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SURVEY OF OPHTHALMOLOGY

VOLUME 48 NUMBER 4 JULYAUGUST 2003

MAJOR REVIEW
Endogenous Bacterial Endophthalmitis: A 17-year
Prospective Series and Review of 267 Reported Cases
Timothy L. Jackson,1 FRCOphth, Susannah J. Eykyn,2 FRCP, FRCPath, Elizabeth M.
Graham,1 FRCP, FRCOphth, and Miles R. Stanford,1 FRCOphth
1

Medical Eye Unit, St Thomas Hospital, London, UK; and 2Department of Infection, St Thomas Hospital, London, UK

Abstract. Endogenous bacterial endophthalmitis is a rare but serious condition that occurs when
bacteria cross the bloodocular barrier and multiply within the eye. We provide an overview of
endogenous bacterial endophthalmitis by reviewing 267 reported cases and integrating this with
our experience of an additional 19 cases. The majority of patients with endogenous bacterial
endophthalmitis are initially misdiagnosed and many have an underlying disease known to predispose
to infection. This condition is often previously undiagnosed. Blood cultures are the most frequent
means of establishing the diagnosis. The most common Gram positive organisms are Staphylococcus
aureus, group B streptococci, Streptococcus pneumoniae, and Listeria monocytogenes. The most common
Gram negative organisms are Klebsiella spp., Escherichia coli, Pseudomonas aeruginosa, and Neisseria
meningitidis. Gram negative organisms are responsible for the majority of cases reported from East
Asian hospitals, but Gram positive organisms are more common in North America and Europe. The
visual outcome is poor with most cases leading to blindness in the affected eye. Many patients
have extraocular foci of infection, with an associated mortality rate of 5%. The outcome of
endogenous bacterial endophthalmitis has not improved in 55 years and clinicians need to have a high
level of awareness of this commonly misdiagnosed condition. (Surv Opthalmol 48:403423, 2003.
2003 by Elsevier Inc. All rights reserved.)
Key words. Bacterial

endogenous

endophthalmitis

Endophthalmitis is defined as any inflammation of


the internal ocular spaces, but in clinical practice it
is usually taken to mean inflammation secondary to
intraocular infection. Although rare, endophthalmitis is a potentially devastating intraocular infection
resulting in a poor visual prognosis for the majority
of patients.76,83,166,172
Endophthalmitis can be classified as either endogenous or exogenous, depending on the route of
infection. Exogenous endophthalmitis occurs when
intraocular surgery, penetrating injury, a corneal
ulcer, or periocular infection breach the external
ocular barriers and allow an infective agent access

metastatic

review

to the intraocular spaces. It most commonly occurs


as a postoperative complication of cataract surgery60,76,140,166,172 and in 70% of cases is caused by
coagulase negative staphylococci.74 Such infections
are rare, with an incidence of 0.070.32%.60,97,157
Endogenous endophthalmitis, also termed metastatic endophthalmitis, occurs when organisms reach
the eye via the bloodstream, and enter the internal
ocular spaces by crossing the bloodocular barrier.
Endogenous bacterial endophthalmitis (EBE) is less
common than exogenous bacterial endophthalmitis and accounts for only 26% of all cases of endophthalmitis.94,166,172
403

2003 by Elsevier Inc.


All rights reserved.

0039-6257/03/$see front matter


doi:10.1016/S0039-6257(03)00054-7

404

Surv Ophthalmol 48 (4) JulyAugust 2003

EBE is associated with underlying medical conditions such as diabetes, cardiac disease, and malignancy in up to 90% of patients.135 Although it can
occur in isolation, hematogenous spread means it
is usually associated with other foci of infection.
Patients may present with systemic infections such as
liver abscess, meningitis, and endocarditis and subsequently develop EBE. In either setting clinicians may
fail to appreciate the overlap of ocular and systemic
disease, particularly given the low incidence of EBE.
Prompt diagnosis and treatment is essential if useful
vision is to be preserved and therefore ophthalmologists, physicians, and microbiologists need to have a
high level of awareness of this disease.
Since the last major review in 1986,71 most reports
of EBE detail the clinical features of a single patient or
small case series. This review collates 267 cases of
EBE reported in the English literature since 1986
and includes 19 cases treated in our own center.

I. Methods
A. ST THOMAS CASE SERIES

A 17-year prospective study from 1984 to 2001 was


conducted in the departments of ophthalmology and
microbiology in a London teaching hospital with
a dedicated medical eye unit. All patients with a
provisional diagnosis of EBE were admitted to the
medical eye unit, and those with positive blood or
intraocular culture were then prospectively identified. As Gram negative bacteria are rarely contaminants of blood or intraocular culture, their isolation
was considered to be significant. Gram positive infection was considered significant if isolated in more
than one culture plate, and if this was consistent with
the Gram stain.
Patients with recent ocular trauma, intraocular surgery within 1 year of presentation, or any other cause
of intraocular inflammation were excluded, as were
those with a history of glaucoma filtration surgery.
The following clinical details were recorded prospectively for all patients, using a standardized format:
age and sex; any medical conditions that might predispose to infection; ocular features; extraocular
manifestations of infection; the provisional diagnosis
and initial treatment; source of the pathogen; definitive treatment; and final outcome in terms of visual
acuity (VA) and survival. All major clinical decisions
were made by the lead clinician of the medical eye
unit, in consultation with the department of microbiology (SJE).
Aqueous samples for microscopy and culture were
obtained by means of a paralimbal injection into
the anterior chamber with a sterile insulin syringe
with the plunger removed. Aqueous spontaneously
filled the barrel of the syringe up to 0.1 ml and then

the syringe was withdrawn. Vitreous specimens were


obtained by aspirating 0.2 ml with a vitrectomy cutter,
introduced through a pars plana sclerotomy. This
was immediately followed by an intravitreal injection
of antibiotic. If the causative organism had not
been identified we routinely selected vancomycin
2 mg in 0.1 ml for Gram positive cover. At the start
of the study period amikacin (0.4 mg) was routinely
selected for Gram negative cover. This was later
replaced by ceftazidime 2 mg in 0.1 ml.86 None of
the patients in our case series underwent therapeutic
pars plana vitrectomy. This reflects the preferred
treatment strategy of the vitreoretinal surgeons
employed at St Thomas hospital during the study
period.
All clinically significant, positive blood cultures at
St Thomas Hospital were also recorded prospectively
on a computer database. This database was used to
determine the number of cases of community and
hospital acquired bacteremia that occurred during
the study period. The species responsible for bacteremia in non-ophthalmic patients were then compared to those responsible for EBE.
B. LITERATURE REVIEW

An Ovid search engine and Medline database were


used to retrieve reports of EBE since the last review
by Greenwald et al in September 1986,71 up to January 2001. Retrospective studies published after September 1986 were included. The following keywords
and MESH headings were used; endogenous, metastatic,
bacterial, endophthalmitis and vitrectomy. Similar search
strategies were repeated using BIDS ISI and BIDS
EMBASE. Additional articles were derived from
the reference list of each article. Articles citing
Greenwalds review were identified using an author
citation search. Reports published only as abstracts
were excluded, as were non-English language reports.
Patients included in the literature review had to
have clinical features of endogenous endophthalmitis in the absence of any other cause of intraocular
inflammation. Laboratory evidence of infection had
to include one of the following:
1. Bacteria isolated from an intraocular specimen,
blood culture, lumbar puncture, or other relevant extraocular site.
2. Bacteria detected on intraocular Gram stain or
polymerase chain reaction (PCR).
The exclusion criteria applied to the St Thomas
case series were also applied to the literature review.
The effect of treatment strategy and causative organism on visual outcome was assessed using univariable and multivariable logistic regression. Robust
standard errors were calculated by clustering within

405

ENDOGENOUS BACTERIAL ENDOPHTHALMITIS

patients to allow for non-independence of observations.

