ESCRS Guidelines on prevention, investigation and ... · 1.1 Endophthalmitis Endophthalmitis is an...

ESCRS Guidelines on prevention, investigation

and management of post-operative endophthalmitis

Version 2

August 2007

EditorsPeter Barry, Wolfgang Behrens-Baumann,

Uwe Pleyer & David Seal

Supported by

Endop Guidelines 2007 15/8/07 6:42 pm Page f1

1. INTRODUCTION 1

1.1 Endophthalmitis 1

1.2 Pathophysiology 1

1.3 Microbial spectrum 2

1.4 Incidence of endophthalmitis after different types of surgery 3

2. PROPHYLAXIS 8

2.1 Operating theatre 8

2.2 Antisepsis 8

2.3 Antibiotics 9

2.4 Limitations of the ESCRS Study 12

2.5 FLOW CHART – PROPHYLAXIS GUIDELINES 14

3. DIAGNOSIS 15

3.1 Commencement and symptoms 15

3.2 FLOW CHART – DIAGNOSTIC GUIDELINES FOR ACUTE VIRULENT ENDOPHTHALMITIS 16

3.3 FLOW CHART – DIAGNOSTIC GUIDELINES FOR CHRONIC ENDOPHTHALMITIS 17

3.4 Differential diagnosis – the toxic anterior segment syndrome 18

4. INVESTIGATION 19

4.1 AC tap, vitreous tap, vitrectomy for Gram stain, culture and PCR tests 19

4.2 Epidemiology 19

5. TREATMENT 20

5.1 Surgical management of endophthalmitis. Diagnostic and therapeutic vitrectomy 20

5.2 Anti-microbial therapy 22

5.3 Anti-inflammatory therapy 25

5.4 Other types of post-operative endophthalmitis 25

5.5 Limitations of EVS study 26

5.6 FLOW CHART – TREATMENT GUIDELINES FOR ACUTE VIRULENT ENDOPHTHALMITIS 27

5.7 FLOW CHART – TREATMENT GUIDELINES FOR CHRONIC ENDOPHTHALMITIS 28

6. REFERENCES 29

7. APPENDIX (Addresses of Contributors) 36

Contents

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1.1 Endophthalmitis

Endophthalmitis is an inflammatory reaction occurring as a result of intraocular colonisation by bacteria,fungi or rarely parasites. It can be exogenous (post-operative, post-traumatic) due to microbial contaminationspreading from the ocular surface or open incision (wound) or contaminated instruments, intraocular lenses(IOLs) or intraocular foreign bodies or endogenous (septicaemia) in origin.

These guidelines on the prophylaxis and treatment of post-operative endophthalmitis are supported in detailwith literature references, which were classified according to the criteria of the Arbeitsgemeinschaft derWissenschaftlichen Medizinischen Fachgesellschaften (AWMF) [Association of the Scientific MedicalSocieties in Germany] and the Ärztliches Zentrum für Qualität [Agency for Quality in Medicine] for evidence-based medicine (EBM) (Table 1.1). This enables the reader to form an accurate opinion of the value of theindividual views stated. At the same time, he or she is able to form an opinion him/herself from theextensive literature. Ultimately, it is apparent that there is a lack of well-founded prospective and controlledstudies of many procedures - an important task for the future. Results of the recently completed ESCRSStudy on the Antibiotic Prophylaxis of Post-operative Endophthalmitis (ESCRS Study) have been included inthese Guidelines.

Table 1.1 Classification of evidence type of studies

1.2 Pathophysiology

The occurrence, severity and clinical course of endophthalmitis depends on the route of infection, thevirulence and number of inoculated pathogens as well as the patient's immune state and the time ofexamination [205]. In 29 to 43 per cent of cataract operations, intraocular contamination occurs withfacultative pathogenic bacteria from the ocular surface without the development of endophthalmitis [41],[68], [106]. Protective mechanisms, which have been summarised as the “immune privilege of the eye“(anterior or posterior chamber-associated immune deviation, ACAID or POCAID) [205], are particularlyeffective in the anterior part of the eye, act as a protective barrier and can limit the inflammatory reaction[191], [198]. If this privilege is compromised, e.g. by an intra-operative capsular defect with vitreous loss,the risk of endophthalmitis increases by a factor of 14 [98].

In microbial endophthalmitis, three phases of infection can be observed: an incubation phase, anacceleration phase and a destructive phase [173]. A clinically inapparent incubation phase is observedinitially, which lasts at least 16 to 18 hours, even with virulent micro-organisms. Intraocular bacterialinoculation above a critical level then leads to breakdown of the aqueous barrier with fibrin exudation andcellular infiltration by neutrophilic granulocytes [24]. The incubation phase is determined mainly by thegeneration time of the pathogen (e.g. Staphylococcus aureus and Pseudomonas aeruginosa up to 10 min,Propionibacterium sp. > 5 h) and the specific characteristics of the pathogen such as toxin production. Withthe commonest pathogens, Staphylococcus epidermidis (CNS) and Staphylococcus aureus, the greatestinfiltration is observed only three days after infection [24], [39].

In the case of primary infection of the posterior part of the eye, inflammation of the anterior chamber occursinitially and this is accompanied within seven days by a specific immune response with macrophages andlymphocytes in the vitreous cavity. Just three days after intraocular infection, pathogen-specific antibodiescan be detected, which contribute to pathogen elimination by opsonisation and phagocytosis within about

Stage Evidence based on:

I a meta-analysis of randomised controlled studies

I b at least one randomised controlled study

II a at least one well-designed controlled study without randomisation

II b at least one well-designed, quasi-experimental study

III well-designed, non-experimental descriptive studies(e.g. comparative studies, correlative studies, case-control studies)

IV reports/opinions of expert circles, consensus conferencesand/or clinical experience of acknowledged authorities

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1. Introduction

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10 days. This can produce negative laboratory culture results but severe inflammatory disease within the eye[39]. The inflammatory mediators of infiltrating cells, especially cytokines, not only recruit further leukocytesbut can directly result in destructive effects, retinal injury and vitreoretinal proliferation (destructive phase)[30], [205].

It has been suggested that the use of phacoemulsification increases pressure within the eye forcing bacteriabackwards into the vitreous, where early multiplication gives rise to the anterior vitritis characteristically seenbehind the posterior capsule (refer to Investigation Section below).

Intraocular lenses are a potential vector for bacteria. There are differences in adherence to different lensmaterials. Staphylococcus epidermidis adheres more to polypropylene haptics than to polymethyl methacrylate,(PMMA) [69], [98], [190]. Hydrophilic heparin-coated lenses demonstrate lower adherence for staphylococci[52]. The clinical effects have been variously interpreted [106]. A recent retrospective study has suggested,but not proven, that use of foldable IOLs inserted via a sterile injector lowers the incidence of post-operativeendophthalmitis [95].

1.3 Microbial spectrum This is described in the table of post-operative endophthalmitis below. The spectrum is dependent on variousfactors including environmental, geographic and climatic conditions and which type of surgery is performed.

Table 1.2: Microbial spectrum of post-operative endophthalmitisIn summary, the most important pathogens causing post-operative phacoemulsification endophthalmitis are:

Post-traumatic endophthalmitis

Single pathogen identified in 62–65%, mixed infection in 12–42% [57], [91], [125], [130], [205],[207], [208]

16 - 44 % CNS17 - 32 % Bacillus sp.

10.5 - 18 % Gram-negative bacteria8 - 21 % Streptococci4 - 14 % Fungi

4 - 8 % Corynebacterium sp.1 - 2 % Clostridum perfringens and other soil bacteria

Delayed post-operative (glaucoma surgery) endophthalmitis [78], [142]

StreptococciGram-negative bacteria (especially Haemophilus influenzae)

Post-operative (glaucoma surgery) endophthalmitis [116], [124]

up to 67 % CNS

Delayed post-operative saccular or capsule bag endophthalmitis with IOL implantation

Propionibacterium acnes, corynebacteria including C. macginleyi [164], [175], [205] and fungi [205]

Post-operative (cataract surgery) endophthalmitis [46], [70], [81], [100], [102], [105], [134], [205], [207]

33 - 77 % CNS (coagulase-negative staphylococci)

10 - 21 % Staphylococcus aureus

9 - 19 % BHS (ß-haemolytic streptococci), S. pneumoniae, ∂-haemolyticstreptococci including S. mitis and S. salivarius

6 - 22 % Gram-negative bacteria including Ps. aeruginosa (occurs rarely)

up to 8 % Fungi (Candida sp., Aspergillus sp., Fusarium sp.)

2


In the ESCRS Study, 29 patients presented with presumed post-operative endophthalmitis, of whom 20 wereclassified as having proven infective endophthalmitis. The causative bacteria were identified bymicrobiological methods and polymerase chain reaction (PCR) [11]. From 19 cases the following bacteriahave been confirmed:

In summary, the most important pathogens causing post-operative phacoemulsification endophthalmitis are:

Acute■ BHS, S. mitis, S. pneumoniae, E. faecalis■ S. aureus, CNS, (MRSA, MRSE) ■ Gram-negative rods (GNR) including Haemophilus influenzae and Pseudomonas aeruginosa

Chronic■ P. acnes■ Diphtheroids ■ CNS■ Fungi

1.4 Incidence of endophthalmitis after different types of surgery

PhacoemulsificationAt the start of the 20th century (c1910), the incidence of endophthalmitis after cataract operations was 10per cent. In the period of ECCE via a scleral or limbal incision and improved hygiene conditions (1970-1990), the infection rate fell to 0.12 per cent in Europe [90] and to 0.072 per cent in the US [88].However, since the introduction of phacoemulsification and clear cornea incisions, the retrospective datawith phacoemulsification are between 0.3 to 0.5 and 0.015 per cent (Table 1.3).

Table 1.3: Reported incidence for endophthalmitis after cataract surgery

Country [reference] Year of Publication Incidence (%) No. of Operations

USA [98] 1991 0.22 24105

USA [203] 1992 0.015 27181

France [40] 1992 0.32 ~ 34690

Germany [126] 1999 0.15 ~ 103090

Netherlands [135] 2000 0.10 ~ 25330

Canada [64] 2000 0.01 to 0.18 13886

Sweden [37] 2002 0.10 54666

Australia [110] 2003 0.16 to 0.36 83677

Japan [8] 2003 0.05 to 0.29 11595

USA [86] 2005 0.29 9079

Ireland [87] 2005 0.5 8763

UK [105] 2007 0.099 101920

Sweden [94] 2007 0.048 225471

Europe [5] 2007 0.05 to 0.35 16211

Staphylococcus epidermidis 6CNS 4Staphylococcus aureus 2other staphylococci 1Streptococcus pneumoniae 2other streptococci 6Propionibacterium acnes 1Gemella haemolysans 1

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While in the majority of studies patients received various additional forms of prophylaxis, the higherincidence rate reported by the ESCRS [5] may be regarded as the true background rate when only povidone-iodine is administered pre-operatively.

Risk factors for endophthalmitis following cataract surgeryThe clear cornea incision is thought to have contributed to the increase in the number of endophthalmitiscases following phacoemulsification surgery [8], [64], [197], [205]. Taban (2005) performed a meta-analysis of 215 studies that addressed post-cataract surgical endophthalmitis which met his selectioncriteria [129]. A total of 3,140,650 cataract extractions were pooled from ECCE and phacoemulsificationsurgery giving an overall incidence of 0.128 per cent for post-operative endophthalmitis. He found thisincidence varied with time from 0.265 per cent in 2000/2003, 0.087 per cent in the 1990s, 0.158 percent in the 1980s to 0.327 per cent in the 1970s. He found the clear corneal incision ofphacoemulsification to be a risk factor between 1992 and 2003 with an increased rate of 0.189 per centcompared to 0.074 per cent for scleral tunnel incision. However, Taban reviewed the limitations of his meta-analysis study depending mostly on retrospective studies with limited statistical power. He commented onthe paucity of prospective randomised case-controlled studies.

