Postcataract procedure Keratitis

Right eye

S. apiospermum

Miconazole only

Bouchard et al42

1991

M, 80

Post ECCE and PCIOL procedure

Right eye

S. apiospermum

Miconazole and ketoconazole

Ruesch et al43

1994

F, 67

Posttrabeculectomy

Left eye

S. apiospermum

Not given

Ksiazek et al44

1994

F, 72

Keratitis

Right eye

S. apiospermum

Not given

Carney et al45

1996

M, 11

Penetrating trauma: wood

Left eye

S. apiospermum

Miconazole

Elliott et al

Site

Microbiology

Antifungal Treatment and Surgery Topical steroids; topical amphotericin B Topical amphotericin B Topical miconazole, PO itraconazole; penetrating keratoplasty and AC washout; IV miconazole; subconjunctival miconazole Urgent vitrectomy and debridement; systemic/IVI amphotericin B; patch graft; PO ketoconazole Vitrectomy/ lensectomy; IVI amphotericin B; IV miconazole Topical gentamicin/ cefazolin; corneoscleral graft; subconjunctival miconazole Primary repair. lensectomy/ vitrectomy/IVI miconazole; IV ketoconazole; PO itrazconazole

Outcome Enucleation VA 20/25 Evisceration

VA: perception of light; phthisical

Evisceration

Enucleation

VA 20/60

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Year

39

Mechanism

Antifungal sensitivity



Reference

Sex, Age (Years)

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Table 3. Exogenous Pseudallescheria Endophthalmitis, Previously Reported Cases

Table 3.

2002

Leck et al47

Reference

Mechanism

Site

F, 57

Penetrating trauma: wood

Right eye

S. prolificans

Resistant to amphotericin B, itraconazole, and ketoconazole; voriconazole not tested

2003

F, 56

Keratitis

Right eye

S. apiospermum

Amphotericin B, miconazole, econazole

Zarkovic and Guest48

2007

F, 9

Penetrating trauma: rusted nail

Right eye

S. apiospermum

Voriconazole

Nochez et al49

2008

M, 29

Penetrating trauma: pump explosion

Left eye

S. apiospermum

Voriconazole

Chakrabarti et al50 Ikewaki et al51

2008

Not given

Not given

S. apiospermum

Not given

2009

M, 58

Penetrating trauma: iron rod Post sub-Tenon triamcinolone injection

Left eye

S. apiospermum

Voriconazole

Taylor et al

46

Microbiology

Antifungal sensitivity

Antifungal Treatment and Surgery Primary debridement and repair; penetrating keratoplasty/ vitrectomy/ buckle/laser/gas; IV/IVI amphotericin B Topical clotrimazole, systemic fluconazole/ amphotericin B; PO itraconazole; corneoscleral graft; penetrating keratoplasty Primary repair; multiple vitrectomy; IVI/ systemic voriconazole Primary repair; systemic voriconazole; vitrectomy and IVI voriconazole for 6 weeks IVI amphotericin B; PO itraconazole Topical itraconazole, systemic voriconazole. vitrectomy

Outcome Enucleation as a result of impending corneal perforation

VA: hand movements

VA: 20/40

VA: perception of light

VA . counting fingers VA: 20/60

PSEUDALLESCHERIA ENDOPHTHALMITIS  MOLONEY AND PARK

Year

Sex, Age (Years)

(Continued )

AC, anterior chamber; ECCE, extracapsular cataract extraction; F, female; IV, intravenous; IVI, intravitreal injection; M, male; PCIOL, posterior chamber intraocular lens; PO, oral; VA, visual acuity.