II. Results
A. ST THOMAS CASE SERIES

During the study period 19 patients (21 eyes) were


diagnosed with EBE (Table 1). There were 12 men
and 7 women with a mean age of 60 years (SD 17.0;
range 777). Four patients have been reported previously.133 Twelve patients presented to an ophthalmologist with ocular symptoms and 7 to a general
physician with manifestations of extraocular infection. All adult patients complained of blurred or altered vision at the onset of infection, and 12 had
ocular pain or discomfort. Seventeen patients had
systemic features of infection at presentation, most
commonly fever (12) and arthralgia (5). Initial
Snellen fraction ranged from 0.33 (6/18) to light
perception. Twelve patients had an hypopyon at
presentation and 10 had elevated intraocular pressure (IOP; mean 38.3 mm Hg; range 2262 mm Hg).
Examination of the fundus was difficult in all patients
due to hazy ocular media.
Twelve patients (63%) were initially misdiagnosed,
10 as acute anterior uveitis, 1 as acute angle closure
glaucoma, and 1 as cavernous sinus thrombosis. Effective treatment was delayed by 2 days or more in
11 of these patients (mean 7.9 days; SD 9.4; range
228). Thirteen patients (68%) had an underlying
medical condition that could predispose to infection,
and in 6 (32%) this condition was previously undiagnosed. The most common predisposing medical condition was Type II diabetes (8). An extraocular focus
of infection was detected in 15 (79%) patients (urinary tract infection [6]; septic arthritis [4]; soft tissue
infections [5]; pneumonia [2]; endocarditis [1]; liver
abscess [1]; psoas abscess [1]). Five patients had extraocular infections in more than one site (Table 1).
A positive blood culture was obtained in 74% of
patients, a positive intraocular culture in 56%. All
patients had either positive blood or intraocular
cultures except patient 13 in whom Gram negative
diplocci were detected in an intraocular specimen.
Neisseria meningitidis was later identified by polymerase chain reaction (PCR) of a skin scraping. Overall,
Gram positive organisms (12) were more common
than Gram negative (7), but one of the most
common predisposing causes of EBE was Escherichia
coli urinary tract infection (4).
During the study period, 5,859 patients were
treated at St Thomas Hospital for bacteremia. Of
these cases, 2,740 (47%) were community-acquired
and 3,119 (53%) were hospital-acquired (Table 2).
Sixteen of the 19 cases (84%) of EBE were community-acquired. Fourteen patients were treated with

both intravitreal and intravenous antibiotics, 4 received intravenous therapy alone, and 1 had intravitreal antibiotics alone. The visual outcome was poor,
with only light perception or worse in 17 of 21 (81%)
eyes. Six of these 17 eyes became phthisical and two
required evisceration. Patients who presented with a
VA of 6/36 or better were more likely to retain useful
(count fingers or better) vision than those with an
initial VA worse than 6/36 (Fishers exact test; p
0.032).
B. LITERATURE REVIEW

We reviewed 123 case reports, 38 case series, and


59 related articles. A total of 316 individual cases of
EBE were reported (including four patients133 in the
present St Thomas case series), but 49 of these failed
to meet our inclusion criteria or were excluded due
to lack of clinical information. Of the remaining 267
cases included in our review series, there were 157
men, 97 women, and in 13 the sex of the patient was
not stated. The mean age was 48.9 years (SD 22.0;
range neonate91 years). In 227 (85%) patients, EBE
was uniocular; 113 (50%) had left eye involvement, 85
(37%) right, and in 29 (13%) the side was not stated.
Thirty-one patients (12%) had bilateral EBE. In 9
(3%) it was not stated whether EBE was unilateral
or bilateral.
Of 267 patients, 149 (56%) had an underlying
medical condition that predisposed to infection
(Table 3). The most common condition was diabetes
(93), particularly in association with klebsiella liver
abscess. Fifty-two patients (19%) had hospital acquired EBE, or EBE that occurred in association with
medical interventions such as intravenous access (9),
surgery (7), invasive therapeutic or diagnostic procedures (5), and hemodialysis (5). Eighteen of these 52
patients were undergoing treatment with an immunosuppressive agent.
There were 197 (74%) patients who were systemically unwell at presentation, 48 (18%) had EBE in
the absence of significant constitutional symptoms,
and in 21 (8%) systemic features were not detailed.
Patients had systemic prodromal symptoms for a
mean of 6.7 days (range 035; SD 7.0). EBE was
initially misdiagnosed in 60 (22%) patients, most
commonly as non-infectious uveitis, fungal endophthalmitis, and acute angle-closure glaucoma (Table
4). Treatment was subsequently delayed by a mean
of 9.5 days (range 0.530; SD 9.3) for these patients.
An additional 11 patients (4%) were not diagnosed
with EBE for a mean of 7.9 days (range 230;SD 9.2)
due to delayed referral to an ophthalmologist.
Positive cultures were obtained from the blood in
160 patients. Vitreous biopsies were positive in 108
eyes, anterior chamber in 27, enucleated, eviscerated,

4 74M S. pneumoniae
(Type 1)

Type 2
diabetes

3 74M Streptococcus
pneumoniae

Heart
failure
and
acute
renal
failure

Type 2
diabetes

Staphylococcus
aureus

Organism

2 50M S. aureus

1 55F

Age/
No. Sex

Underlying
Medical
Condition

Pain
Redness
Blurred
vision

Floaters

Ocular
Symptoms

Confusion Pain
Shortness Redness
of breath Blurred
vision
Floaters

Productive Pain
cough
Redness
Blurred
vision

Fever
Weight
loss

Spiking
fever

Systemic
Features

LE:
PL
Chemosis
Hypopyon
IOP 26 mm Hg
No fundal view

RE:
PL
Corneal edema
Hypopyon
IOP 62 mm Hg
RAPD
No red reflex

LE: 6/18
Hypopyon
IOP 13 mm Hg
Poor fundal view

LE: 6/18
Anterior
chamber cells
Vitritis
IOP 14 mm Hg

Ocular
signs
Side:

Posterior
diffuse

Posterior
diffuse

Posterior
diffuse

Posterior
diffuse

Principal
Site of
Ocular
Inflammation

Pneumonia

Pneumonia

IV canula

Other
Foci

Intraocular IntraGram ocular Blood


Stain Culture Culture

Clinical Details of Patients with Endogenous Bacterial Endophthalmitis


(Present Case Series)

TABLE 1

Sputum

Sputum

IV canula

Other
Positive
Cultures

IV
clarithromycin
and
levofloxacin

Intravitreal
amikacin
and
vancomycin

IV
benzylpenicillin

Intravitreal
gentamicin
and
vancomycin

IV
flucloxacillin

Intravitreal
amikacin
and
vancomycin

IV
flucloxacillin

Intravitreal
ceftazidime
and
vancomycin

Definitive
Treatment

(continued)

PL (1)

Evisc
(12)

NPL (2)

6/12 (0.25)