Wallin et al. identified potential risk factors in a study of 27 endophthalmitis cases compared with 1525patients in the cohort control. Main factors found to be statistically associated with endophthalmitisincluded i) wound leak on the first post-operative day (p<0.001), ii) capsular or zonular surgicalcomplication (p<0.001), and iii) use of topical antibiotic started the day after surgery rather than the day ofsurgery (p=0.005) [136].

There are only a few data on the incidence of endophthalmitis between inpatient and outpatient surgeryrespectively. Various studies give no evidence of any difference [56], [84], [118], [143].

There is a range of technical factors relating to the cataract operation that influence the risk ofendophthalmitis. With regard to the incision, leak-proof closure plays an important role. When the clearcornea incision (CCI) was first used, the data regarding the incidence of infection tended to be poor; in1991, Stonecipher et al. published three cases of infectious endophthalmitis after CCI [128] and describedhow 65 per cent of all CCIs demonstrated wound dehiscence [197]. Williams et al. reported that they foundan infection rate of only 0.015 per cent in nearly 30,000 CCIs [203].

The risk of wound dehiscence appears to be greater with CCI [192] than with the corneo-scleral (scleraltunnel) incision (CSI). In Germany, there was an incidence rate of endophthalmitis after CCI of 0.1 per centversus 0.07 per cent for CSI [126], in Canada the rate was 0.13 per cent for CCI versus 0.05 per cent forCSI [64]. However, in a recent prospective randomised multi-centre study (11,595 eyes), theendophthalmitis risk was reduced fivefold in superior CSI (p = 0.037) compared to temporal CCI [8].

Recently published data from the Swedish National Cataract Register including 225471 cataract extractionsbetween January 2002 and December 2004 showed only a trend for a higher risk of endophthalmitis forCCI. This prospective, non-randomised, observational study indicated that the use of clear corneal and/ortemporal approaches would result in one additional post-operative endophthalmitis case in approximately5500 procedures compared to sclero-corneal or superior incisions [94]. However, not reaching statisticalsignificance may have been a consequence of the widespread use of prophylactic intracameral cefuroximewith its low overall rate of post-operative endophthalmitis in Sweden.

The clear corneal incision as a risk factor has been assessed prospectively in the multi-centre ESCRS studyof antibiotic prophylaxis of endophthalmitis with similar results. Patients receiving the clear corneaprocedure were found to be 5.88 times more likely to experience endophthalmitis than patients receivingscleral tunnel. While the risk associated with CCIs remains an important finding of the study, the resultsmust be treated with caution. Only two of the participating 24 centres used scleral tunnel incisionsroutinely, with none of the others using it more than occasionally. It is therefore conceivable that thereduced risk associated with the scleral tunnel technique is due to some other unidentified factors commonto both centres, but absent from most of the other centres in the study [5].

An important factor appears to be the construction of the tunnel. In CSI the tunnel is more quadratic, whereas in CCI often double wide than radial and thus more prone to gaping. Therefore, the increased riskassociated with CCI may be reduced by suturing the corneal incision [183]. Thoms et al. reviewed rates ofendophthalmitis among 815 consecutive eyes that received clear corneal cataract surgery over five years. Ofthese, the incision was sutured in 436 eyes and unsutured in 379 eyes. The researchers found five cases ofculture-positive endophthalmitis, all of which occurred in the unsutured group [132].

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In a case-control study of post-operative endophthalmitis cases in Sweden between 1994 and 2000, Wejde et al. foundthat silicone intraocular lenses carried a higher risk than heparin surface modified PMMA implants [138]. Likewise, inthe prospective ESCRS study, the type of IOL material was found to be a risk factor which was significantly associatedwith endophthalmitis. Patients receiving a silicone intraocular lens were 3.13 times more likely to experienceendophthalmitis than patients receiving an acrylic (or other material) lens. The hydrophobic nature of silicone may notbe the main characteristic explaining the apparent increased risk; the explanation is likely to be more subtle involvingan understanding of how differing biofilms are formed based on the surface properties of varying types of IOLs [5].

Finally, the ESCRS study demonstrated that surgical complications contribute to a higher incidence of contractingendophthalmitis following phacoemulsification cataract surgery. Patients experiencing complications at the time ofsurgery had a 4.95 times higher risk of infection [5].

There are no definite data with regard to other factors such as duration of operation, tissue trauma, and choice ofviscoelastic and irrigation solution [127], while there is limited retrospective data for use of injectors for lens (IOL)implantation, suggesting they reduce the infection rate [95], and operative experience, suggesting a higher complicationrate by junior staff. All these factors have been assessed prospectively in the multi-centre ESCRS study (Table 1.4).

Because of the low incidence of childhood cataract, an exact estimate of the endophthalmitis risk in this patientpopulation is not possible. In 1990, Good et al. found three cases of endophthalmitis after 671 operations forpaediatric or congenital cataract (0.45 per cent). Two of the three cases occurred within the first 24 hours and Gram-positive bacteria were isolated as the cause (S. aureus, S. epidermidis, Strep. pneumoniae) [76]. Wheeler et al. reported11 cases of endophthalmitis after cataract surgery out of 24,000 cataract or glaucoma operations in children [139].

Table 1.4: Risk factors for endophthalmitis following phacoemulsification surgery beinginvestigated in the ESCRS multi-centre study

Glaucoma surgeryEarly post-operative endophthalmitis following glaucoma surgery has an incidence of about 0.1 per cent [89], [142].However, the majority of cases of endophthalmitis after glaucoma surgery occur after months or years; the incidence isabout 0.2 per cent to 0.7 per cent [89], [142]. The risk of endophthalmitis when using anti-metabolites depends,among other things, on the location of the filter bleb, where the inferior position has a markedly higher risk (Wolner:three per cent with superior vs. 9.4 per cent with inferior position, Greenfield: 1.3 per cent with superior vs. 7.8 percent with inferior position, Caronia: 11.9 per cent with inferior position, Higginbotham: 1.1 per cent with superior vs. 8per cent with inferior position) [59], [78], [82], [142]. After 5-FU the incidence of endophthalmitis is 5.7 per cent[142].

In children, six cases of endophthalmitis after glaucoma surgery were reported after 24,000 cataract and glaucomafiltering operations [139]. However, it is not reported how many of the 24,000 operations were glaucoma surgeriesalone.

Endophthalmitis after filter bleb operation commences within four weeks in about 19 per cent, so the majority of casesoccur later [92], [123]. In about half of the cases, the infection is due to streptococci and Gram-negative bacteriaincluding Moraxella sp. [55], [60], [181]. The endophthalmitis is sometimes preceded for days or weeks by eyebrowpain, headache, blepharitis and conjunctivitis [123]. Filter bleb infection can still occur after many years [60], [78],[142].

Risk Factor Odds Ratio

Intra-cameral injection of cefuroxime – given or not given 4.92

Clear cornea (and position) versus scleral tunnel incision 5.88

Type of wound closure – suture or sutureless no evidence found

Insertion of IOL – injector or forceps not retained as a risk factor

Type of IOL material 3.13

Diabetic or non-diabetic no evidence found

Immuno-suppression or not no evidence found

Equipment sterilisation – disposable vs reusable no evidence found

Complications of surgery 4.95

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Penetrating keratoplastyThe incidence of post-operative endophthalmitis after penetrating keratoplasty reported in the literature isbetween 0.08 per cent and 0.2 per cent (Eifrig: 0.08 per cent, Kattan: 0.11 per cent, Somani: 0.2 percent) [71], [88], [127]. Contamination of the donor cornea appears to be an important risk factor [152].Fungal endophthalmitis after keratoplasty tends to be rare [99], [151], [189].

Pars plana vitrectomyThe incidence of post-operative endophthalmitis reported in the literature after pars plana vitrectomy isbetween 0.05 per cent and 0.14 per cent [83], [88]. A few authors assumed that there was an increasedincidence of endophthalmitis after pars plana vitrectomy, as the patient often suffers at the same time from,for example, diabetes mellitus. However, this assumption has not been confirmed.

The largest sample size comes from Cohen et al. in 1995 with 12,216 vitrectomies in eight centres; ninecases of endophthalmitis were reported with an incidence of 0.07 per cent [63]. Since then, Jager et al.have presented a retrospective review for 1972-2002 with 10,563 intravitreal taps in 1326 eyes from 42published reports [171]; the overall incidence of endophthalmitis was 0.17 per cent (18 cases). For thosevitrectomies performed in the operating theatre, the rate was 0.11 per cent (4/3720) while for thoseperformed in out-patients, the rate was 0.17 per cent (5/2965) which was not statistically significant.However, when there was use of topical povidone iodine prior to the tap, the incidence rate was 0.14 percent (9/6314), which increased to 0.69 per cent (6/869) when iodine was not used - this is statisticallysignificant at p = 0.0009, but relates to multiple taps in non-inflamed eyes.

Post-traumatic endophthalmitisPost-traumatic endophthalmitis, along with post-operative endophthalmitis, is the second commonest formof endophthalmitis. The incidence of endophthalmitis after perforating injury is between two per cent and17 per cent [75], [154].

Trauma due to an intraocular foreign body involves a greater risk of endophthalmitis than trauma without aforeign body [131]. The signs of infection usually occur early, but are often masked by the post-traumaticreactions of the injured tissue.

An exact history (e.g. “did the accident happen in the country or in the city?”, type of foreign body,symptoms) enables an early diagnosis to be made. In rural districts, the occurrence of post-traumaticendophthalmitis was reported in 30 per cent of 80 patients after an injury. In contrast, post-traumaticendophthalmitis occurred in 11 per cent of 204 patients in non-rural districts [154].

The start, course and symptoms of endophthalmitis after trauma are very varied, corresponding to thecausative organisms. The initial symptoms are usually pain, intraocular inflammation, hypopyon and vitreousclouding. Similar to post-operative endophthalmitis, two thirds of the bacteria in post-traumaticendophthalmitis are Gram-positive and 10 to15 per cent are Gram-negative [25]. In contrast to post-operative endophthalmitis, virulent Bacillus species are the commonest pathogens in post-traumaticendophthalmitis. They were isolated in 20 per cent of all cases of post-traumatic endophthalmitis. In therural population, they are found in 42 per cent of cases of post-traumatic endophthalmitis. They are thesecond commonest cause of all cases of endophthalmitis. Most Bacillus infections are associated withintraocular foreign bodies [154]. Infections that are caused by Bacillus species usually commence with rapidloss of vision together with severe pain.

Fungi are the causative organisms in 10 to 15 per cent of cases of endophthalmitis after trauma. Fungalendophthalmitis usually commences only weeks to months after the injury. While mixed infections tend to berarer in post-operative endophthalmitis, they were isolated in 42 per cent of the trauma-associated cases ofendophthalmitis [154].

Compared to post-operative endophthalmitis, the prognosis of post-traumatic endophthalmitis is usuallypoor. This is due to a spectrum of more virulent pathogens, to mixed infections, to the degree of tissueinjury caused by the preceding trauma and to the failure to instil prophylactic intravitreal antibiotics at thetime of surgery. While final vision of 20/400 or better occurs in 85 per cent of cases of post-operativeendophthalmitis, patients with post-traumatic endophthalmitis achieve a final vision of 20/400 or better inonly 26 to 54 per cent with the remaining losing all vision [49], [57], [114], [131].

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Medical conditions

Diabetes mellitusAbout 14 to 21 per cent of all patients who develop post-operative endophthalmitis after cataractoperations are diabetic [67], [122]. However, pre-existing diabetes mellitus has not been confirmed as anisolated risk factor for post-operative endophthalmitis after cataract extraction [4], [5]. If endophthalmitisoccurs in diabetics after cataract extraction, however, the functional prognosis must be regarded as poorerespecially if diabetic retinopathy is present pre-operatively [67]. Endophthalmitis in diabetics is causedmore often by Gram-negative bacteria than in non-diabetics [122]. In the EVS, endophthalmitis patientswith diabetes mellitus benefited particularly from vitrectomy even when their initial vision was better thanlight perception [4].