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2014  VOLUME 34  NUMBER 8

Table 4. Summary Statistics for Pseudallescheria Endophthalmitis Cases Queensland Series

Previous Endogenous Cases

Previous Exogenous Cases

4 4

35 43

13 13

3 (75%) 8 4 (50%) 3 3 (100%)

4 (11%) 18 15 (83%) 24 21 (88%)

0

1 (25%) 2 (50%) 1 (25%)

28 (80%) 0 7 (20%)

12 (92%) 0 1 (8%)

0 0 0 0

10 (29%) 4 (11%) 4 (11%) 7 (20%)

0 0 0 0

2 (50%)

14 (40%)

6 (50%)

3 (75%)

21 (60%)

7 (58%)

0

3 (9%)

5 (38%)

2 (50%) 1 (25%)

12 (34%) 21 (60%)

5 (38%) 0

Number of patients Number of eyes involved Diagnosis Initial diagnosis of uveitis Vitreous taps Positive fungal vitreous taps Vitrectomy specimens Positive fungal vitrectomy specimens Microbiology Causative organism Scedosporium apiospermum Scedosporium auranticum Scedosporium prolificans Other positive systemic cultures Blood cultures Sputum Urine Skin Treatment Empirical amphotericin B (intravitreal injection or systemic) Vitrectomy Outcomes Final best-corrected visual acuity better than counting Fingers Enucleation/evisceration Mortality

reviews by Belenitsky et al37 and Larocco et al.25 Not only does this show that this condition is more prominent than first thought but also it seems that Pseudallescheria endophthalmitis is increasing in incidence with 34 reported cases since 1998. Now, including the cases from the current series, 79% of cases have been reported from North America, Australia, and Spain, and this correlates with the major geographical incidence of other Pseudallescheria infections.1 Endogenous Pseudallescheria endophthalmitis seems to be more common and comprises 75% of the reported cases. Major risk factors for endogenous Pseudallescheria endophthalmitis include organ transplantation with immunosuppression, hematological malignancy with impaired immune system, endocarditis, and aspiration pneumonia secondary to drowning. At presentation, patients often have an associated acute pulmonary condition and fever. From the summaries of the current series and the past reported cases (Tables 1 and 2), it is clear that endogenous Pseudallescheria endophthalmitis is a difficult condition to diagnosis, and it is then difficult to treat successfully. Most importantly, it is also associated with a mortality rate of 56%. The four cases reported in our series are unique because we report the first two cases of endophthalmitis

caused by S. auranticum isolates and only the eighth case of endophthalmitis caused by S. prolificans. One case identified as S. auranticum endophthalmitis in our series has been reported by Bhuta et al52 mistakenly as a S. apiospermum endophthalmitis, and thus, we rereport it in our series. It is important to differentiate these newer Scedosporium isolates because recent studies10,53 show that both S. auranticum and S. prolificans are being more commonly isolated in Australia from a variety of other infections. In terms of outcomes, our series demonstrates the aggressive nature of this organism and its resistance to treatment. Despite the fact that all four Pseudallescheria isolates in our series were sensitive to voriconazole on in vitro testing, our outcomes were still very poor even with the extensive systemic/intravitreal voriconazole and vitrectomies our patients were treated with. Unfortunately, the results of our series were consistent with the poor outcomes previously reported from endogenous Pseudallescheria endophthalmitis cases (Table 4). Interestingly, in comparison to previous endogenous endophthalmitis cases, previous cases of exogenous Pseudallescheria endophthalmitis had slightly better outcomes with 41% of patients recovering bestcorrected visual acuity of 20/60 or better in the affected eye (Table 4). These slightly improved

Table 5. Other Reported Cases of S. apiospermum Endophthalmitis Without Proven Intraocular Cultures

Reference

Year

Region

Sex, Age (Years)

1977 North America

M, 58

Dworzack et al55

1989 North America

M, 29

Wilichowski et al56

1996 Germany

Site

Microbiology

Hemodialysis, lung abscess, liver cirrhosis, sinusitis MVA, aspiration pneumonia, fever

Bilateral

S. apiospermum Amphotericin B, miconazole

Left eye

S. apiospermum Not reported

M, 2

Drowning/aspiration pneumonia, endocarditis

Right eye

S. apiospermum

O’Bryan et al57 2002 North America

M, 78

S. apiospermum

Apostolova et al58

2005 North America

M, 56

Peptic ulcer, Left eye pneumonia, fever, endocarditis IVDU, hepatitis, Bilateral endocarditis, fever