Visual
Outcome
(Follow-up in
months)

406
Surv Ophthalmol 48 (4) JulyAugust 2003

8 65M Group B
streptococcus
(Type 1b)

Fever
Confusion

Falls
Arthralgia
Fever

Type 2
Arthralgia
diabetes
Fever
(previously
undiagnosed)

None

7 76F

Group B
streptococcus
(Type 1b/c)

Systemic
Features

Psoriasis
Rigors
(treated
Confusion
with oral
prednisolone)

Alocohol
abuse

Group A
streptococcus

Organism

6 72M Group A
streptococcus

5 67F

Age/
No. Sex

Underlying
Medical
Condition

Blurred
vision

Blurred
vision

Redness
Blurred
vision

Blurred
vision

Ocular
Symptoms

RE:
PL
Hypopyon
IOP 28 mm Hg
No fundal view

BEs:
PL
Hypopyon
Proptosis
Restricted
extraocular
movements

LE:
HMs
Hypopyon
IOP 8
mm Hg
Reduced red reflex

RE:
PL
Hypopyon
IOP 24 mm Hg
Corneal epithelial defect
Poor fundal view
Central retinal vein
occlusion fellow eye

Ocular
signs
Side:

Septic
arthritis
Cellulitis

Infected
skin
lesions

Other
Foci

Posterior
diffuse

Mitral
valve
endocarditis
Septic
arthritis

PanUrinary
ophthalmitis tract
infection
Orbital
cellulitis

Posterior
diffuse

Posterior
diffuse

Principal
Site of
Ocular
Inflammation

Continued

TABLE 1

ND

ND

Conjuntiva
Urine

Knee
aspirate

Definitive
Treatment

IV
benzylpenicillin

Intravitreal
ceftazidime

IV
erythromycin
ceftazidime

IV
benzylpenicillin

Intravitreal
ceftazidime
and
vancomycin

IV
benzylpenicillin

Conjunctiva Intravitreal
ceftazidime
and
vancomycin

Other
Positive
Cultures

Intraocular IntraGram ocular Blood


Stain Culture Culture

(continued)

Phthisis (2)

RE: PL
LE: NPL (1)

Phthisis (5)

PL (05)

Visual
Outcome
(Follow-up in
months)

ENDOGENOUS BACTERIAL ENDOPHTHALMITIS


407

Organism

Ocular
Symptoms

Fever
Nausea
Vomiting
Leg pain

Type 2
diabetes
(previously
undiagnosed)

11 57M Streptococcus
milleri

Pain
Redness
Blurred
vision

Pain
Redness
Blurred
vision

Sore throat Pain


Arthralgia Redness
Fever
Blurred
vision

Multiple
Fever
myeloma
Loin pain
(previously
Arthralgia
undiagnosed)

None

Systemic
Features

10 55M Group B
streptococcus
(Type 1b)

9 60M Group B
streptococcus
(Type 1a/c)

Age/
No. Sex

Underlying
Medical
Condition
LE:
6/60
Chemosis
Corneal edema
IOP 55 mm Hg
Poor fundal view
RE:
HMs
Hypopyon
IOP 40 mm Hg
No fundal view
LE:
6/36
Mild anterior
uveitis
IOP 18 mm Hg
Mild vitritis
RE:
PL
Fibrin in anterior
chamber
RAPD
No fundal view

Ocular
signs
Side:

Posterior
diffuse

Anterior and
posterior
diffuse

Posterior
diffuse

Posterior
diffuse

Principal
Site of
Ocular
Inflammation

Continued

TABLE 1

Cellulitis of
lower limb

Septic
arthritis

Other
Foci

Intraocular IntraGram ocular Blood


Stain Culture Culture

Other
Positive
Cultures

IV
flucloxacillin
and gentamicin

Intravitreal
ceftazidime

IV amoxycullin
and gentamicin

Intravitreal
ceftazidime
(RE only)

(continued)

Phthisis
(32)

RE: PL
LE: 6/6 (24)

IV
Evisc (1)
benzylpenicillin
and
gentamicin

Definitive
Treatment

Visual
Outcome
(Follow-up in
months)

408
Surv Ophthalmol 48 (4) JulyAugust 2003

15 38M Escherichia
coli
(0101)

Lisieria
None
monocytogenes
(Serotype 1/2)

14 73F

HIV

None

Neisseria
meningitidis

13 7F

Systemic
Features
Pain
Blurred
vision

Ocular
Symptoms

Nausea
Diarrhea
Vomiting

None

Pain
Blurred
vision

Pain
Redness
Blurred
vision

Rash
Pain
Fever
Redness
Transient
headache
& neck
stiffness

Type 2
Loin pain
diabetes
Dysuria
Renal failure
Fever
(previously
undiagnosed)

Serratia
marcescens

Organism

12 55F

Age/
No. Sex

Underlying
Medical
Condition

RE:
PL
Hypopyon
IOP not
recorded
No red
reflex

LE:
6/24
IOP 40 mm Hg
Poor fundal view
Red reflex
present

RE:
Clear corneal
epithelial defect
Anterior
uveitis

LE:
PL
Chemosis
Hypopyon
IOP 46 mm Hg
No red reflex

Ocular
signs
Side:

Posterior
diffuse

Posterior
diffuse

Anterior
diffuse

Posterior
diffuse

Principal
Site of
Ocular
Inflammation

Continued

TABLE 1

Urinary
tract
infection

Obstructive
pyonephrosis

Other
Foci

Intraocular IntraGram ocular Blood


Stain Culture Culture
Intravitreal
ceftazidime
and
vancomycin
IV
piperacillin
and
gentamicin

Definitive
Treatment

Urine

IV
ceftazidime
and
co-amoxjclav

Intravitreal
ceftazidime
and
vancomycin

Intravitreal
vancomycin

IV
ceftazidime

Skin
Intravitreal
scrapings* amikacin
and
vancomycin

Urine

Other
Positive
Cultures

(continued)

PL (3)

6/60 (2)

PL (2)

NPL
(42)

Visual
Outcome
(Follow-up in
months)

ENDOGENOUS BACTERIAL ENDOPHTHALMITIS


409

Organism

E. coli
(06)

Weight
loss

Pain
Blurred
vision

Ocular
Symptoms

RE:
PL
Proptosis
Renal
Hypopyon
parenchymal
IOP 40 mm Hg
malakoplakia
RAPD
(previously
Iris bombe
undiagnosed)
Reduced
red reflex
Type 2
None
Blurred
LE:
diabetes
vision
PL
Eyelid
Proptosis
swelling Chemosis
Hypopyon
IOP 18 mm Hg
RAPD
No red reflex
Alcohol
Arthralgia Redness LE:
abuse
Blurred
PL
vision
Hypopyon
Posterior
synechiae
IOP 22 mm Hg
Poor fundal view
Type 2
Loss of
Pain
RE:
diabetes
appetite Redness
6/36
(previously
Weight loss Blurred
Swollen lids
undiagnosed) Fever
vision
IOP 10 mm Hg
Moderate Vitritis

Type 2
diabetes

Systemic
Features

Ocular
signs
Side:

Posterior
diffuse

Anterior
and
posterior
diffuse

Liver
abscess

Septic
arthritis

Urinary
tract
infection

PanUrinary
ophthalmitis tract
infection

Psoas
abscess

PanRenal
ophthalmitis abscess

Other
Foci

Intraocular IntraGram ocular Blood


Stain Culture Culture

Urine

Urine

Psoas
abscess
aspirate

Other
Positive
Cultures

Phthisis (6)

Phthisis
(5)

IV
co-amoxyclav
and
cefuroxime
Intravitreal
amikacin
and
vancomycin
IV
vancomycin

Phthisis (21)

IV
cefuroxime
and gentamicin
Intravitreal
6/36 (12)
ceftazidime

Intravitreal
amikacin
and
vancomycin

IV
amoxycillin

Definitive
Treatment

Visual
Outcome
(Follow-up in
months)

*N. meningitidis serogroup C indentified with polymerase chain reaction of skin scraping. Abbreviations: Left eye (LE), right eye (RE), intraocular pressure (IOP), hand Movements vision (HMs), perception
of light (PL), no perception of light (NPL), relative afferent pupillary defect (RAPD), not done (ND), intravenous (IV). Visual acuity given as best corrected, metric Snellen acuity.