Immune-suppressionPatients on topically or systemically administered immuno-suppressant therapy (corticosteroids, anti-metabolites) at the time of intraoperative procedures have a significantly higher risk of endophthalmitis[106]. A change in the local pre-operative flora was not confirmed in patients on immuno-suppressanttherapy, nor was there an alteration in the spectrum of the organisms causing the endophthalmitis [185].

Altered bacterial floraAtopic patients and those with rosacea have altered conjunctival and lid bacterial flora with a preponderanceof Staphylococcus aureus [12]; in addition rosacea patients have enhanced systemic cell-mediated immunityto S. aureus which is thought to contribute to their blepharitis and keratitis [12]. While no trial data existsfor an increased incidence of endophthalmitis after cataract surgery in these patients, anecdotal evidencedoes exist and it is prudent to give them anti-staphylococcal prophylaxis prior to and after surgery [207].

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2.1 Operating theatre

Air flow designThere are no current guidelines or data for the type of airflow best required to prevent post-operativeendophthalmitis after phacoemulsification. For ECCE operations, it has been shown in the past that 85 percent of endophthalmitis cases could be traced to the patient by comparing DNA profiles of vitreous isolatesof bacteria with those collected from the lid and skin flora of the patient [42]. Nevertheless, a risk remainsof infecting the eye with bacterial flora from the surgical team by the airborne route.

Old data on aerobiology has suggested that a hospital operating theatre should have a minimum of 20 airchanges per hour to reduce the airborne bacterial count, but this is arbitrary as all the airborne bacteria,attached to skin scales, will settle to the floor in still air after 30 minutes. Research on ultra-clean air forhip surgery has shown that a fast laminar flow of air in an operating theatre can remove airborne bacteriawithin seconds, rather than minutes with traditional airflow systems at 20 air changes per hour, but is thisrequired for phacoemulsification surgery through a very small incision? This question has been investigatedby the ESCRS multi-centre study of endophthalmitis after phacoemulsification surgery, as some clinicalpartners operate with minimal airflow, others 20 air changes per hour and others have ultraclean air systemswith either horizontal or vertical laminar flow. However, the result of this investigation was inconclusive, arelationship between air changes per hour and incidence of endophthalmitis has not been established [5].

Equipment – sterilisation and single-useAll instruments for surgery should be sterile. Single-use is even more robust, as there have been occasionsrecently when instruments have not been washed properly prior to sterilising which itself may have beenfaulty. Care is required with both washing the instruments and autoclaving them, as the latter is neverabsolute nor an exact science! Both matters should be investigated if there is an ongoing 'epidemic' of post-operative endophthalmitis with different types of skin bacteria viz. coagulase-negative staphylococci within asurgical unit for no obvious reason.

Single-use of tubing and other equipment that becomes wet within the operative procedure is alwayspreferable, if cost allows. Tubing is not easy to effectively sterilise unless an ethylene oxide gas steriliser isavailable. Bottles of solution containing BSS (balanced salt solution) etc. should never be kept or used formore than one operating session. Any air vent applied to these bottles should be protected by a bacterialfilter. Wet areas are easily contaminated with Pseudomonas aeruginosa, which can then cause devastatingendophthalmitis.

2.2 Antisepsis

The goal of pre-operative antisepsis is to reduce the likelihood of a wound infection by reducing the totalbacterial count in the wound area and immediate wound environment. In view of the low incidence ofendophthalmitis, controlled studies comparing the effectiveness of different antiseptics are hardly feasiblebecause of the random sample sizes required.

For peri-orbital skin antisepsis, a five to 10 per cent povidone-iodine solution is recommended which shouldbe allowed to act for a minimum of 3 min, as the skin contains many sebaceous glands. If this iscontraindicated (allergy or hyperthyroidism), an aqueous solution of chlorhexidine (0.05 per cent) should beused instead [212]. Single use of chlorhexidine is non-toxic at this concentration.

For antisepsis of the conjunctiva and cornea, povidone-iodine is the chemical preparation of choice. Thenumbers of bacteria on the conjunctiva and cornea can be reduced by 1 log10 count (10 fold) to amaximum of 2 log10 count (100 fold) in the pre-operative phase by a five per cent povidone-iodine solutionleft in place for a minimum of three minutes [22], [23], [27], [28], [85]; a 10 per cent solution ofpovidone-iodine can be diluted 1:1 with BSS or isotonic saline. Post-operatively, a significant reduction inbacterial count in the conjunctival sac can also be achieved by antisepsis with a 1.25 per cent povidone-iodine solution [28].

Schmitz et al. in their questionnaire survey of 469 ophthalmic surgical institutions in Germany, came to theconclusion that the pre-operative use of povidone-iodine on the conjunctiva significantly reduced the risk ofendophthalmitis [126]. However, the survey gave no indication of the method of application, contact time,or concentration of the povidone-iodine solution employed, so the conclusion remains unproven. In ananalysis of the literature from 1966 to 2000 listed in Medline, the benefit of povidone-iodine antisepsis isalso confirmed, even if only with category EbM III (= moderately important to clinical outcome) [61].

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2. Prophylaxis


In 1991, Bohigian was able to show in a retrospective analysis of a total of 19,269 cataract extractions thatthe incidence of endophthalmitis fell from 0.08 per cent to 0.03 per cent following the introduction ofantisepsis with five per cent povidone-iodine. This difference indicates a benefit but was not statisticallysignificant and it is doubtful whether it can be attributed exclusively to povidone-iodine antisepsis [56]. Inthe same year, Speaker and Menikoff in their study of 8,083 patients showed a significant difference, at the0.05 level, between the incidence of endophthalmitis with antisepsis using five per cent povidone-iodine(0.06 per cent) and the control group in which silver-protein solution was used (0.24 per cent) [18].

The optimum concentration of povidone-iodine for use in pre-operative eye antisepsis has not beenestablished at present. From the aspect of tolerability, there is evidence that even a 10 per cent povidone-iodine solution (without the addition of detergent) is associated with low external corneal toxicity [177]. Onthe other hand, considerable side effects can be expected if even a five per cent povidone-iodine solutiongets into the anterior chamber [145]. In animal experiments, the healing of skin wounds is significantlydelayed even by two per cent povidone-iodine [211], while it is tolerated by the sensitive nasociliaryepithelium in a concentration of 1.25 per cent [17] and by adult cartilage at one per cent [16] without theefficacy in vitro being restricted at these dilutions even with a large protein and blood load [38].

Studies of the use of chlorhexidine digluconate on the conjunctiva or cornea give conflicting results. A fourper cent chlorhexidine solution induces corneal damage and should NOT be used [177], [200].Complications have also been described for the 0.02 per cent chlorhexidine solution [188], but when usedas long-term therapy (four times daily for eight weeks in the presence of a corneal ulcer presumed due toAcanthamoeba) rather than as single-use prophylaxis on an intact epithelium prior to surgery. On the otherhand, pre-operative conjunctival irrigation with 0.05 per cent chlorhexidine diacetate solution [107], as usedby Per Montan and all colleagues in Sweden, is found satisfactory.

Application of 10ml of five per cent povidone-iodine onto a sponge pad one hour prior to surgery clampedagainst the closed lids was associated with significantly fewer positive conjunctival cultures immediatelyprior to surgery (p = 0.02) and at the conclusion of the surgery (p = 0.05) compared with the application oftwo drops of five per cent povidone-iodine [35].

Clinicians should avoid use of large bottles of readily diluted povidone-iodine or chlorhexidine wheneverpossible, and use single-use sachets or vials instead, as both antiseptics can become contaminated withPs. aeruginosa.

In conclusion, it can be stated on the basis of the available clinical studies that only povidone-iodine in aconcentration of five per cent in BSS or isotonic saline can be recommended at present as the pre-operativeantiseptic of choice. It has not been established whether similar results can be obtained with a lowerconcentration, such as 2.5 or 1.25 per cent. However, a significant effect for a reduction in the conjunctivalbacterial count after surgery has been confirmed when 1.25 per cent povidone-iodine was used [28].Povidone iodine solution containing a detergent must NOT be used as it coagulates the cornea irreversibly.

2.3 Antibiotics

Pre-operative prophylaxisPre-operative topical antibiotic prophylaxis appears rational to reduce the number of bacteria in theconjunctival sac. Various antibiotics have been used in the past including fluoroquinolones,chloramphenicol, aminoglycosides, fusidic acid and combination products of polymyxin / bacithracin /neomycin, but their use, including current use of topical fluoroquinolones, is not yet scientifically proven toreduce the rate of post-operative endophthalmitis [53], [61], [77], [146], [178]. However, a recentretrospective analysis has suggested a lower endophthalmitis rate following use of topical ofloxacin comparedto topical ciprofloxacin [86].

The randomised, placebo-controlled prospective multi-centre ESCRS study has investigated if use of peri-operative topical levofloxacin, which reaches significantly higher concentrations in the anterior chamber thanofloxacin and ciprofloxacin [2], [3], [7], can prevent post-operative endophthalmitis. Patients wereadministered one drop of levofloxacin 0.5 per cent solution one hour before surgery, one drop 30 minutesbefore surgery and three drops at five-minute intervals immediately following surgery. Dosing was interrupteduntil the following day to study the effect of peri-operative prophylaxis only. Although there appeared to besome benefit from the use of peri-operative levofloxacin, the effect was smaller than for intracameralinjection of cefuroxime (see below) and did not reach statistical significance [5]. To maintain an adequatelevel of levofloxacin in the anterior chamber it may be considered continuing to dose every two hours post-operatively on the day of surgery [43].

9


In a retrospective analysis of 20,013 cataract surgeries, the effect of gatifloxacin 0.3 per cent and moxifloxacin0.5 per cent given three times within one hour before surgery and four times daily for one week after surgerywas shown to be comparable with other prophylactic measures. Estimated endophthalmitis rates of 0.06 percent for gatifloxacin and 0.1 per cent for moxifloxacin, respectively, were reported. The authors concluded thatolder fluoroquinolones may be used instead and these newer ones be reserved for frank infections [112].

Combining prophylaxis for three days by the oral route with short-term prophylaxis by the topical route (1 h)provides higher antibiotic levels in the anterior chamber than either alone [44]. However, a reduction inintraocular bacterial contamination using this approach has not been proven [74], [157]. From considerationsof principle (development of resistance, allergies) and because of the higher efficacy of antiseptics in vitro,equivalent results can be expected with antiseptics (e.g. povidone-iodine) on the ocular surface, but with themajor disadvantage of a lack of an antibiotic effect within the anterior chamber.

The effect of a combined antiseptic and antibiotic approach with ciprofloxacin, ofloxacin and povidone-iodinehas been investigated in vitro [174], but large numbers of patients are needed for a prospective clinical trial.Ofloxacin and levofloxacin are absorbed through the cornea into the anterior chamber to give an antibioticeffect which does not happen with povidone iodine. Topical levofloxacin four times on the day prior to surgeryand three drops within one hour before surgery in combination with povidone-iodine irrigation was shown to behighly effective in reducing the bacterial conjunctival flora compared to the use of povidone-iodine prophylaxisalone. This schedule may be prudent in reducing bacteria from the surgical field in order to minimise the riskof endophthalmitis [36].

Vancomycin and other reserve antibiotics should not be used for prophylaxis [156].

Systemic antibiotic prophylaxisIntravenous antibiotic prophylaxis is not used for conventional intra- and extra-ocular procedures and is notproven to be of benefit against post-operative endophthalmitis. As low levels of antibiotic penetrate the globe inthe non-inflamed eye, this route is NOT recommended. Oral quinolones, however, penetrate the globe to giveconcentration levels (up to 1.3 µg/ml after three doses of 200mg levofloxacin), which increase up to 1.86µg/ml with topical therapy pre-operatively [6]. However, routine cataract surgery does not require oralprophylaxis unless the patient has severe atopic disease when the lid margins are more frequently colonisedwith S. aureus [133].