Sarvat and Sarria59

2007 North America

M, 58

Pacemaker endocarditis

S. apiospermum

Left eye

S. apiospermum

Antifungal Treatment and Surgery Nil empirical; IV amphotericin B

Nil empirical; IV miconazole, vitrectomy, IVI miconazole Empirical Resistance to flucytosine, IV amphotericin fluconazole B, flucytosine, fluconazole Not reported Nil empirical; PO itraconazole; palliative care Empirical Resistant to flucytosine; amphotericin systemic B, flucytosine, voriconazole, fluconazole mitral valve replacement Not reported Empirical amphotericin B; systemic voriconazole long term; tricuspid valve replacement

Outcome VA: RE, no perception of light; LE, 20/200 VA: no perception of light Patient died

Patient died VA: RE, perception of light; LE, 20/ 630

VA: blind left eye

(continued on next page)

PSEUDALLESCHERIA ENDOPHTHALMITIS  MOLONEY AND PARK

Gluckman et al54

Comorbidities

Antifungal Sensitivity

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Reference Lamaris et al

Year 60

2008 North America

Site

Microbiology

Antifungal Treatment and Surgery

Not Hematological reported malignancy

Not reported

S. apiospermum Not reported

Systemic antifungal therapy

Not Hematological reported malignancy

Not reported

S. apiospermum Not reported

Systemic antifungal therapy

Not Hematological reported malignancy

Not reported

S. apiospermum Not reported

Systemic antifungal therapy

Not Hematological reported malignancy

Not reported

S. apiospermum Not reported

Systemic antifungal therapy

F, 60

Not reported

S. apiospermum Not reported

Empirical amphotericin B

Myocardial infarction, intracranial hemorrhage

Outcome High mortality; no specific visual outcome reported High mortality; no specific visual outcome reported High mortality; no specific visual outcome reported High mortality; no specific visual outcome reported Patient died

F, female; IV, intravenous; IVDU, intravenous drug use; IVI, intravitreal injection; LE, left eye; M, male; MVA, motor vehicle accident; PO, oral; RE, right eye; VA, visual acuity.

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2009 Greece

Comorbidities

Antifungal Sensitivity



Bibashi et al61

Region

Sex, Age (Years)

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Table 5. (Continued )

Table 6. Other Reported Cases of S. prolificans Endophthalmitis Without Proven Intraocular Cultures

Year 9

Berenguer et al

Region

1997 Spain

M, 52 M, 66

Comorbidities Acute leukemia, neutropenic, lung infiltrates Acute leukemia, neutropenic, lung infiltrates AML, neutropenic, lung infiltrates

Site

Microbiology

Antifungal Sensitivity

Not reported

S. prolificans Not reported

Not reported

S. prolificans Not reported

Right eye

S. prolificans

Gosbell et al62

1999 Australia

F, 33

Maertens et al63

2000 Belgium

M, 77

AML, neutropenic, lung infiltrates

Right eye

S. prolificans

Carreter de Granda et al64

2001 Spain

F, 52

Multiple myeloma, neutropenic, endocarditis

Right eye

S. prolificans

McKelvie et al20

2001 Australia

M, 59

AML, neutropenic

Bilateral

S. prolificans

Antifungal Treatment and Surgery

Outcome

Empirical Patient died amphotericin B

Patient died Empirical amphotericin B; G-CSF Empirical Patient died Resistant to amphotericin B, amphotericin B, PO itraconazole flucytosine, itraconazole, fluconazole Patient died Not reported Empirical amphotericin B, vitrectomy; PO itraconazole Patient died Not reported Empirical amphotericin B; PO itraconazole. aortic valve replacement Patient died Not reported Empirical amphotericin B, IVI amphotericin B; systemic voriconazole

PSEUDALLESCHERIA ENDOPHTHALMITIS  MOLONEY AND PARK

Reference

Sex, Age (Years)

AML, acute myeloid leukemia; F, female; G-CSF, granulocyte-colony stimulating factor; IVI, intravitreal injection; M, male; PO, oral.