19 57M Klebsiclla
pneumoniae
(K2)

18 74M E. coli
(075)

17 77F

16 47M E. coli
(018ac)

Age/
No. Sex

Underlying
Medical
Condition

Principal
Site of
Ocular
Inflammation

Continued

TABLE 1

410
Surv Ophthalmol 48 (4) JulyAugust 2003

411

ENDOGENOUS BACTERIAL ENDOPHTHALMITIS


TABLE 2

Number of Cases of Bacteremia and Blood Culture Positive Endogenous Bacterial Endophthalmitis Treated
at St Thomas Hospital During Study Period
Community Acquired
Causative Pathogen
Staphylococcus aureus
Streptococcus pneumoniae
Group A streptococcus
Group B streptococcus
S. melleri
Escherichia coli
Klebsiella spp.
Serratia marcescens
Other
Total

Hospital Acquired

Bacteremia

EBE

Bacteremia

EBE

281
431
82
68
41
720
127
3
987
2740

1
1
2
4
1
2
1

12

725
61
19
29
24
466
257
62
1476
3119

EBE endogenous bacterial endophthalmitis.


Data excludes five cases of EBE that were blood culture negative.

or perforated ocular contents in 13, and from biopsy of a choroidal abscess in 5. Many small series
gave limited details of cultures but for those larger
series that included relevant negative investigations,36,102,135,191 blood cultures were positive in 94%
(61/65) of patients and vitreous cultures in 56%
(35/63).
An extraocular focus of infection was found in
180 (67%) patients. Twenty-two (12%) of these had
involvement of more than one site giving a total of
229 extraocular infections. The most common sites
were liver (60), lung (32), central nervous system
(25), endocardium (24), and renal and urinary tracts
(24) (Table 5).
In 56% of patients (150), EBE was caused by Gram
negative organisms, most commonly Klebsiella spp.
(80), E. coli (22), Pseudomonas aeruginosa (16), N. meningitidis (15), and Serratia marscescens (6). Eighty
percent (64) of all patients with klebsiella EBE were
from East Asian hospitals. Gram positive organisms
were responsible for 40% (105) of cases. The most
common Gram positive organisms were Staphylococcus
TABLE 3

Predisposing Medical Conditions (Literature review)


Predisposing Medical Condition
Diabetes
Type 1
Type 2
Type not stated
Intravenous drug use
HIV infection/AIDS
Autoimmune disease
Blood malignancy
Alcohol abuse
Asplenia
Other
Total

n
93
14
31
48
15
11
8
5
5
5
7
149

aureus (27), group B streptococci (14), Streptococcus


pneumoniae (13), Listeria monocytogenes (10), Nocardia
asteroides (9), and group G streptococci (8). Six
patients had mycobacterial EBE and 6 had mixed
infection.
When compared to two previous reviews of EBE
(Table 6) there was a statistically significant increase
in reports of klebsiella EBE (Fishers exact test:
p 0.0001) and a decrease in N. meningitidis
(p 0.0001). There were also more reports of P.
aeruginosa but this was not statistically significant (p
0.0652).
Fifty-six percent of cases (168/299 eyes) were
treated with intraocular antibiotics in addition to
systemic antibiotics. The initial choice of systemic
antibiotic therapy was subsequently modified after
culture results became available in 74 (28%) patients.
Intraocular steroids were given in 30 (10%) eyes.
TABLE 4

Diagnostic Errors (Literature Review)


Misdiagnosis
Non-infectious uveitis
Fungal endophthalmitis
Acute angle closure glaucoma
Conjuctivitis
Retinoblastoma
Metastatic tumor
Keratouveitis
Orbital cellulitis
Phacoanaphylaxis
Mucormycosis
Cavernous sinus thrombosis
Orbital pseudotumor
Cytomegalovirus retinitis
Giant cell arteritis
Congenital glaucoma
Not stated
Total

n
24
6
6
5
4
3
2
1
1
1
1
1
1
1
1
6
64

412

Surv Ophthalmol 48 (4) JulyAugust 2003


TABLE 5

more likely to retain useful vision, and less likely to


require evisceration or enucleation.

Extraocular Foci of Infection (Literature Review)


Infection
Liver abscess
Pneumonia
Endocarditis
Soft tissue infectiona
Urinary tract infection
Meningitis
Septic arthritis
Orbital cellulitis
Renal abscess and pyonephrosis
Brain abscess
Other sitesb
Total

n
60
27
24
21
17
18
12
10
6
6
28
229

Skin and wound infections (10), cellulitis (7), necrotizing fasciitis (3) myositis (1).
bPeritonitis (3), Prostate infection (3) lung abscess (2),
osteomyelitis (2), pancreatic abscess or pancreatitis (2),
mediastinal infection (2), splenic emboli (1), cholecystitis
(1), abdominal abscess (1), gastroenteritis (1), perinephric-psoas abscess (1), pericarditis (1), testicular abscess
(1), pneumonitis (1), empyema (1), pleural abscess (1),
epidural abscess (1), chorioamnionitis (1), infected hemodialysis fistula (1), sinusitis (1).

Twenty-one (8%) patients received systemic steroids. Pars plana vitrectomy was performed in 68
(23%) eyes, lensectomy in 15 (5%), and repair of
retinal detachment in 6 (2%). Other operations included cataract extraction (3), drainage of subretinal
abscess (2), trabeculectomy (1), implantation of
Molteno tube (1), and penetrating keratoplasty (1).
The final VA of the 271 eyes with known outcome
was poor (Fig. 1). Only 5% of eyes had a VA of 20/
20 or better and the majority (69%) had vision worse
than counting fingers. Twenty-five percent of eyes
required evisceration or enucleation and 5% of patients died as a direct result of extraocular infection.
The results of univariable and multivariable analysis of the effect of causative pathogen and treatment
strategy on visual outcome are shown in Table 7.
Compared to Gram positive infection, eyes with Gram
negative EBE were less likely to retain useful (count
fingers or better) vision, but had a similar rate of evisceration or enucleation. Eyes that received intravitreal antibiotics had a similar probability of retaining
useful vision to those that did not, but univariable
analysis suggested that they were less likely to
require evisceration or enucleation. This difference
was not significant with multivariable analysis. The
small number of eyes that received intravitreal
steroids were more likely to retain useful vision than
those that did not. They were also less likely to require
evisceration and enucleation, but this difference was
not significant. Eyes that underwent vitrectomy were