After a penetrating injury, a prophylactic antibiotic is given systemically, as well as by the intravitreal route, andthe same drug should be used. This has been reviewed recently [150], [205]. Antibiotic cover must includeBacillus sp., with vancomycin, gentamicin or clindamycin, as well as CNS, S. aureus and Clostridium sp. Theimportance of intravitreal antibiotic was shown in two recent studies. In the first study, at the end of woundrepair, vancomycin (1mg) plus ceftazidime (2.25mg) were injected intravitreally in 32 eyes, whereas 38 eyesremained without this prophylaxis. Seven of the latter 38 eyes (18.42 per cent) developed endophthalmitiscompared to only two of the prophylaxis group (6.25 per cent), which had an initially undetected intraocularforeign body (cilia) in the vitreous cavity [9]. In the second study, 179 eyes were randomly assigned to eitherintracameral injections of 40µg of gentamicin and 45µg of clindamycin or to injection of balanced salt solution.Endophthalmitis developed within two weeks postop in eight eyes (2.3 per cent) in the control group, comparedto one eye (0.3 per cent) in the study group. [13]. A significant association was also noted betweenendophthalmitis and the presence of an intraocular foreign body (IOFB). Endophthalmitis developed in seven of25 control eyes with an IOFB, but in none of the 27 antibiotic-treated eyes with an IOFB.

Irrigation of the lacrimal passages Pre-operative irrigation of the lacrimal passages has no significant effect on the contamination of investigatedaqueous aspirates. However, it should not be performed immediately before the operation, as then even morebacteria are washed from the lacrimal sac into the conjunctival sac [51].

Covering the periorbital areaWith regard to the endophthalmitis risk, there has been no randomised controlled study of pre-operative cuttingof the eyelashes.

The information available in the literature suggests that cutting the lashes is not associated with a reduction ofrisk [126], and demonstrates that the periocular flora is not influenced on the day of the operation or in theimmediately succeeding days [194].

Taping back the lashes with adhesive tape nevertheless appears recommendable after PVP treatment of the skin[53], as in this way a conceivable additional risk is eliminated without side effects, all the more so as theannoying presence of lashes in the operating area can be avoided.

10


Intra-operative prophylaxis

Addition of antibiotic to irrigating solutionsAccording to Questionnaire Reporting Surveys in various countries, antibiotics are used in the irrigating solutionby approximately 60 per cent of responding cataract surgeons in Germany [126], 35 per cent in the US [182],16 per cent in New Zealand [163], 8.5 per cent in England [161] and 8 per cent in Australia [186]. However,while these surveys can be used for crude comparative rates, they are not accurate because of a limitedresponse rate around the 65 per cent limit [205]. Antibiotics added to the irrigating solution includevancomycin and gentamicin.

While it is suggested in various surveys that the addition of antibiotics to the irrigating solution has a protectiveeffect, it has not been possible to reduce the incidence of endophthalmitis in any prospective scientific study.All information on the incidence of endophthalmitis comes either from retrospective studies or from studies ofantibiotic use where there was no control group [108], [167], [169].

Anterior chamber contamination at the end of a cataract operation varies between 0 per cent (0 of 98 eyes) andan extreme figure of 43 per cent (13 of 30 eyes) [68], [93], but even with a greater number of investigatedeyes it is between 0.18 per cent (1/552) and 13.7 per cent (98/700) [104], [187]. Whether the reduction inthe contamination rate from 12/100 to 5/100 when vancomycin is used in the irrigation solution [97] and from22/110 to 3/110 with vancomycin/gentamicin [54] is meaningful remains doubtful, especially as no differencewas found in another corresponding study (8/190 control, 9/182 vancomycin) [72].

In any case, the onset of action of various antibiotics, but in particular vancomycin, in vitro is observed onlyafter three to four hours and full activity only occurs after about one day [31], [58], [79], [174]. This contrastswith the half-life of the drug in the anterior chamber of three hours. In animal studies of pars plana vitrectomy,antibiotic prophylaxis can be established only for low but not for moderate numbers of bacteria [33].

There is also the risk of overdose (aminoglycoside retinal toxicity) and the danger of developing resistance,which is disturbing particularly with the reserve antibiotic vancomycin. Relevant scientific organisations andauthors therefore advise against giving prophylactic antibiotics in the irrigating solutions or call this in question,especially as a benefit has not so far been proven (Center for Disease Control in 1995 regarding vancomycin[156], American Academy of Ophthalmology in 1999 regarding vancomycin [144] and May et al. in 2000regarding aminoglycosides [184]).

Addition of antibiotic as an intra-cameral injection in 0.1ml at the end of surgeryAll Swedish cataract surgeons now routinely give an intra-cameral injection of 1mg cefuroxime in 0.1ml atthe end of phacoemulsification surgery before closing the wound [108], [109]. This technique has beendeveloped in Sweden and data from over 400,000 Swedish patients both retrospective and prospectivedemonstrate the efficacy of intracameral cefuroxime [94][137]. The technique has now been proven by theresults of the prospective, randomised and controlled multi-centre ESCRS study [1], [5], [10]. Cefuroxime isvery active against staphylococci and streptococci (except MRSA, MRSE and Enterococcus faecalis), Gram-negative bacteria (except Pseudomonas aeruginosa) and P. acnes.

The study found that the risk for contracting endophthalmitis following phacoemulsification cataract surgerywas significantly reduced (five fold) by an intracameral injection of cefuroxime at the end of surgery,p=0.001 for presumed endophthalmitis and p=0.005 for proven endophthalmitis [1], [5], [10]. The lowestobserved incidence rates were in Group D of this four-arm study [10], which received both intracameralcefuroxime and peri-operative topical levofloxacin. These rates were 0.049 per cent for presumedendophthalmitis and 0.025 per cent for proven endophthalmitis.

It must be remembered that some patients still developed post-operative endophthalmitis even after theyreceived intracameral cefuroxime in both Sweden and the ESCRS study. There were three isolates ofcoagulase-negative staphylococci in the ESCRS study that were shown to be resistant to cefuroxime. On sub-analysis, the evidence for benefit of cefuroxime against CNS endophthalmitis appears to be weaker thanagainst streptococcal endophthalmitis, while intensive peri-operative antibiotic eye drops are likely to worksynergistically with cefuroxime.

The risk of an allergic reaction to cefuroxime in patients with a known allergy to penicillin is present butsmall [195] and must be weighed up against the increased risk of endophthalmitis if the cefuroximeinjection is withheld. In these patients, an antihistamine tablet 15 minutes before surgery may beconsidered. There has been a case report of severe anaphylactic reaction attributed to intracameral injectionof cefuroxime [199]. In patients with a known allergy to cephalosporins, cefuroxime should not be used and

11


as an exception an intracameral injection of vancomycin should be considered instead. Intensive topicalquinolones, e.g. levofloxacin, may be a useful adjunct for coverage of Gram-negative bacteria.

Besides cefuroxime, other antibiotics that have been given intracamerally include vancomycin (effectiveagainst all Gram-positive bacteria only) [168], gentamicin (effective against staphylococci, but notstreptococci and P. acnes, and effective against Gram-negative bacteria including Ps. aeruginosa) andclindamycin in combination with gentamicin [13], [14]. Anecdotal evidence from those who use antibioticsin this way suggests that they prevent post-operative or post-traumatic endophthalmitis but no scientificstudy has been mounted in their support.

The intracameral application of antibiotics, including cefuroxime, vancomycin and aminoglycosides, is notlicensed by regulatory authority and it is given at the surgeon's discretion. Clinicians should be aware ofcountry specific implications as regards liability, medical insurance and reimbursement.

Subconjunctival antibiotic injection prophylaxisThis technique has been much used over the last 30 years, especially in the UK, but probably has littleprophylactic effect on the prevention of endophthalmitis [61], [205]. While there has been no formal studyto establish the technique, there have been plenty of studies, including the EVS, in which patients whodevelop endophthalmitis have received a prophylactic subconjunctival injection. One of the reasons why thismight have occurred is that many surgeons used gentamicin which has no antibiotic effect on streptococciand Propionibacterium acnes. Researchers have investigated the pharmacokinetics of cefuroxime when125mg given by the subconjunctival route gave levels of 20 µg/ml in the anterior chamber [29], which isfar lower than that (3,000 µg/ml) which occurs when injected by the intracameral route. However, onerecent retrospective uncontrolled study from Canada found one case of endophthalmitis in 8856 surgeriesusing subconjunctival antibiotics and nine cases of endophthalmitis out of 5030 surgeries not using them[64]. While this was statistically significant (p < 0.009), the study was open to bias as regards surgeon,incision and type of patient; such data needs to be repeated in a controlled prospective study.

Post-operative prophylaxisIn order to minimise the risk of infection, particularly after clear cornea incisions (see above) until woundhealing is secure, use of the pre-operatively applied topical antibiotic (a quinolone or other drug - see below)is recommended for up to two weeks but is not proven. Longer application (more than two weeks) isdiscouraged unless there are other medical reasons for it. Post-operative quinolone drops should be appliedevery one to two hours after surgery to sleeping and from the next day on four times daily, from first wakingin the morning to just before sleeping, with one drop well placed in the conjunctival sac [193]. Alternatively,topical chloramphenicol has been demonstrated to be safe for use for one week, without the risk of causingaplastic anaemia [45], or a combination product such as polymyxin/bacithracin/neomycin may be used,which has broad spectrum, low resistance and is not used systemically.

2.4 Limitations of the ESCRS Study

One of the objectives of the study was to assess the true background rate of post-operative endophthalmitisin Europe when no antibiotics were given on the days before or at the time of surgery. Patients in Group A,the control group, received instead peri-operative placebo eye drops without the cefuroxime injection [10].However, it was considered unethical to withhold povidone iodine at the time of study design as it was theonly prophylaxis for which there was a true evidence base [18]. Hence, all patients received povidone-iodineantisepsis following a standard protocol, which the background rate was established with. Topicallevofloxacin was given as standardised medication for six days beginning on the first post-operative day, toprevent wound infection [149], but this was considered irrelevant for testing, whether or not an antibioticadministered at the time of surgery was effective.

The study did not evaluate the role of pre-operative antibiotics, which are normally administered anywherebetween one hour to three days before surgery. Instead, it tested intensive peri-operative antibiotic dropsversus intensive peri-operative placebo drops, commencing one hour before and concluding 15 minutes afterthe surgery.

Cefuroxime was chosen for the study, because its benefit had been demonstrated in more than 32,000procedures in Sweden by the time of study design [109], [149], and it is effective against the majority oforganisms that cause post-operative endophthalmitis [10]. The objective of the study was to prove theefficacy of the technique of intracameral cefuroxime in a prospective, randomised controlled trial. Althoughother intracameral agents or alternative systems of drug delivery might be superior to cefuroxime, they wouldhave required additional safety studies prior to their use in this trial.

12


13

Levofloxacin was chosen as a topical antibiotic for similar reasons. It is well absorbed into the anteriorchamber and has enhanced antibacterial activity compared to older fluoroquinolones [10]. Whilst newerfluoroquinolones, such as moxifloxacin and gatifloxacin may have a higher potency against Gram-positivebacteria and are widely used pre-operatively in the US, their use, like that of intracameral vancomycin,raises ethical questions about the utilisation of reserve antibiotics for prophylaxis as opposed to treatment[149]. Furthermore, both antibiotics are not yet available for topical ophthalmic use in Europe.

The applied dosing regimen of topical levofloxacin was based upon studies investigating its ocularpenetration with four or five drops pre-operatively [2], [3], [7]. There has been a lack of specificpharmacokinetic data of fluoroquinolones in the anterior chamber and the PK study by Sundelin et al. [43]was conducted only after completion of the ESCRS study. The results of this latter study suggest acontinued dosing on the day of surgery to maintain adequate drug levels in the aqueous humour. This isendorsed by Wallin et al., who showed that commencing post-operative topical antibiotics as late as one dayafter surgery is associated with a higher risk of contracting endophthalmitis [136].

Preparation of cefuroxime solution for intra-cameral injection

The use of cefuroxime should be discussed with the hospital pharmacist and, in particular, themethod agreed about how to make the dilution to 10 mg/ml.