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outcomes could potentially be the result of earlier antifungal agent treatment and earlier surgical debridement/vitrectomy. Of further note are several other reports of patients with suspected Pseudallescheria endophthalmitis that are summarized in Tables 5 and 6. These 17 cases were reported without proven intraocular cultures and so were technically excluded from this review. However, of particular note are the 7 additional cases suspicious for S. prolificans endophthalmitis summarized in Table 6. All these seven patients were associated with a background of hematological malignancy, had disseminated disease, and died shortly after the diagnosis of endophthalmitis. Scedosporium prolificans has proven to be multiresistant to all antifungal agents, including voriconazole, and is also increasing in incidence.9 Overall, results confirm that Pseudallescheria endophthalmitis is difficult to diagnosis and treat, even with voriconazole, and it is an important prognostic factor for mortality in disseminated pseudallescheriasis. Poor outcomes are the result of difficulty in accurate diagnosis and the resulting delay in treatment and to the lack of efficacy of current antifungal therapies to eradicate the organism. Delay in the diagnosis of Pseudallescheria endophthalmitis occurs for several reasons. First, in endogenous cases, initial diagnosis can be difficult because many patients present with panuveitis, which has a broad differential diagnosis. Possible causes include toxoplasma retinitis, viral retinitis, bacterial endophthalmitis, fungal endophthalmitis, intraocular malignancy, and inflammatory uveitis. Initially, several Pseudallescheria endophthalmitis cases have been diagnosed with anterior uveitis and treated with topical corticosteroids. Failure of this treatment typically ensues, and vitreous biopsy is often then undertaken. Further diagnostic uncertainty then occurs as a result of possible false-negative and false-positive results of viral/bacterial/fungal cultures from vitreous or aqueous samples. In some previous cases, this resulted in the inappropriate withdrawal of empirical antifungal treatment.28 Even in some cases with a definitive fungal culture, there have been reports of microbiologic difficulty in differentiating Pseudallescheria from Aspergillus species. Hence, there is often a long delay between vitreous/aqueous tap and notification of a positive fungal culture and then an even further delay waiting to obtain accurate sensitivities. As a result of the aggressive nature of Pseudallescheria organisms and their resistance to the widespread use of empirical amphotericin B, this delay to the administration of an antifungal agent to which the organism is actually susceptible significantly contributes to poor outcomes.



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One important finding of this review was the identification of the critical diagnostic role of vitreous biopsy in cases of endogenous endophthalmitis accompanying disseminated disease. Of the 35 previously reported cases of endogenous Pseudallescheria endophthalmitis, 21 patients (60%) were clinically diagnosed with disseminated infection. In 15 of these 21 patients (71%), vitreous samples were the first specimen of any specimen collected to culture the causative organism, Pseudallescheria. Of these 21 patients, only 10 patients had Pseudallescheriapositive blood cultures, 5 had Pseudallescheriapositive skin lesions, 2 had Pseudallescheria-positive urine samples, and 3 had Pseudallescheria-positive sputum samples. This emphasizes the importance of prompt vitreous tap not only for the diagnosis of endophthalmitis but also for the potential diagnosis of the underlying disseminated infection. In terms of the efficacy of antifungal treatment, despite 22 previously described cases of endogenous endophthalmitis culturing a Pseudallescheria isolate that was sensitive to at least one agent, both the visual outcomes and overall clinical outcomes were still very poor even after the extended courses of the appropriate agent. Now including our cases, 20 of the 39 known cases of endogenous Pseudallescheria endophthalmitis were treated with systemic/intravitreal voriconazole, and results were still poor despite studies demonstrating this agent as having excellent intraocular penetration.65 Although Jain et al29 reported adequate intravitreal voriconazole concentrations in three patients with Pseudallescheria endophthalmitis who were treated with systemic voriconazole, Nochez et al49 did report one case where the patient required higher systemic doses because of variable voriconazole pharmacokinetics. Thus, poor outcomes could be related to possible variations in systemic bioavailability and adequate ocular penetration of antifungal agents, and this emphasizes the importance of voriconazole therapeutic drug monitoring. It has also been shown that systemic voriconazole may increase concentrations of cyclosporine and tacrolimus, and this interaction may be important in immunosuppressed patients.66 Ongoing immunocompromise or immunosuppression may also contribute to poor outcomes, and administration of granulocyte/macrophage colony-stimulating factor or granulocyte colony-stimulating factor have been suggested to facilitate reversal of an underlying deficient immune status.9 With increasing resistance to antifungal agents, especially among novel fungal species, it is clear that there is a critical need for new broad-spectrum antifungal compounds. Recent studies67,68 have demonstrated the promise of micafungin and the compound E1210— both of which have shown excellent in vitro activities