III. Patient Characteristics


Although our literature review suggests that the
incidence of EBE peaks at about 50 years of age,
there is a wide distribution from neonates to patients
in their tenth decade. The last major review by
Greenwald et al in 198671 reported a lower mean age
of 35 years (range 1 week to 85 years) with 24 of 72
patients aged less than 20 years. They also suggested
that the right eye was twice as likely to be affected as
the left and postulated that this is because of the
more proximal and direct arterial blood flow to
the right carotid. In our literature review the left eye
was more commonly involved. A right-sided preponderance seems unlikely given that blood flow is equal
to both eyes and the extra transit time to the left
carotid is unlikely to have an important effect on
bacterial survival.
The two largest case series of EBE135,191 observed
a male preponderance (16 vs. 12 and 19 vs. 8), similar
to that observed in our case series (12 vs. 7). Review
of the literature also suggests that men are more
commonly affected than women (158 vs. 97) although this may partly result from a large number
of male patients with klebsiella EBE reported from
a veterans hospital in Taiwan. However, even if all
patients with klebsiella infection are excluded there
are still more reports of EBE in men than women
(107 vs. 73). The reason for this apparent male predisposition to EBE is not clear.

IV. Clinical Features


The classic features of EBE include ocular pain,
blurred vision, swollen eyelids, injected and chemosed conjunctiva, anterior chamber inflammation
and hypopyon, elevated IOP with associated corneal
edema, a reduced or absent red reflex, and poor
fundal view secondary to intraocular inflammation.
In our case series all adult patients complained of
blurred vision and two-thirds had ocular pain. Hypopyon and elevated IOP were inconstant findings in
our patients, but when the IOP was raised it was
often 40 mm Hg or higher. All patients in our case
series had a reduced or absent red reflex and a poor
fundal view due to vitritis. Most patients in our case
series had systemic symptoms at initial presentation as did the majority of those reported in the literature.
Greenwald et al71 classified EBE into 5 groups on the
basis of the predominant focus of inflammation. Cases
were described as anterior focal, anterior diffuse,
poster focal, posterior diffuse, and panophthalmitis.

Klebsiella spp.28,36,91,102,104,113,135,186,193,29,30,34,37,41,44,55,68,77,81,89,99,103,132,154,173,191,192
Escherichia coli8,40,43,58,61,63,83,135,141,145,148,160,172,178,184,186,188,191
Pseudomonas aeruginosa16,51,67,87,120,126,131,135,147,159,172,177
Neisseria meningitidis1,11,15,33,67,68,90,108,109,112,135,163,164,190,191
Serratia sp.4,6,46,114,125,135

Gram negativee

1
4
2
56

11
14
9
1
6
1
(1)
(4)
(2)
(52)

(10)
(13)
(8)
(1)
(6)
(1)

Cases
1935197570,88,162
n 108 (%)

5
5
2
8
3

7
2
10
3
3
11

(7)
(7)
(3)
(11)
(4)

(10)
(3)
(14)
(4)
(4)
(15)

Cases
1976198571
n 72 (%)

80 (30)d
22 (8)
16 (6)
15 (6)
6 (2)

27 (10)a
13 (5)
29 (11)b
10 (4)
9 (3)
6 (2)

Cases
19862001
n 267 (%)

References shown in superscript in the second column are for present literature review, 19862001.
Note: In the present review series there was an additional six cases caused by acid fast bacilli7,73,101,152,191 and six by mixed infection.26,67,104,135,149,172
a
Includes three cases of methicillin resistant S. aureus.151,169
b
Other streptococci included (n), Group B streptococci (14),20,49,66,82,115,128,133,167,191 Group C streptococci (2),80,124 Group G streptococci (8),13,135,140,175,183
S. milleri (1),135 Viridans group streptococcus (2),75,91 S. sanguis (1),164 Streptococcus-species not stated (1).107
c
Other Gram positive organisms in present literature review included S. epidermidis (3),62,166 Bacilus-species not stated (1),181 Clostridium septicum (3),25,100,139C. perfringens
(2),10,130 Enterococcus faecalis (1),180 Propionibacterium acnes (1).48
d
Klebsiella species not stated in 1 case. Other 79 cases reported as K. pneumoniae; 80% of these occurred in East Asian hospitals.
e
Other Gram negative bacteria in the present review series included Enterobacter agglomerans (2)186,194 Kingella kingae (1),27 Aeromonas hydrophila (1),64 A. sobria (1),35
Ochrobactrum anthropi (1),14 Brucella melitensis (1),3 Haemophilus influenzae (1),172 Tropheryma whippelii (1),150 Actinobacillus actinomycete incomitans (1),84 Salmonella typhimurium (1).191

Staphylococcus aureus9,38,39,67,98,119,127,129,134,135,140,151,156,169,171,179,185,191
Streptococcus pneumoniae2,31,47,135,140,145,163,189
Other Streptococcus sp.
Listeria monocytogenes5,18,50,54,56,78,105,110,118,140
Nocardia asteroides45,59,72,85,111,144,146,174,191
Bacillus cereus42,79,125,135,181

Gram positivec

Organism

The Most Common Causative Organisms Since 1935 (Literature Review)

TABLE 6

ENDOGENOUS BACTERIAL ENDOPHTHALMITIS


413

414

Surv Ophthalmol 48 (4) JulyAugust 2003


Fig. 1. Visual acuity of cases in literature
review expressed as Snellen fraction
(e.g., 20/20 1 and 20/40 0.5). CF
counting fingers vision, HM hand
movements vision, PL perception of
light, NPL no perception of light.
Visual acuity values relate to the number
of eyes as a percentage of those with
known visual outcome. Last column represents percentage of patients who died
as a direct result of extraocular infection.
Figures are rounded to the nearest
whole number.

This system was used to guide the treatment and


investigation of EBE, and to help determine prognosis. Most patients in our case series had posterior
diffuse disease.

V. Diagnosis
A. INCIDENCE OF DIAGNOSTIC ERRORS

Although some of the above clinical features may


help identify patients with EBE, most are nonspecific
and it remains a difficult diagnosis, especially given
its low incidence. Greenwalds review71 found that
16% (11/67) of patients with EBE were initially misdiagnosed, and our literature review suggests a figure
of 22%. Both are probably an underestimate as diagnostic errors may be under-reported. In our case
series 63% of cases were initially misdiagnosed.
B. DIFFERENTIAL DIAGNOSIS

1. Adults
The differential diagnosis of EBE depends largely
on the predominant clinical features, but review of
the literature indicated that there were several
common misdiagnoses. The most common in adults
was acute, non-infectious, anterior uveitis. Early in
the disease process EBE was sometimes misdiagnosed
as conjunctivitis while later presentation with severe
inflammation and high IOP led to several patients

being misdiagnosed with acute angle-closure glaucoma. Fungal endophthalmitis was another commonly reported diagnostic error, especially in
patients with intravenous drug use (IVDU). Unlike
the association of endogenous fungal endophthalmitis and IVDU, the association of EBE and IVDU may
be less well recognized. This may explain why there
were several reports of patients with EBE and IVDU
who were misdiagnosed as having fungal endophthalmitis. IVDU was the second most commonly reported
predisposing factor associated with EBE.
N. asteroides choroidal abscesses may also be mistaken for fungal endophthalmitis, or alternatively,
neoplastic choroidal metastases. All three conditions
may have a similar fundal appearance, abnormal
cells in the vitreous and extraocular manifestations
of disease. In this setting, transvitreal fine needle
aspiration of a choroidal abscess has been used to
establish the diagnosis.72,144
Eyelid swelling and chemosis may be a feature of
EBE and this may wrongly suggest mucormycosis,
cavernous sinus thrombosis, or orbital cellulitis.
Similarly, headache, systemic malaise, and localised
tenderness may lead to a misdiagnosis of temporal
arteritis. Although none of the patients in our case
series or literature review were originally thought to
have either ocular lymphoma, sympathetic ophthalmia, necrosis of an intraocular tumor, or granulomatous conditions such as sarcoidosis, these conditions