It is recommended to use ZINACEF (GlaxoSmithKline) or an equivalent preparation containingcefuroxime as cefuroxime sodium in powder form, without any excipients. It MUST be diluted insterile 0.9 per cent sodium chloride solution (saline) and NOT sterile water for injection as stated inthe product data sheet, to achieve the correct pH of approx. 7.4 and osmolality of approx. 310mOsm/kg for ocular injection [109]. 250mg cefuroxime are dissolved in 2.5ml of 0.9 per cent saline.1ml of this solution is mixed with 9ml of 0.9 per cent saline to obtain a cefuroxime concentration of10 mg/ml. 0.4ml of this solution are drawn up in a 1ml syringe and a fine metal cannula is attachedto it. The first 0.1ml is displaced through the cannula for disposal. The cannula is inserted throughthe clear corneal wound or the corneo-scleral tunnel to the location of the intra-ocular lens and 0.1mlis injected intra-camerally.


14

2.5 FLOW CHART – PROPHYLAXIS GUIDELINES

(Based on the results of ESCRS multi-centre study [1], [5], [10] as well as Healy et al. 2004 [26], Jensen et al. 2005 [86] and Peyman, Lee & Seal 2004 [205]

Consider use of topical quinolone (levofloxacin* or ofloxacin one drop four times daily) or a topicalcombination of polymyxin B/bacithracin/neomycin for 24 or 48 hours prior to surgery

and/or Apply topical quinolone (same type) to cornea and conjunctiva with one drop one hour prior to surgery and one drop one half-hour prior to surgery

It is mandatory to apply one drop povidone iodine five per cent [61], or 10ml povidone iodine fiveper cent on a sponge pad [35], or aq. chlorhexidine 0.05 per cent [107], to the cornea and

conjunctival sac for a minimum of three minutes prior to surgery – preferably this is done in thepreparation room prior to taking the patient into the operating theatre (OT)

Apply 10 per cent povidone iodine or 0.05 per cent chlorhexidine to the peri-orbital area in the OTas skin antisepsis, and allow to spill over into the conjunctival sac

Surgeon washes hands with antiseptic soap solution (povidone iodine or chlorhexidine), gowns upand wears sterile gloves and a mask. Check that theatre airflow is running and that doors are closed

Apply surgical drapes and taping of eyelids to remove eye lashes from the surgical field (do not cut eyelashes)

Perform phacoemulsification surgery. Consider using foldable IOLs that can be inserted through a sterile injector

Apply 1mg cefuroxime in 0.1ml saline (0.9 per cent) by intra-cameral injection [108], [109] at theend of surgery. This is an unlicensed use of cefuroxime given at the surgeon's discretion.

Use of vancomycin (or gentamicin) in the irrigation fluid or by intra-cameral injection is not proven and is not encouraged (refer to text)

Re-apply topical quinolone (same type) at the end of surgery as one drop stat, one drop five minutes later and one drop five minutes later again, or reapply polymyxin B/

bacithracin/neomycin or apply topical chloramphenicol (1 drop stat)

Use of subconjunctival antibiotic (gentamicin, cefuroxime) is not thought to offer effectiveprophylaxis (refer to text)

Give post-operative topical prophylaxis with the same quinolone as one drop every one to two hourson the day of surgery. From the next day, give four times daily (six hourly) for one week if scleraltunnel or sutured clear cornea incision was used, and for two weeks if an unsutured clear cornea

incision was used. If not using quinolones, give topical chloramphenicol or polymyxin B/bacithracin/neomycin using the same regimen as with quinolones.

* gives three to four times higher levels of the active isomer in the anterior chamber than ofloxacin [7], [26], [205]


3.1 Commencement and symptoms

Acute early endophthalmitis after cataract operations commences between the first post-operative day andapproximately two weeks after the operation. It is associated in 74 to 85 per cent with ocular pain and in >90 per cent with reduced vision [15], [122]. It is characterised in 75 to 86 per cent by hypopyon, in > 80per cent by a red eye and in 35 per cent by lid swelling [141]. Additionally, there can be corneal oedemaand involvement of the posterior segment (refer to chart below) [205].

Chronic late endophthalmitis after cataract operations commences only after two weeks but may also takemany months to appear [50], [96], [113], [117]. It is usually caused by Propionibacterium acnes, S.epidermidis (CNS), diphtheroids and fungi [15], [122]. In P. acnes endophthalmitis, whitish plaques arefound in the capsular sac in 40 to 89 per cent [50], [62], [205]. Hypopyon is found in 67 per cent, cornealoedema in 48 per cent and keratitis in 26 per cent of cases of fungal endophthalmitis [113], [124];pyramid-shaped hypopyon is typical of a mycotic cause [204], [210]. Refer to chart below.

The course and final outcome depend on the type and number of pathogens. In 44 to 53 per cent there isan achievement of only one metre vision with bacterial infection [15], [122], and similar for fungal infectionin 41 to 70 per cent of patients [113], [151]. Endophthalmitis after pars plana vitrectomy has a poorerprognosis than after cataract or glaucoma surgery [46], [63].

The diagnosis of acute bacterial endophthalmitis is a medical emergency requiring an immediate vitreal tapand instillation of intravitreal antibiotics and corticosteroid.

Figure 3.1 Early presentation of acute endophthalmitis due to Streptococcus mitis(Courtesy of Suleyman Kaynak)

Figure 3.2 Presentation of acute endophthalmitis due to Staphylococcus aureus (Courtesy of Uwe Pleyer)

15

3. Diagnosis


16

3.2 FLOW CHART – DIAGNOSTIC GUIDELINES FOR ACUTE VIRULENT ENDOPHTHALMITIS [205]

Observe the patient for:■ pain

■ blurring or loss of vision, which may appear as a darkened image

due to developing vitritis, down to perception of light

■ swollen lids

■ inflamed or oedematous conjunctiva

■ discharge into conjunctiva

■ corneal oedema sometimes with an infiltrate or ring abscess

■ cloudy anterior chamber with cells, hypopyon or fibrin clot

■ afferent pupillary defect

■ vitreous clouding (vitritis) from inflammation precluding a view of the retinal vessels

■ involvement of posterior segment with retinitis, and/or retinal periphlebitis, retinal oedema andpapillary oedema

■ absent red reflex when the vitreous is viewed through the pupil may be a poor guide to the state ofthe vitreous, which may be most opaque anteriorly where the inflammatory process has begun. Ifthe pupil is observed while transilluminating the sclera, the red reflex may become apparent andcan then form a better guide to control of the disease.

Check B-scan ultrasonography for vitritis and retinal detachment – this is a useful adjunct for the clinical evaluation of infectious endophthalmitis especially in an eye with opaque media.

MAKE A CLINICAL DIAGNOSIS OF ENDOPHTHALMITIS (with photography if possible)

BEWARE OF DELAYING THE DIAGNOSIS WITH A TRIAL OF CORTICOSTEROID DROPS(refer to Section 5.3)

THIS IS A MEDICAL EMERGENCY!

PERFORM AN INTRAVITREAL TAP WITHIN ONE HOUR!

■ Perform a vitreous tap in the OT using a vitrector or phaco/vitrector or use a portable vitrector(BD Visitrec 5100) in the outpatient clinic (refer to text)

■ Also, perform an anterior chamber tap for microbiology

■ Collect samples of vitreous and aqueous for microbiology (Gram stain, culture & PCR*)

■ Inject empirical choice of antibiotics** (refer to text and flow diagram below) AND dexamethasone(400 µg unpreserved drug in 0.1ml) into vitreous with separate syringes and needles

* Expert PCR (polymerase chain reaction) for bacteria and fungi causing acute and chronic endophthalmitis isavailable from Dr Udo Reischl, Institute for Medical Microbiology and Hygiene, University Hospital, 93053Regensburg, Germany ([email protected]; Tel: +49-941-944-6450, Fax: -6402) or from ProfJorge Alio & Dr Consuelo Ferrer, VISSUM-Instituto Oftalmologico de Alicante, 03016 Alicante, Spain([email protected]; Tel: + 34-9651-50025, Fax: -60468) at a cost of 250 EUR per sample. Collect samplesof one drop of aqueous and one drop of vitreous, each placed in a separate sterile Eppendorf plastic tube orother sealable tube. Specimens should be stored at + 4°C for up to 24 hours and sent by next-day courierservice to the laboratory or stored at -20°C for longer periods. Do not send by courier over a weekend. It isadvisable to contact the units by telephone, email or fax before sending any samples.

** ALWAYS have a chosen empirical regime of antibiotics ready in advance for intravitreal use in a clinic or OTsetting. Have instructions prepared for making-up correct dilutions and have necessary sterile equipment (bottlesand syringes) available in an 'endophthalmitis pack' within the operating theatre.


Figure 3.3 Gram stain of vitreous tap from acute endophthalmitis due to Streptococcus salivarius (Courtesy of Roland Koerner)

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3.3 FLOW CHART – DIAGNOSTIC GUIDELINES FOR CHRONIC ENDOPHTHALMITIS [205]

Observe the patient for:■ pain■ blurring or loss of vision ■ cloudy anterior chamber with cells■ recurrent hypopyon uveitis that fails to respond to corticosteroids■ plaque in the capsular bag (= saccular or granulomatous endophthalmitis)■ vitreous clouding (vitritis) from chronic inflammation reducing a view of the retinal vessels

Check B-scan ultrasonography for vitritis and retinal detachment

MAKE A CLINICAL DIAGNOSIS OF CHRONIC ENDOPHTHALMITIS

INVESTIGATE FOR A MICROBIAL SOURCE

■ perform an anterior chamber tap for microbiology (Gram stain, culture & PCR) (refer above fordetails) – PCR is often positive here when culture is negative as bacteria are intra-cellular

■ perform a vitreous tap, if vitritis is present, for microbiology (Gram stain, culture & PCR)■ if a decision is made to remove the IOL, then collect and send the capsule fragments to the

microbiologist and to the histopathologist for paraffin-section based Gram stained films whichwill reveal the presence of intra-cellular Gram-positive bacteria within macrophages lining thecapsule [47], [205]. Also collect a sample into glutaraldehyde to perform election microscopy,which can identify the intra-cellular bacteria [205].


3.4 Differential diagnosis – the toxic anterior segment syndrome

The toxic anterior segment syndrome (TASS) is an acute inflammation of the anterior chamber of the eye.TASS may be related to any of the irrigating solutions, medications, or materials that gain access to the eyeduring anterior segment surgery. In addition, factors related to the cleaning and sterilisation of instrumentsmay be a major problem causing TASS. Some cases have been related to heat stable endotoxins fromovergrowth of Gram-negative bacilli in water baths of ultrasonic cleaners.

TASS rarely occurs in one patient only, but usually in three or more, because most or all the patients havebeen exposed to the incriminating toxin during one or two operating sessions. If an outbreak occurs, thenthe surgeon must stop operating and investigate for the source of the problem.

The common signs noted in the patients in a recent outbreak of TASS in the US included blurred vision,marked increase in anterior segment inflammation, including hypopyon formation as well as fibrin in theanterior chamber of the eye. It is always Gram stain and culture negative. There may be diffuse cornealoedema, classically from limbus to limbus, with endothelial cell damage. Patients present within 12 to 48hours of cataract surgery and seem to respond well to intense topical corticosteroid treatment [147],[148], [179].

18


4.1 AC tap, vitreous tap, vitrectomy for Gram stain, culture and PCR tests

The previous section describes diagnostic guidelines. A medical emergency exists as soon as the clinicaldiagnosis is made of acute bacterial endophthalmitis. There is a need to perform an anterior chamber tap and avitreous tap within ONE hour of clinical diagnosis and to instil intravitreal antibiotics. The acute bacterialprocess is very 'unforgiving', giving rise to massive inflammation within the posterior segment with a breakdownof the blood-ocular barrier. Hence, to save vision there is need to stop the acute bacterial process but also tominimise the acute inflammation that it has caused, hence the current opinion that unpreserved dexamethasone400 µg in 0.1ml should be injected intravitreally at the same time as the antibiotics. The full arguments for andagainst this approach, based on a scientific review, are considered by Peyman, Lee & Seal [205].