PSEUDALLESCHERIA ENDOPHTHALMITIS  MOLONEY AND PARK

against Pseudallescheria species. E1210 is particularly interesting because it has also been found to be highly active against the multiresistant strain S. prolificans.68 Future options for the treatment of Pseudallescheria endophthalmitis could include the use of these compounds, possible combinations of existing antifungal agents, or even novel antifungal delivery devices for fungal endophthalmitis like the use of polylactic-coglycolic acid polymers.69 In summary, Pseudallescheria endophthalmitis is a devastating condition that is more common than previously described. To ensure the overall care of the patient, involvement of infectious disease specialists and other physicians is crucial. If predisposing factors for Pseudallescheria endophthalmitis, such as immunocompromise/immunosuppression, acute pulmonary condition, and fever are present, prompt diagnostic testing and early treatment with systemic and intravitreal voriconazole, not amphotericin B, seems to be indicated empirically. Empirical therapy could also involve the use of a synergistic combination of voriconazole with another antifungal agent. This would also ensure coverage of Zygomycetes species while the causative organism is being identified. As a result of variations in resistance to antifungal agents within the Pseudallescheria genus, fungal polymerase chain reaction testing of positive fungal specimens is also crucial to ensure the identification of newer subspecies and to then direct appropriate antifungal therapy. In addition, early surgical debridement/vitrectomy may be indicated as demonstrated by the slightly improved outcomes in cases of exogenous Pseudallescheria endophthalmitis, where early surgery occurred. With further development of antifungal therapies that are more active against increasingly resistant organisms and the use of faster diagnostic approaches, outcomes for these patients could be optimized. Key words: endophthalmitis, fungal endophthalmitis, Pseudallescheria, Pseudallescheria boydii, Scedosporium apiospermum, Scedosporium prolificans. References 1. Cortez KJ, Roilides E, Quiroz-Telles F, et al. Infections caused by Scedosporium spp. Clin Microbiol Rev 2008;21:157–197. 2. Ryan SJ. Endogenous endophthalmitis: bacterial and fungal. Retina 2013;2:1515–1522. 3. Connell PP, O’Neill EC, Fabinyi D, et al. Endogenous endophthalmitis: 10-year experience at a tertiary referral centre. Eye 2011;25:66–72. 4. Davis WA, Isner JM, Bracey AW, et al. Disseminated Petriellidium boydii and pacemaker endocarditis. Am J Med 1980;69: 929–932. 5. Gilgado F, Cano J, Gené J, et al. Molecular phylogeny of the Pseudallescheria boydii species complex: proposal of two new species. J Clin Microbiol 2005;43:4930–4942.