415

ENDOGENOUS BACTERIAL ENDOPHTHALMITIS


TABLE 7

Univariable and Multivariable Analysis of Visual Outcome in Relation to Causative Pathogen and
Treatment Strategy (Patients in Literature Review with Known Visual Outcome)
Odd Ratio (95% confidence interval)a
Outcome

Univariable Analysis

Final visual acuity count fingers or better


Intravitreal antibiotics
Intravitreal steroids
Vitrectomy
Gram negative infection
Evisceration or enucleation
Intravitreal antibiotics
Intravitreal steroids
Vitrectomy
Gram negative infection

Multivariable Analysis

0.94
3.92
2.35
0.40

(0.541.62)
(1.5310.1)
(1.314.24)
(0.230.71)

0.64
4.44
2.93
0.43

(0.341.20)
(1.4313.8)
(1.525.64)
(0.240.78)

0.54
0.31
0.27
1.12

(0.300.94)
(0.071.45)
(0.120.62)
(0.622.03)

0.68
0.45
0.30
1.10

(0.371.23)
(0.092.30)
(0.120.74)
(0.592.04)

a
Odds ratio given for each treatment strategy compares eyes that had undergone the intervention with those that had not.
For example, eyes that received intravitreal steroids were more likely to have a favourable visual outcome (count fingers or
better) than those that did not (Odds ratio 3.92 with univariable analysis, confidence interval 1.53 to 10.1). Outcome in eyes
with Gram negative infection compared to those with Gram positive infection. Mixed and Tuberculous infection excluded
from analysis.

could potentially be mistaken for EBE and should


be included in the differential diagnosis.
2. Children
The most commonly reported misdiagnosis in children was retinoblastoma,75,164 presumably a result of
the loss of a red reflex and the practical difficulties
of examining young children. One 13-month-old
child was misdiagnosed as having uveitis and cataract,11 and one case was not detected until routine
screening for retinopathy of prematurity, 30 days
post-delivery.63

VI. Investigations
A. MICROSCOPY AND CULTURE

1. Blood Culture
Blood culture is the most reliable way of establishing the diagnosis. In four large series of
EBE,36,102,135,191 blood cultures were more likely to
be positive than vitreous. Review of all 267 cases shows
that blood culture was the commonest means of confirming the diagnosis, and in our own case series
almost three-quarters of blood cultures were positive.
2. Intraocular Cultures
Although useful, blood cultures alone cannot be
relied upon to establish the diagnosis. In the absence of positive cultures from elsewhere, we advocate obtaining intraocular specimens in most
patients. In our own case series 56% of intraocular
specimens were positive. The two most common
methods of obtaining an intraocular specimen are
anterior chamber paracentesis (AC tap) and removal

of a vitreous sample using either needle aspiration or


a vitrectomy cutter. Clinical153 and experimental21,95
studies of exogenous endophthalmitis suggest that
vitreous samples are more reliable. Their reliability
in EBE is less clear. Greenwald et al advocated AC
taps for most patients requiring intraocular culture,
particularly those with predominantly anterior segment involvement. In our literature review, more
positive cultures were obtained from vitreous samples
than from AC taps, but the sensitivity of these investigations cannot be reliably determined, as few reports
detailed all negative investigations.
A study of 206 microbial culture results from patients with suspected endophthalmitis indicated that
washings from the vitrectomy cassette are more likely
to be positive than vitreous needle aspiration;53 however, it is not clear what proportion of these patients
had EBE. If a vitrectomy is not required a specimen
can still be obtained by aspirating 0.2 ml with a vitrectomy cutter. If the appropriate staff and facilities are
not available to take a specimen using a vitreous
cutter it may be preferable to obtain a vitreous needle
aspiration rather than delay obtaining a specimen or
the delivery of intravitreal antibiotics. If necessary,
vitreous needle aspiration and intravitreal injection
of antibiotics can be performed in adults under sterile conditions in the office, although in the United
Kingdom this procedure is usually performed in the
operating room.
Microscopy of a Gram stained film of a centrifuged
deposit of a vitreous aspirate or washings will usually
show pus cells and sometimes organisms. Cultures
should be set up both aerobically and anaerobically84,139 and incubated for up to 5 days. All pathogens in our case series were recovered within 24
hours.

416

Surv Ophthalmol 48 (4) JulyAugust 2003

3. Extraocular Cultures
Three-quarters of the patients in our case series,
and almost two-thirds of those in the literature review,
had at least one extraocular focus of infection. Although these involved a wide range of sites, lung,
liver, endocardium, and soft tissue were most commonly reported.
B. POLYMERASE CHAIN REACTION

PCR is becoming increasingly utilized in the diagnosis of endophthalmitis, and has a number of potential advantages.136,182 PCR greatly amplifies the
quantity of bacterial DNA available for analysis and
this may enable the detection of a single organism.138
The process of DNA replication can also be performed within a few hours. In one report, PCR of an
AC tap identified L. monocytogenes 3 days before the
definitive culture result.105 PCR is particularly helpful
in the detection of unusual organisms such as Tropheryma whippelii150 and Mycobacterium avium-intracellulare.152 It may also enable detection of organisms in
culture-negative samples, especially those that are obtained after antibiotic therapy has been commenced.182 PCR of extraocular specimens may also
help identify the causative organism, as demonstrated
in patient 13 of our own case series.
Although PCR is a rapid and highly sensitive test
it also has disadvantages. The high sensitivity may
lead to false-positive results, and specimens need to
be carefully collected and processed to avoid exogenous or cross-contamination.106 False-negative results
are also possible, particularly with unusual organisms.93 Careful control experiments are therefore
required if the results of PCR are to be meaningful.137,176 PCR may be used to rapidly establish the
presence of bacterial infection but may take 4872
hours for final species identification,93 and unlike
tradition culture techniques, it does not detect the
ability of an organism to replicate, or its antibiotic
sensitivity.106,138 In addition, PCR is not yet routinely
available182 and is of limited use in mixed infections.138 For these reasons PCR is likely to become a
useful adjunct to microscopy and culture, rather than
replacing it.