The question arises how to carry out the urgent taps and antibiotic instillation. In some hospitals it is notpossible to take the patient to the operating theatre (OT) at any given time because of use of the OT by others. Itis not advisable to keep the patient waiting for more than three hours, because the chances of retainingreasonable vision are diminishing fast. For this reason, a portable vitrector has been developed by Peyman andVisitec (Figure 5.1) to make an intravitreal tap within the outpatient clinic and to instil intravitreal antibioticsand dexamethasone at the same time in the clinic (refer to surgical section below). Jager et al. [171] have foundthat it is safe to perform vitrectomy in the outpatient (OP) clinic providing that antiseptic prophylaxis is usedwith povidone iodine; they found no statistical difference in acquired endophthalmitis rates after vitrectomybetween the two sites – OT and OP (refer to incidence section above).

Use of the phaco/vitrector equipment, for a partial or full vitrectomy, is considered below in the treatment(surgical) section. It can be used for both sample collection and a full vitrectomy.

Antibiotics (refer below) are instilled with separate syringes and 25 or 30 G needles for each drug, eitherinjecting directly through the pars plana or by injecting through the sclerotomy wound if present. The scleralwound is usually self-sealing and does not need to be sutured.

Identification of the pathogen in infectious endophthalmitis is rational as this allows targeted antibiotic therapy.The sampling should be done as soon as possible, and within ONE hour, after the diagnosis is made. Enlist thehelp of the microbiologist.

Microscopy and Gram stain results are available after one hour, pathogen culture results after 24 h, andantibiotic sensitivity testing results after six to 10 hours when the RAST method is used, or after 24 to 48 hwith conventional methods [103].

The highest rate of pathogen identification is obtained with microscopic and microbiological processing ofvitreous material, obtained either using the vitrectomy cutter before switching on the irrigation or as an aspirate,or using the portable vitrector. Use of a syringe and needle gives an unreliable sample that is often dry andculture-negative.

Pathogen identification from the anterior chamber is less successful and also potentially contaminated by thevitrectomy cassette [20], [101]. Conjunctival and corneal swabs are pointless, as the correlation with the micro-organisms isolated is too low [42]. The culture media should be inoculated directly in the operating theatre[189]. Transportation of material on cotton buds produces a high loss of pathogens and reduces the detectionrate, which ideally is about 90 per cent [102].

The polymerase chain reaction (PCR) method offers much improved pathogen detection especially in the case ofchronic endophthalmitis with low pathogen counts [34], [205]. However, the increased risk of contaminationbecause of the high sensitivity of the method, the lack of antibiotic sensitivity testing and the partial lack ofquality control standards in routine diagnostic laboratories have limited its routine use so far. PCR has beenevaluated in depth in the multi-centre ESCRS study by the two expert laboratories mentioned above. Results ofthis cross-validation study are not yet published [11].

4.2 Epidemiology

For detailed discussion on how to investigate an outbreak of cataract-surgery-associated post-operativeendophthalmitis, the reader is referred to Chapter 4 of Peyman, Lee & Seal's book [205]. This chapterconsiders the epidemiology of post-operative endophthalmitis in detail and has tables from which actualnumbers of cases of endophthalmitis can be compared with predicted numbers for different incidence ratesof infection, and thus determine whether the number of cases is greater-than-expected statistically, requiringthe unit to close for detailed investigations. One of the most important aspects to then determine is whetherthere is a common source outbreak or whether it is due to a selection of different types of bacteria out ofthose normally found on the lid margin or in the conjunctival sac [214]. The former is often associated witha staff carrier for Staphylococcus aureus or Pseudomonas aeruginosa if contaminated solutions are involved,while the latter is more often associated with failures of either washing the instruments or with theirsterilisation or with a failure of the air conditioning system in summer, causing the surgeons to shedexcessive numbers of bacteria. It may be necessary to introduce an intra-cameral injection of antibiotic whenthe unit reopens if the source cannot be found.

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4. Investigation


5.1 Surgical management of endophthalmitis.Diagnostic and therapeutic vitrectomy

The GOLD STANDARD of treatment of acute post-operative endophthalmitis is immediate (within a fewhours) "complete" three port pars plana vitrectomy by a vitreoretinal surgeon. First, the infusion port isinserted through the pars plana, 3.5mm from the limbus, but is NOT TURNED ON. The vitreous cutter isinserted through a separate 3.5mm sclerotomy and directly visualised through the pupil. A hand-held syringeis attached to the aspirating line and the surgical assistant aspirates whilst the surgeon activates the cutteruntil the eye visibly softens and the cutter is disappearing from view. The infusion is turned on to reform theglobe and the cutter removed. The syringe and the tubing now contain 1-2ml of infected but undilutedvitreous and the two together are promptly sent to the laboratory for immediate Gram stain, culture and PCRanalysis.

The microbiologist has previously been informed the sample is en route.

The vitreous cutter is now connected to the machine for aspiration control and a light pipe is insertedthrough the pars plana. A standard three-port vitrectomy is performed within the limits of visualisation. It isuseful to perform a posterior capsulotomy with the cutter and aspirate the fibrin and pus from the anteriorchamber and intraocular lens surface. This procedure not only improves visualisation but permits flowthrough the entire eye and facilitates recovery.

Caution must be exercised against too aggressive surgery. These eyes have concomitant retinal vasculitis andretinal oedema and the inadvertent creation of a retinal break can be catastrophic. Iatrogenic retinaldetachment in eyes with acute endophthalmitis is comparable to that of AIDS.

Once the vitrectomy is as complete as possible, the intravitreal antibiotics (see text) are injected. Note thatthe dose is reduced by 50 per cent if a full vitrectomy has been performed. This injection should be givenSLOWLY, over minutes, and the needle pointed away from the macula. Separate syringes and separateneedles are used through an existing entry site. Intravitreal dexamethasone (preservative free) is theninjected.

The procedure is performed under general, peribulbar or retrobulbar anaesthesia but not topical.

The authors favour general anaesthesia as the patients are usually old, frail, sick, and in pain. Furthermore,the eyes are inflamed, hyperaemic and bleed.

While the above GOLD STANDARD achieves immediate diagnostic and therapeutic vitrectomy and reducesthe need for re-operation, it is often not possible due to the lack of a vitreoretinal surgeon and a vitreoretinaloperating room. The duty surgeon frequently does not have the required skill.

As TIME is of the essence, a SILVER STANDARD may be the practical option. The basic fundamentalrequirement is the intravitreal injection of the antibiotics. This should be preceded by vitreous biopsy.Simple aspiration with a needle is frequently unsuccessful unless the needle fortuitously enters the synereticvitreous cavity; infected vitreous cannot be aspirated with a syringe and needle. Every duty surgeon must betaught to perform a vitreous biopsy with a vitreous cutter. The simplest technique is with the portablevitrector with a microvitreoretinal (MVR) blade at its tip as marketed by Visitec (Becton Dickinson VisitrecVitrectomy System 5100 Visitrec™ Surgical Vitrectomy Unit) and Insight Instruments, Inc. (The Intrector®Portable Office-based Drug Injection/Vitrectomy System). Following the sampling, antibiotics andcorticosteroids are injected through the sclerotomy as above. The incision does not require suture closureand no conjunctival incision is necessary.

This SILVER STANDARD has the advantage of time over completeness. While it ignores the fundamentalsurgical principle of "Ubi pus, ibi evacuat" (where there is pus, let it out) and it provides a smaller sample, itpermits the earlier injection of intravitreal antibiotics and earlier microbiology. It also buys time pending theavailability of a vitreoretinal surgeon and vitreoretinal operating room and the technique should bemandatory for all cataract surgeons.

The portable vitrector consists of a battery box, with 'off/on' and cutting speed switches, and a handheldvitrector (Figure 5.1). The vitrector has a 23 G guillotine probe, for use through a sclerotomy puncture site.In addition, a 20 G bevel needle can be placed on it, to allow direct puncture and use at the pars plana.The micro-guillotine cutter is controlled with a switch on the hand-piece. There is also an irrigating andaspiration module, to allow collection of the vitreous sample (Figure 5.1). The portable vitrector is designedfor sample collection only and not for use for a therapeutic vitrectomy. These techniques are also describedby Peyman et al. [206].

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5. Treatment


Figure 5.1 Portable Vitrector* – Becton Dickinson Visitrec VitrectomySystem 5100 Visitrec™

Figure 5.2 Site of insertion of vitrector guillotine

* PORTABLE VITRECTOR – Becton Dickinson Visitrec Vitrectomy System 5100 VisitrecTM Surgical Vitrectomy Unit marketed by Visitec, Waterloo Industrial Estate, Bidford-on-Avon, Warwickshire B50 4JH, UK.Tel: +44-1789-490909 Fax: +44-1789-490511

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The patient is supine (lying flat). The eye is prepared with povidone iodine and then anaesthetised bytopical, peri- or retro-bulbar anaesthetic. A lid speculum is inserted and an anterior chamber tap is made forGram stain, culture and PCR.

For the portable vitrector, the biopsy probe is inserted through the pars plana transconjunctivally. The probehas a MVR blade at its tip so no incision is necessary. The single instrument provides one-step sclerotomy,cutting and aspiration. A mini-core vitrectomy can also be performed with slow manual aspiration of up to 1ml vitreous for microbiology and PCR.

The cutting probe is removed from the eye. Antibiotics and corticosteroids are injected with a 30mm (30 G)needle through the same incision site with separate syringes and needles. The incision is small enough notto need suture closure.

5.2 Anti-microbial therapy

An antibiotic combination is injected intravitreally and repeated as necessary according to the clinicalresponse at intervals of 48 to 72 hours, depending on the persistence of the drugs selected within the eye.Intravitreal antibiotic doses are scaled down to avoid retinal toxicity but the margin for error betweenchemotherapy and toxicity is narrow for the aminoglycosides (for gentamicin, 200 µg is effective but 400 µgcan be toxic, causing macular infarction); thus, the total dose injected must be highly accurate.

A combination of intravitreal antibiotics should be instilled as vancomycin (1mg) plus ceftazidime (2mg)(first choice) [32] (cave: physical incompatibility of vancomycin and ceftazidime [165], [176]) or amikacin(0.4mg) plus vancomycin (2mg) (second choice); 0.1ml of each of the two chosen antibiotics should beinjected separately intravitreally after the tap or vitrectomy has been performed. An intravitreal injection ofdexamethasone 0.4mg in 0.1ml should be given at the same time in most circumstances, again by aseparate syringe and needle.

Antibiotics that have been used relatively safely for intravitreal use are shown in Table 5.1 below. The tablelists the non-toxic doses of antibiotics, but the dose should be reduced by at least 50 per cent if given witha full vitrectomy, since the vitreous prevents rapid diffusion of antibiotics towards the retina [205]; someclinicians reduce the dose even by 90 per cent.

Table 5.1 - Doses of antibiotics for intra-vitreal treatment of acute post-operative endophthalmitis

Antibiotic injection intravitreal dose* (micrograms) Duration (h)

Amikacin 400 24-48Ampicillin 2000 24Amphotericin 5 or 10 24-48Cefazolin 2000 16Ceftazidime 2000 16-24Cefuroxime 2000 16-24Clindamycin 1000 16-24Erythromycin 500 24Gentamicin 200 48Methicillin 2000 16-24Miconazole 5 or 10 24-48Oxacillin 500 24Vancomycin 1000 48-72

* maximum intravitreal injection volume is usually 0.3ml but give each drug separately in 0.1ml amounts (use theintrathecal preparation when available because they are preservative free); intravitreal ciprofloxacin has been used[205], while the use of intravitreal levofloxacin is still experimental [19]. Intravitreal concentrations of 625µg orless of levofloxacin and 400µg or less of gatifloxacin appeared to be non-toxic in rabbit eyes [172].