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6. Gilgado F, Cano J, Gené J, et al. Molecular and phenotypic data supporting distinct species statuses for Scedosporium apiospermum and Pseudallescheria boydii and the proposed new species Scedosporium dehoogii. J Clin Microbiol 2008; 46:766–771. 7. Gilgado F, Cano J, Gené J, et al. Different virulence of the species of the Pseudallescheria boydii complex. Med Mycol 2009;47:371–374. 8. Malloch D, Salkin IR. A new species of Scedosporium associated with osteomyelitis in humans. Mycotaxon 1984;21:247–255. 9. Berenguer J, Rodriguez-Tudela JL, Richard C, et al. Deep infections caused by Scedosporium prolificans. A report on 16 cases in Spain and a review of the literature. Medicine (Baltimore) 1997;76:256–265. 10. Cooley L, Spelman D, Thursky K, et al. Infection with Scedosporium apiospermum and S. prolificans, Australia. Emerging Infect Dis 2007;13:1170–1177. 11. Lutwick L, Galgiani J, Johnson R, et al. Visceral fungal infections due to Petriellidium boydii (Allescheria boydii). Am J Med 1976;61:632–639. 12. Meadow W, Tipple M, Rippon J. Endophthalmitis caused by Petriellidium boydii. Am J Dis Child 1981;135:378–380. 13. Stern RM, Zakov ZN, Meisler DM, et al. Endogenous Pseudallescheria boydii endophthalmitis. A clinicopathologic report. Cleve Clin Q 1986;53:197–203. 14. Caya JG, Farmer SG, Williams GA, et al. Bilateral Pseudallescheria boydii endophthalmitis in an immunocompromised patient. Wis Med J 1988;87:11–14. 15. Pfeifer JD, Grand MG, Thomas MA, et al. Endogenous Pseudallescheria boydii endophthalmitis. Clinicopathologic findings in two cases. Arch Ophthalmol 1991;109: 1714–1717. 16. Marin J, Sanz MA, Sanz GF, et al. Disseminated Scedosporium inflatum infection in a patient with acute myeloblastic leukemia. Eur J Clin Microbiol Infect Dis 1991;10:759–761. 17. Wood GM, McCormack JG, Muir DB, et al. Clinical features of human infection with Scedosporium inflatum. Clin Infect Dis 1992;14:1027–1033. 18. Orr P, Safneck J, Napier L. Monospermium apiospermum endophthalmitis in a patient without risk factors for infection. Can J Ophthalmol 1993;28:187–190. 19. Luu KK, Scott IU, Miller D, et al. Endogenous Pseudallescheria boydii endophthalmitis in a patient with ring-enhancing brain lesions. Ophthalmic Surg Lasers 2001;32:325–329. 20. McKelvie PA, Wong EY, Chow LP, et al. Scedosporium endophthalmitis: two fatal disseminated cases of Scedosporium infection presenting with endophthalmitis. Clin Experiment Ophthalmol 2001;29:330–334. 21. Fortún J, Martín-Dávila P, Sánchez MA, et al. Voriconazole in the treatment of invasive mold infections in transplant recipients. Eur J Clin Microbiol Infect Dis 2003;22:408–413. 22. Vagefi MR, Kim ET, Alvarado RG, et al. Bilateral endogenous Scedosporium prolificans endophthalmitis after lung transplantation. Am J Ophthalmol 2005;139:370–373. 23. Schiedler V, Scott IU, Flynn HW, et al. Culture-proven endogenous endophthalmitis: clinical features and visual acuity outcomes. Am J Ophthalmol 2004;137:725–731. 24. Figueroa MS, Fortun J, Clement A, et al. Endogenous endophthalmitis caused by Scedosporium apiospermum treated with voriconazole. Retina 2004;24:319–320. 25. Larocco A, Barron JB. Endogenous Scedosporium apiospermum endophthalmitis. Retina 2005;25:1090–1093. 26. Symoens F, Knoop C, Schrooyen M, et al. Disseminated Scedosporium apiospermum infection in a cystic fibrosis patient

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Pseudallescheria endophthalmitis: four cases over 15 years in Queensland, Australia, and a review of the literature.

To describe the clinical features and outcomes of patients with culture-proven Pseudallescheria endophthalmitis in the context of previously published...
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