VII. Causative Organisms


Although our literature review suggests that EBE
is more commonly caused by Gram negative bacteria,
there was considerable regional variation. In a large
literature review, Wong et al191 compared cases of
EBE reported from East Asian hospitals with those
from the world literature. In East Asia, EBE was overwhelmingly caused by Gram negative organisms,
particularly Klebsiella spp. Cases reported from outside

that region were more likely to be caused by Gram


positive organisms. Unusual organisms may be more
likely to get reported, but Wongs own case series
considered all patients presenting with EBE and
found that Gram negative organisms were responsible for 70% of infections. A comparable large series
from North America135 found that only 32% of
cases were caused by Gram negative organisms. In
our own case series 37% of patients had Gram negative infection.
A major difference between this and previous literature reviews71,162 is the significant increase in klebsiella infection (Table 6). Klebsiella is now the most
commonly reported species responsible for EBE.
There is a particularly high incidence of klebsiella
infection in East Asia where the K1 and K2 serotypes
are most common.65 In Wongs review,191 Klebsiella
spp. accounted for about 90% of EBE cases from that
region and 80% of cases in the present review were
from East Asian hospitals.29,30,34,36,81,99,102,104,186,191
The reason for this apparent predisposition to
klebsiella EBE is not clear, but there is also a high
incidence of klebsiella liver abscesses in this population.29,30 Patients with klebsiella liver abscess have
a 3% risk of developing EBE29 and our literature
review found that almost two-thirds of patients with
klebsiella EBE also had a liver abscess.
In our literature review, 54% of patients with klebsiella EBE were diabetic compared to 27% of those
with EBE caused by other organisms (Fishers exact
test: p 0.0001). Although diabetes predisposes to
klebsiella liver abscesses,117 the incidence of diabetes
was also high (55%) in patients with klebsiella EBE
whose liver was not affected. This suggests that the
association between klebsiella EBE and diabetes is
not always mediated by infections of the hepatobiliary system.
There was an increase in reports of EBE caused by
P. aeruginosa. A quarter of the patients who developed
pseudomonal EBE were neonates and half were
under 25 years of age. In older patients there was a
high proportion who developed infection following
medical intervention such as urinary catheterization
or immunosuppression. Previous literature reviews71
observed a reduction in the number of adult cases
caused by N. meningitidis and this was also evident in
the present review. However, N. meningitidis remained an important pathogen in children, in
whom Gram negative infections predominated. Bacillus
cereus EBE was less common than in previous reviews,71 but it remained an important cause of infection in IVDU.42,79,125,135,181 In the present literature
review, all six patients with B.cereus EBE had a history
of IVDU, and all required evisceration or enucleation
of the affected eye.

417

ENDOGENOUS BACTERIAL ENDOPHTHALMITIS

VIII. Treatment
A. INTRAVITREAL ANTIBIOTICS

1. Role in Endogenous Endophthalmitis


Just over half of the patients in our literature review
were treated with intravitreal antibiotics. This reflects
debate in the literature regarding their role in EBE.
Many topical, subconjunctival, and systemic antibiotics do not reach therapeutic levels within the vitreous12 and this may explain why patients can develop
EBE while on appropriate systemic antibiotics, despite therapeutic blood levels.169
Wong et al performed univariable analysis of visual
outcome in a large literature review of EBE191 and
found that intravitreal antibiotics did not significantly
improve visual prognosis. This was similar to the results of the present literature review, however our
univariable analysis suggested that eyes that received
intravitreal antibiotics were less likely to require evisceration or enucleation. This difference was not significant with multivariable analysis, but there may
be considerable selection bias, as many clinicians
choose intravitreal antibiotics for patients with severe
infection, or those that fail to respond to systemic
treatment.19,71,97
We advocate combined vitreous biopsy and intravitreal injection of antibiotics as a relatively simple procedure that may help establish the diagnosis, and
delivers rapid therapeutic levels of intraocular antibiotic. In the four largest series36,102,135,191 of EBE,
82% (65/78) of patients underwent vitreous biopsy
and 81% (63/78) received intravitreal antibiotics.
Not all authors agree with this treatment strategy; in
particular, Greenwald et al concluded that intravitreal antibiotics are not required for most patients.71
In the absence of randomized trials of intravitreal
antibiotics it seems reasonable to select intravitreal
antibiotics on an individual case basis. The treatment
of EBE must also be balanced with the need to
treat systemic disease in a facility that provides adequate general medical support.

be safe in primate studies23 of exogenous endophthalmitis and clinical studies of postoperative endophthalmitis found that it had a similar,74 or
better,83 spectrum of activity than amikacin. There
have been no equivalent studies of EBE, but in
the present case series all Gram negative organisms
were sensitive to ceftazidime.
B. INTRAVITREAL STEROIDS

Ten percent of patients in our literature review


were treated with intravitreal steroids (usually dexamethasone 0.4 mg) with the aim of diminishing intraocular tissue destruction from the host
inflammatory response.158 Most,116,142,170 but not
all,121 animal experiments suggest that intravitreal
dexamethasone helps preserve retinal structure and
function. These studies relied on direct intraocular
inoculation of rabbit eyes, and they therefore simulated exogenous, rather than endogenous, endophthalmitis. Compared to humans, rabbits have an
exaggerated, intraocular inflammatory response to a
wide range of insults. The results of these studies
must therefore be interpreted with caution.
There have been no randomized clinical trials of
intravitreal steroids for the treatment of either exogenous or endogenous endophthalmitis. A recent retrospective study161 of postoperative endophthalmitis
indicated that patients treated with intravitreal dexamethasone had a worse visual outcome than those
that did not. The authors conceded that confounding
variables could not be excluded but recommended
caution in the use of intravitreal steroids. The present
literature review found that eyes treated with intravitreal steroids were more than four times more likely
to retain useful (count fingers or better) vision that
those that did not. This result also needs to be
interpreted with caution given the relatively small
numbers involved, and the potential influence of
confounding variables.
C. VITRECTOMY

2. Choice of Agent
Although 1 to 2 mg vancomycin is the intraocular
antibiotic most commonly chosen for treatment of
Gram positive infection, the choice of antibiotic for
Gram negative infection is contentious.52 Most ophthalmologists no longer use intravitreal gentamicin
because of the risk of macular infarction.22 Many now
use amikacin (0.4mg) instead, despite the known risk
of retinal toxicity22,24,86 and dilution errors19 from
this aminoglycoside. In view of these risks, several
authors recommend intravitreal ceftazidime (2 mg
in 0.1 ml).22,24,32,86 Ceftazidime has been shown to

The present literature review suggests that eyes


that undergo vitrectomy are almost three times more
likely to retain useful vision than those that do not,
and more than three times less likely to require evisceration or enucleation. As with the analysis of the
effect of intravitreal steroids and antibiotics on visual
outcome, the influence of confounding variables
cannot easily be determined. The theoretical advantages of vitrectomy include removal of the infecting
organisms, endotoxins, exotoxins, and vitreous membranes that could lead to retinal detachment, clearing of vitreous opacities, collection of abundant
material for culture, and possibly better distribution

418

Surv Ophthalmol 48 (4) JulyAugust 2003

of intravitreal antibiotics.57 The disadvantages of vitrectomy include the added cost and inconvenience,
and the risk of anesthetic and surgical complications,
such as cataract formation.