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How To Make Up The AntibioticsThe antibiotics should be supplied freshly diluted by the hospital pharmacy department. However, foremergency cases, a method for diluting the drugs in the operating theatre is given below. The proceduremust use sterile equipment and be undertaken on a sterile surface; ideally, the hospital makes up sterilepacks with drugs, bottles for dilution and instructions in advance for this purpose. All drugs should be mixedby inverting or rolling the bottle 25 times, avoiding frothing.

Some important “dos” and “don’ts” are:

■ Never return diluted drugs to the same or original vial for further dilution■ Never dilute at greater than 1 in 10■ Do not use syringes more than once■ Do not reuse bottles ■ Avoid use of drugs with preservatives if possible■ Do inject the drugs slowly over 1 to 2 minutes

Prior to preparing the dilutions it is mandatory to check the amount of the antibiotic in the vial as the sameantibiotic may be sold in different strengths in each EU country.

Vancomycin Dose for use = 1000µg. Reconstitute one vial of 250mg and make up to 10ml with sterilenormal (0.9 per cent) saline (SNS) in a sterile bottle with lid. Mix well. Withdraw 2ml accurately and add to3ml of SNS in a sterile bottle with lid. Mix well (= 10mg/ml). Use 0.1ml = 1000µg.

Ceftazidime (or other cephalosporin) Dose for use = 2000µg. Reconstitute one vial of 500mg and make upto 10ml with SNS in a sterile bottle with lid. Mix well. Withdraw 2ml accurately and add to 3ml of SNS in asterile bottle with lid. Mix well (= 20mg/ml). Use 0.1ml = 2000µg.Note: the percentage of drug precipitation is less when using SNS instead of BSS [32].

Amikacin Dose for use = 400µg. Reconstitute one vial of 500mg and make up to 10ml with SNS orbalanced salt solution (BSS) in a sterile bottle with lid. Mix well. Withdraw 0.8ml, using a 1ml syringe, andadd to 9.2ml of SNS or BSS in a sterile bottle with lid. Mix well (= 4.0mg/ml). Use 0.1ml = 400µg.

Gentamicin Dose for use = 200µg. Method 1: Use a 'Minim' which contains 3000µg/ml. Dilute to2000µg/ml by adding 2ml of the Minim formulation to 1ml SNS in a sterile bottle with lid. Mix well. Use0.1ml = 200µg for injection. Method 2: Remove 0.5ml, using a 1ml syringe, from a vial containing40mg/ml unpreserved gentamicin and place in a sterile bottle with lid. Add 9.5ml of SNS or BSS and mixwell (= 2.0mg/ml). Use 0.1ml = 200µg.

Clindamycin Dose for use = 1000µg. Transfer the contents of a 2ml ampule containing 300mg to a sterilebottle and add 1ml SNS or BSS, replace lid, and mix well. Withdraw 1ml, using a 1ml syringe, and add to9ml of SNS or BSS in a sterile bottle with lid. Mix well (=10mg/ml). Use 0.1ml = 1000µg.

Amphotericin Dose for use = 5µg. Reconstitute a 50mg vial with 10ml water for injection. Withdraw 1ml,using a 1ml syringe, and add to 9ml of water in a sterile bottle with lid for injection. Mix well. Withdraw 1mlof this dilution, using a 1ml syringe, and add to 9ml of dextrose five per cent in a sterile bottle with lid, tocomplete a dilution of 1/100. Mix well (= 50µg/ml). Use 0.1ml = 5µg. (A dose of 10µg has been used bysome clinicians.)

Miconazole Dose for use = 10µg. Withdraw 1ml, using a 1ml syringe, from an ampule of intravenousmiconazole containing 10mg/ml and add to 9ml SNS or BSS in a sterile bottle with lid. Mix well. Withdraw1ml, using a 1ml syringe, and add to 9ml SNS or BSS in a sterile bottle with lid. Mix well (= 100µg/ml).Use 0.1ml = 10µg.

Within Europe, various manufacturers produce sterile bottles of saline of different volumes for injection withside-ports, but many are not sold universally. For example in Spain and Portugal, the following method canbe used with Braun's 50ml bottles of saline, suitable for drug dilution with two rubber injection ports [159]:

Vancomycin - mix vial of 500mg with 5ml saline withdrawn from Braun 50ml bottle, shake well and thenreturn to Braun bottle. Dilution gives 10mg/ml (dose of 0.1ml contains 1mg).

Ceftazidime - mix vial of 1g (1000mg) with 5ml saline withdrawn from Braun 50ml bottle, shake well andthen return to Braun bottle. Dilution gives 20mg/ml (dose of 0.1ml contains 2mg).

Amikacin - add 2ml saline to vial of 500mg. Shake well and remove 0.8ml (= 200mg) to Braun 50ml bottleand shake well. Dilution gives 4 mg/ml (dose of 0.1ml contains 400µg).

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Acute purulent endophthalmitis should be treated with additional systemic antibiotic therapy with the samedrugs as used for intravitreal therapy. This adjunctive regimen will maintain effective intravitreal levels of thedrug for a longer period by reducing the diffusion gradient out of the eye as well as its penetration into theinflamed eye [205]. High doses are required and there is a need to be aware of the risks of systemic toxicity.Vancomycin levels should be assayed. Use of oral probenecid (dose 500mg every 12 hours) retards outwardtransport of penicillins, cephalosporins and fluoroquinolones across the retinal capillary endothelial cells,thus extending the half-life of the drug within the vitreous. Probenecid also raises the plasma level byblocking secretion of these drugs by the proximal renal tubule.

Dexamethasone (preservative-free) is often given by intravitreal injection (dose = 400 µg in 0.1ml [use thecommercial preparation containing 4 mg/ml]) but should NOT be mixed with antibiotics in the same syringe.Refer to section 5.3. Prednisolone can be added to the systemic regimen to reduce the vitreousinflammatory response and subsequent vitreous organisation (oral prednisolone e.g. 200mg (see p. 21) dailyon a reducing scale).

Antibiotic therapy may be modified after 24 to 48 hours according to the clinical response and theantibiotic sensitivity profile of the cultured organism. However, the inflammation usually becomes worsebefore becoming better, even with the correct antibiotic regime, hence the need to give a broad-spectrumantibiotic combination empirically by the intravitreal route that will be effective against most Gram-positiveand negative bacteria causing post-operative endophthalmitis.

Intravitreal administration of the antibiotic gives the highest drug concentration “at the target site” but onlylasts for a limited time period. Injection alone can be successful [119], but is usually combined with parsplana vitrectomy (PPV). Vancomycin (1mg/ 0.1ml) is suitable for Gram-positive bacteria [15], [180] and isabove the MIC90 of Staphylococcus epidermidis (CNS) for > 48 h [80]; even 0.2mg/ 0.1ml vancomycin canremain at a therapeutic level for three days [73]. For treating Gram-negative bacteria, many surgeons areabandoning the use of aminoglycosides because of retinal toxicity and low therapeutic spectrum and areinstead giving ceftazidime 2mg/ 0.1ml [155], [166], [170]. Vancomycin is used for Propionibacteriumacnes [50], [62], but P. acnes is also very sensitive to cefuroxime.

Amphotericin B (5-7.5 µg) is the only fungicidal antibiotic available for intravitreal injection but itsspectrum does not cover all fungi; in particular, Scedosporium apiospermum (Pseudallescheria boydii) isresistant to it but sensitive to miconazole which can be used instead [120], [121], [205], [210]. Miconazoleis fungistatic but can be given intravitreally (Table 5.1). Systemic anti-fungal therapy is also required andthe source of the infection needs to be identified.

How To Give The AntibioticsUP TO 0.1ML CAN BE LOST IN THE HUB OF THE SYRINGE AND THE NEEDLE when drugs are diluted ormade up for injection into the eye. Always draw up sufficient drug to fill a 1ml syringe to at least thehalfway mark (0.5ml) and expel 0.1ml accurately from the syringe. Never expel the drug from the 0.1mlmark, because of errors with the hub.

Adjunctive Routes

Systemic administration According to the randomised, multi-centre “Endophthalmitis Vitrectomy Study” (EVS), systemic antibioticsdo not appear to have any effect on the course and outcome of endophthalmitis after cataract operations[15]. However, the study design used different drugs systemically (amikacin and ceftazidime) to those usedintravitreally (vancomycin and ceftazidime [162], [196]), which does not contribute towards maintainingeffective antibiotic levels within the eye. Thirty-eight per cent of the endophthalmitic eyes demonstratedGram-positive cocci, against which ceftazidime has limited activity, whereas vancomycin would have beenmuch more effective. Thus, adjunctive systemic antibiotic therapy with the same antibiotics as those givenintravitreally is recommended for management of acute virulent bacterial endophthalmitis [162], [196],[209] when the patient should be closely observed in hospital. This may not be needed for less severe casessuch as those caused by CNS.

Vancomycin provides good cover for Gram-positive bacteria including methicillin-resistant staphylococci(MRSA, MRSE). Ceftazidime is used to cover the Gram-negative spectrum incl. Ps. aeruginosa [153], [158].Imipenem, which is also suitable for Gram-positive bacteria, and fluoroquinolones for Gram-negativebacteria, have not yet been fully evaluated for intravitreal use and should only be administered if there arecontraindications against vancomycin and ceftazidime [21], [48], [153]. Experimental studies have beenperformed to show that levofloxacin can be used to kill bacteria causing experimental endophthalmitis in

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25

rabbits but the final dose to use, that is also non-toxic, has not yet been established [19], [205].

Clindamycin, vancomycin or cefuroxime are effective for Propionibacterium acnes endophthalmitis [47],[140]. However, this must often be preceded by surgery [66], combined with intravitreal antibiotic injection[50], [62].

For fungal infection, amphotericin should be used systemically if it has been given by the intravitreal route.It is relatively toxic, but quite safe with experience, and the help of an infectious disease specialist shouldbe found. In addition, systemic imidazoles are often given but are more likely to be effective for systemicinfection than for the endophthalmitis. Voriconazole or fluconazole (for Candida albicans) or itraconazole (forother Candida species, Aspergillus or Cryptococcus) can be given but are not usually as effective asamphotericin [113], [205], [210]. 5-fluorocytosine can be used in combination therapy for Candidaalbicans. Fusarium endophthalmitis is particularly difficult to treat requiring both surgical removal wherepossible and chemotherapy (intravitreal, AC instillation or wash-outs, topical and systemic routes); Fusariumis usually but not always sensitive to amphotericin and combination therapy is often given with imidazoles[205].

5.3 Anti-inflammatory therapy

Effective anti-inflammatory therapy, e.g. with corticosteroids, is rational in order a) to limit tissue destructionby infiltrating leukocytes, b) to stem the effect of antigens and highly inflammatory cell walls released bybacterial disintegration after administration of antibiotics and c) to diminish the toxic effects of intraocularcytokines. Intravitreal dexamethasone injection (400 µg in 0.1ml) at the end of the vitrectomy leads underantimicrobial therapy to a more rapid subsidence of the intraocular inflammation [65], but withoutimproving the long-term functional outcome although this finding may reflect studies in whichdexamethasone or corticosteroid has been given later rather than initially with the first injection ofantibiotics.

Oral administration of prednisolone (1mg/kg body weight) one day after intravitreal antibiotic therapy with orwithout vitrectomy has not shown any negative effect on the course of infection in bacterial endophthalmitis[15]. There have also been case reports of systemic steroid administration with mycotic infections, likewisewithout adverse effects [173]. 200mg prednisolone is often rationally given systemically in parallel withintra-venous antibiotics; however, there are no published studies on this subject.

From reports of recent experience from others, there seems to be quite a widespread use of a trial ofcorticosteroid drops in post-operative inflammation. Our view is that in uncomplicated phacoemulsificationsurgery with significant post-operative inflammation the patients should have an immediate vitreous biopsyand intravitreal antibiotics with no delay, and a trial of corticosteroid drops should not be performed.

To summarise, not only the microbes but also their interplay with the immune mechanisms, are important inthe outcome of endophthalmitis. Cell walls of dead bacteria, especially those of streptococci, and includingthose recently killed by antibiotics, are highly inflammatory. As a direct consequence, anti-inflammatorytreatment with intravitreal dexamethasone (400 µg in 0.1ml) should be given along with specific intravitrealanti-microbial therapy. In addition, surgical removal of a high bacterial load in the vitreous can also beimportant to save vision, by removing the main source of the acute inflammatory effect.

5.4 Other types of post-operative endophthalmitis

Late cases of endophthalmitis after cataract operation are the second commonest form of endophthalmitisaccounting for 20 to 30 per cent in past studies following ECCE surgery; the symptoms are milder andPropionibacterium acnes has been identified as the principal pathogen. There is difficulty in culturing it asthe bacterium is often enclosed in the synechised capsular sac. The high rate of recurrence is problematic,which can only be reduced by vitrectomy, possibly combined with posterior capsulectomy [160]. A furtheradvantage of vitrectomy is that adequate material for culturing the causative organism can be obtained butcapsular bag material is needed as well (refer to Flow Chart 3.3). Early vitrectomy is advisable [111]. A trialof therapy should be given with clarithromycin 250mg twice daily (refer to Flow Chart 5.7, [115]) which canbe effective without surgery because the drug is well absorbed and concentrated 200 times intomacrophages and other cells.


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5.5 Limitations of EVS study

The Endophthalmitis Vitrectomy Study (EVS) [15] conclusions refer mostly to sub-acute post-operativeendophthalmitis due to coagulase negative staphylococci (CNS) (80 per cent of cases) and the advice andconclusions overall do not relate to acute pyogenic pathogens such as Staphylococcus aureus, Streptococcuspyogenes and Streptococcus pneumoniae. The conclusions also do not apply to late post-operative(saccular), bleb-induced, post-traumatic or endogenous endophthalmitis. These forms of endophthalmitishave a more aggressive bacterial spectrum and therefore require different operative techniques (vitrectomy),and both intravitreal and systemic antibiotics [205], [206]. The principles of management are the same forpost-traumatic and endogenous endophthalmitis, as for acute post-operative endophthalmitis, but the visualoutcome is poorer [205].

According to the EVS, conducted in the US [15], patients with acute endophthalmitis after a cataractoperation with an initial vision of hand movements or better should be treated by vitreous biopsy andintravitreal antibiotics. In patients whose vision consists only of light perception, immediate vitrectomy isrecommended. This advice however was based on the selection of patients admitted to the study and doesnot reflect the management of acute streptococcal endophthalmitis, where there is good reason to proceedwith an immediate vitrectomy in order to remove the highly inflammatory bacterial cell walls from within thevitreous milieu. Retrospective studies have shown that affected patients can profit from early vitrectomy[192].

In the EVS, ceftazidime and amikacin were used systemically, while vancomycin and amikacin were usedintravitreally, which does not contribute towards maintaining effective drug levels within the eye. However,38 per cent of the eyes with < 5/200 outcome were infected by gram-positive strains. Ceftazidime is not thedrug of choice for these bacteria. Therefore, the design of the EVS can not answer the question ofintravenous use of antibiotics [162], [196]. In fact, this was not the primary objective of this study.

Follow-up EVS analyses showed differences between diabetics and non-diabetics. Diabetics with a visualacuity of hand movements or better obtained vision of 20/40 more often (57 per cent) by vitrectomy thanafter biopsy (40 per cent) but the results ultimately were not statistically significant because of the lownumber of diabetic participants in the study [4].


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5.6 FLOW CHART – TREATMENT GUIDELINES FOR ACUTEVIRULENT ENDOPHTHALMITIS

(presumed and not proven) [205]

Make clinical diagnosis of endophthalmitis

Perform ultrasonography of vitreous and retina

Perform aqueous and vitreous tap and/or vitrectomy, through the pars plana, collectingsamples for microbiology investigation (Gram stain, culture & PCR)

Inject antibiotics empirically into the vitreous using a combination of either vancomycin 1mg in 0.1ml and ceftazidime 2mg in 0.1ml (first choice) or amikacin 400 µg in 0.1ml

and vancomycin 2mg in 0.1ml (second choice).

USE A SEPARATE SYRINGE AND 30 G NEEDLE FOR EACH DRUG AND DO NOT MIX DRUGS TOGETHER IN THE SAME SYRINGE.Do NOT point the needle towards the retina but forwards instead

and inject very slowly into the mid-vitreous

Inject dexamethasone 400 µg (preservative-free) in 0.1ml into the vitreous at the same time by a separate syringe and needle

For acute virulent endophthalmitis begin adjunctive systemic therapy with the sameantibiotics as those used intravitreally for 48 hours to maintain higher levels within the

posterior segment of the eye (measure serum levels for intravenous vancomycin therapy); this may not be needed for less severe cases due to CNS

Consider beginning systemic therapy with corticosteroids (prednisolone 1 or even 2 mg/kg/day)

Consider referral to a vitreoretinal surgeon for an opinion on a full vitrectomy (refer to text) and repeated intravitreal antibiotics

OBSERVE PATIENT (inflammation becomes worse before better again, hence need for a defined initial empirical approach)


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5.7 FLOW CHART – TREATMENT GUIDELINES FOR CHRONIC ENDOPHTHALMITIS

(presumed and not proven) [205]

Make a clinical diagnosis

Investigate for a microbial source

CONDUCT A TRIAL OF THERAPY WITH CLARITHROMYCIN 250mg twice daily for two weeks (this derivative of erythromycin is well absorbed orally, penetrates well into the eye and is

concentrated 200 times into PMNs and macrophages, to kill intra-cellular Gram-positive bacteriaand Haemophilus sp., but not other Gram-negative rods; clarithromycin is also effective against

many atypical bacteria) [115], [201], [205]

If successful, retain IOL but if therapy fails, make a decision on whether to retain or remove theIOL and consider performing a vitrectomy possibly combined with a posterior capsulectomy [160]

If IOL is retained, give trial of therapy with intravitreal vancomycin and cefazolin or cefuroxime,together with intravenous therapy for one week

If combination anti-microbial therapy fails as well, remove the IOL – collect samples of capsule fragment for histology, electron microscopy and microbiology investigation

(Gram stain, culture & PCR) [47], [202], [205]

Inflammation usually subsides after the IOL has been removed with the capsule but furtherantibiotic therapy can be given, such as an oral quinolone, but may not be needed


References categorised as EbM IB

[1] Barry, P., Seal, D. V., Gettinby, G., Lees, F., Peterson, M., Revie, C. W.: ESCRS study of prophylaxis of post-operativeendophthalmitis after cataract surgery: Preliminary report of principal results from a European multi-centre study. J CataractRefract Surg. 32, 2006, 407 - 410

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[192] Okada, A. A., Johnson, R. P., Liles, W. P., D'Amico, D. J., Baker, A. S.: Endogenous bacterial endophthalmitis. Report of a ten-year retrospective study. Ophthalmology 101, 1994, 832 - 838

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[195] Pichichero, M. E.: Cephalosporins can be prescribed safely for penicillin-allergic patients. J Fam Pract 55, 2006, 106 - 112

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[205] Peyman, G., Lee, P., Seal, D.V. Endophthalmitis – diagnosis and management. Taylor & Francis, London: 2004, pp 1 - 270

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References to book chapters

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[210] Behrens-Baumann, W.: Mycosis of the Eye and its Adnexa. In: Developments in Ophthalmology 32, S. Karger AG, Basel 1999(with a contribution by R. Rüchel)

[211] Bolton, L., Oleniacz, W., Constantine, B., Kelliher, B. O., Jensen, D., Means, B., Rovee, D.: Repair and antibacterial effects oftopical antiseptic agents in vivo. In: Maibach, H., Lowe, I. (Eds.): Models in Dermatology 2, S. Karger AG, Basel 1985, 145-158

[212] Kramer, A. and Rudolph, P.: Efficacy and tolerance of selected antiseptic substances in respect of suitability for use on theeye. In: Kramer, A. and Behrens-Baumann, W. (Eds.): Antiseptic Prophylaxis and Therapy in Ocular Infections. S. Karger AG,Basel 2002, 117-144

[213] Meredith, T. A.: Vitrectomy for infectious endophthalmitis. In: Ryan, S. J. (Ed.): Retina. Mosby Year Book Inc 3, St. Louis2001, 2242-2263

[214] Osato, M. S.: Normal ocular flora. In: Pepose, J., Holland, G. N., Wilhelmus, K. R. (Eds.): Ocular Infection and Immunity.Mosby, St Louis 1995


36

Augusto Abreu

Servicio de Oftalmología

Hospital Universitario de Canarias

38320 La Laguna

Tenerife

Spain

Jorge Alió

Instituto Oftalmológico VISSUM,

Avda. de Denia s/n,

03016 Alicante

Spain

Albert J Augustin

Augenklinik des

Städtischen Klinikums

Moltkestr. 90

76133 Karlsruhe

Germany

Peter Barry

Royal Victoria Eye & Ear

and St. Vincent's UniversityHospital,

Dublin 4

Republic of Ireland

Wolfgang Behrens-Baumann

Universitäts-Augenklinik

Leipziger Str. 44

39120 Magdeburg

Germany

Alexander Bialasiewicz

Department of Ophthalmology

Sultan Qaboos University Hospital

P.O. Box 38

Al-Khod 123

Sultanate of Oman

Stefano Bonini

Istituto di Oftalmologia

Università degli Studi di Roma

Campus BioMedico

Via Moscati 31

00168 Roma

Italy

Joseph Colin

Service d'Ophtalmologie

CHU Pellegrin

Place Amélie Raba Léon

33076 Bordeaux Cedex

France

Luis Cordoves

Servicio de Oftalmología

Hospital Universitario de Canarias

38320 La Laguna

Tenerife

Spain

Burkhard Dick

KnappschaftskrankenhausBochum-Langendreer

Universitätsklinik, Augenklinik

In der Schornau 23-25

44892 Bochum

Germany

Ekkehard Fabian

Bahnhofstr. 12

83022 Rosenheim

Germany

Susanne Gardner

St. Joseph's Hospital/Research

4765 Woodvale Dr.

Atlanta, Ga. 30327

USA

Klaus Geldsetzer

Santen GmbH

Industriestrasse 1

82110 Germering

Germany

Veronika Huber-Spitzy

Augenambulanz der

Krankenanstalt Sanatorium Hera

Lustkandlgasse 24

1090 Wien

Austria

Suleyman Kaynak

Retina Ophthalmic ResearchCentre

1488 Sok. No. 3

35220 Alsancak

Izmir

Turkey

Volker Klauß

Universitäts-Augenklinik

Mathildenstr. 8

80336 München

Germany

Hans-Reinhard Koch

Hochkreuz-Klinik

Godesberger Allee 90

53175 Bonn

Germany

Axel Kramer

Institut für Hygiene undUmweltmedizin

Ernst-Moritz-Arndt-Universität

Hainstr. 26

17487 Greifswald

Germany

Franz-Albert Pitten

Institut für Hygiene undMikrobiologie der

Bayerischen Julius-Maximilians-Universität

Josef-Schneider-Str. 2

97080 Würzburg

Germany

Uwe Pleyer

Charité - UniversitätsmedizinBerlin

Campus Virchow-Klinikum

Augenklinik

Augustenburger Platz 1

13353 Berlin

Germany

David Seal

Applied Vision Research Centre

City University

Northampton Square

London EC1V 0HB

England

Ulf Stenevi

SU/Mölndals sjukhus

Ogenkliniken

Göteborgsvägen 31

431 80 Mölndal

Sweden

Jerzy Szaflik

Kierownik Katedry i KlinikiOkulistyki

II Wydz. Lek. AkademiiMedycznej w Warszawie

Samodzielny Publiczny Kliniczny

Szpital Okulistyczny

ul. Sierakowskiego 13

Warsaw 03-709

Poland

J. Zeitz

Berliner Allee 15

40212 Düsseldorf

Germany

7. Appendix (Addresses of Contributors)


37

Notes


Published by The European Society for Cataract & Refractive Surgeons

Copyright © The European Society for Cataract & Refractive Surgeons

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