IX. Prognosis
The visual outcome of EBE has not improved in
55 years. Review of the literature from 19761985
showed that 41% of patients had count fingers vision
or better, 26% were blind, and 29% required evisceration or enucleation.71 Similar figures were reported
over the preceding 30 years.162 Review of the literature since 1986 also indicates a poor outcome, with
equivalent figures of 32%, 44%, and 25% (Fig. 1).
The studies that investigated prognostic factors in
EBE71 were retrospective, and although selection bias
cannot be excluded, they identified several factors
that adversely effect prognosis. These included delay
in diagnosis;71 use of inappropriate antibiotics;187 diffuse infection of the vitreous and retina, or panophthalmitis;71 infection with virulent organisms;191 and
Gram negative infection.71,191 The present literature
review also suggests that Gram negative infection
carries a poor prognosis and our case series indicates
that poor VA at presentation is associated with poor
visual outcome.
EBE had an appreciable mortality rate with 5% of
patients in our literature review dying as a direct
result of extraocular infection. This may be lower
than expected as a prospective study of patients with
bacteremia reported that those with even minor
ocular lesions had a mortality rate of 32%.17

X. Pathogenesis
EBE occurs when bacteria cross the bloodocular
barrier, resist host defenses, and multiply within the
eye. The bloodocular barrier may prevent many organisms reaching the internal ocular spaces as relatively few bacteremic patients develop EBE. In one
prospective study of 202 patients with bacteremia,
none developed EBE although 12 developed minor
ocular lesions such as cotton-wool spots and microhemorrhages.17 Another prospective study of 101 patients with septicemia131 reported that 24 patients
developed minor ocular lesions and one developed
EBE.
Most studies of EBE failed to differentiate between
community and hospital acquired infection. Seventeen of 19 (89%) patients in our own case series
had community acquired infection. Blood culture
positive EBE accounted for only 0.24% (14/5859) of
all cases of bacteremia in our hospital, and 0.44%
(12/2740) of community acquired bacteremias.

Although the choroid is not protected by the


bloodocular barrier, there were few reports of choroidal abscesses. This is perhaps unexpected given
that 70% of the ocular blood volume is found in the
choriocapillaris143 and injection of live bacteria into
the carotids of dogs can produce multifocal choroidal
lesions.123 Possible reasons for the apparent predisposition to infection of the retinal circulation include
the fact that it is an end-artery system, the avascular
vitreous may act as a bacterial reservoir, and the
bloodocular barrier may interfere with the host inflammatory response.
Bacteria that cross the bloodocular barrier do not
necessarily cause EBE. Roths spots are septic retinal
emboli and occur in about 1% of bacteremic patients,17,131 but not all patients with Roths spots progress to EBE.17,131 This suggests that the host immune
response can eliminate small infective foci. It is not
known why some patients develop EBE but it may
relate to the size of the inoculum, immunodeficiency, the virulence of the organism, and co-morbidity
such as diabetes.
Diabetes was common in patients in both our case
series and literature review, but the incidence of diabetes in bacteremic patients without EBE is similar
(1928%).17,131 This suggests that diabetes is associated with bacteremia rather than EBE per se. However, the incidence of diabetes was particularly high
in patients with klebsiella EBE. The reason for this
association is not well understood.29

XI. Pathology
Animal experiments suggest that tissue damage results from a combination of direct invasion of ocular
tissue by bacteria, the release of bacterial toxins, and
the host inflammatory response. Callegan et al21
studied the effect of intravitreal injections of rabbit
eyes with live S. aureus, Bacillus cereus, and Enterococcus faecalis, as well as bacterial cell walls and exotoxins. B.cereus directly invaded the retina and cornea,
and both S.aureus and B.cereus reduced the electroretinogram response, indicating functional retinal impairment. In contrast, the supernatant from cultures
of E.faecalis was not directly toxic to the retina but
induced a marked inflammatory response, as did injection of bacterial cell walls, albeit to a lesser degree.
Similar studies with P. aeruginosa,92 Staphylococcus epidermidis,92 and Klebsiella oxytoca122 also suggest that
the host response is an important cause of tissue
damage and that irreversible photoreceptor degeneration may occur within 24 hours of inoculation.122 By
directly inoculating the vitreous cavity, these studies
created exogenous rather than endogenous endophthalmitis. As noted by Greenwald et al,71 the route

419

ENDOGENOUS BACTERIAL ENDOPHTHALMITIS

of infection is important as this will influence the


integrity of the blood-ocular barrier. Experimental
studies of exogenous endophthlamitis do provide
helpful data on intraocular infection, but their findings cannot be directly applied to EBE.

XII. Guidelines for Reporting EBE


Large randomized studies of EBE are unlikely to be
forthcoming in the near future. The quality of case
reports is therefore important, as these form the principal evidence base. Some case reports provide inadequate details of the presentation, management, and
outcome of EBE. We therefore advocate that the
following minimum information is included when
reporting cases of EBE: age; sex; affected side(s);
ocular clinical features including classification using
Greenwalds system;71 systemic features and extraocular foci of infection; presence of any underlying
disease known to predispose to infection; any misdiagnosis or delay in diagnosis; results of blood culture,
intraocular Gram stain and culture (positive, negative, or not done); positive cultures from other sites;
ophthalmic procedures undertaken; details of any
intraocular and systemic antibiotic therapy; final VA
expressed as Snellen fraction, counting fingers vision,
hand movements vision, light perception, no perception of light, evisceration, or enucleation; and
survival.
Most cases included in the larger series of
EBE135,191 were confirmed by either positive blood
or intraocular culture. In the present series, 18 of 19
cases were confirmed in this manner. One (patient
13) had Gram negative diplococci in an intraocular
specimen and PCR of a skin scraping confirmed N.
meningitidis. However, for most case reports, either
positive blood or intraocular culture should be provided. Specific exclusion criteria should also be applied, as detailed in the Methods section of the
present case series.

XIII. Conclusions
EBE has a poor visual prognosis that has not improved in over half a century. There are several possible reasons for this. First, EBE is very uncommon yet
it may mimic several common ophthalmic conditions.
This may explain why many patients are initially misdiagnosed. EBE can be rapidly progressive and delayed
treatment may result in a poor outcome. Second, clinicians may fail to appreciate the overlap of ocular and
extraocular disease. Third, there have been no large
prospective studies of EBE to determine the benefits
of intravitreal antibiotics, intravitreal steroids, and vitrectomy. Lastly, there is a significant increase in reports of klebsiella EBE, which may be associated with
a poor visual prognosis.191

Most patients with EBE have underlying medical


conditions that may be undiagnosed at initial presentation. Extraocular foci of infection are also
common and are associated with an appreciable mortality rate. EBE must therefore be regarded as both
an ocular and extraocular disease. If the outcome of
EBE is to improve then ophthalmologists, physicians
and microbiologists need to have a high level of
awareness of this rare, but potentially blinding and
fatal condition.

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The authors wish to thank Andrew Hutchings, London School
of Hygiene and Tropical Medicine, for statistical support. Dr Jackson
was supported by a research grant from the Lady Anne Allerton Fund
and a personal training award from the Special Trustees of St
Thomas Hospital. The authors reported no proprietary or financial
interest in any product mentioned or concept discussed in this
article.
Correspondence: Tim Jackson, Academic Department of Ophthalmology, The Rayne Institute, St Thomas Hospital, London SE1
7EH, United Kingdom.

Outline
I. Methods
A. St Thomas case series
B. Literature review
II. Results
A. St Thomas case series
B. Literature review
III. Patient characteristics
IV. Clinical features
V. Diagnosis
A. Incidence of diagnostic errors
B. Differential diagnosis
1. Adults
2. Children
VI. Investigations
A. Microscopy and culture
1. Blood culture
2. Intraocular cultures
3. Extra-ocular cultures
B. Polymerase chain reaction
VII. Causative organisms
VIII. Treatment
A. Intravitreal antibiotics
1. Role in endogenous endophthalmitis
2. Choice of agent
B. Intravitreal steroids
C. Vitrectomy
IX.
X.
XI.
XII.

Prognosis
Pathogenesis
Pathology
Guidelines for reporting endogenous bacterial endophthalmitis
XIII. Conclusions

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