Infectious Endophthalmitis in Boston Keratoprosthesis: Incidence and Prevention

Acta Ophthalmologica 2014

Infectious endophthalmitis in Boston keratoprosthesis: incidence and prevention

Irmgard Behlau,1,2,3,4 Kathryn V. Martin,1,* Jacqueline N. Martin,1,* Elena N. Naumova,5 James J. Cadorette,6 J. Tammy Sforza,7 Roberto Pineda II1 and Claes H. Dohlman1

1Ophthalmology, Massachusetts Eye and Ear Infirmary, Schepens Eye Research Institute, Harvard Medical School, Boston, Massachusetts, USA 2Molecular Biology & Microbiology and Ophthalmology, Tufts-Sackler Graduate School of Biomedical Sciences, Tufts University School of Medicine, Boston, Massachusetts, USA 3Division of Infectious Diseases, Department of Medicine, Harvard Medical School, Mount Auburn Hospital, Cambridge, Massachusetts, USA 4Division of Infectious Diseases, Department of Medicine, Tufts University School of Medicine, Newton-Wellesley Hospital, Newton, Massachusetts, USA 5Tufts Initiative for Forecasting and Modeling of Infectious Diseases (InForMID), School of Engineering, Tufts University, Medford, Massachusetts, USA 6Henry Whittier Porter Bacteriology Laboratory, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, USA 7Pharmacy Department, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, USA

ABSTRACT. Introduction Purpose: To determine the cumulative worldwide incidence of infectious endoph- For the 4–8 million persons who are thalmitis and associated vision loss after Boston keratoprosthesis (B-KPro) Type I/II blind from corneal disease worldwide implantation and to propose both safe and inexpensive prophylactic antibiotic regimens. Methods: (Smith & Taylor 1999; Mariotti 2010; Two retrospective methods were used to determine the incidence, visual Silva et al. 2006) and who cannot be outcomes and aetiologies of infectious endophthalmitis associated with the B-KPro helped by standard corneal transplan- divided per decade: (i) systematic review of the literature from 1990 through January tation (Garg et al. 2005), an artificial 2013 and (ii) a surveillance survey sent to all surgeons who implanted B-KPros cornea is an obvious concept (Pellier de through 2010 with 1-year minimum follow-up. In addition, a single-Boston surgeon Quengsy 1789), yet only a small num- 20-year experience was examined. ber of devices have been implanted Results: From 1990 through 2010, there were 4729 B-KPros implanted worldwide over its history prior to 1990 (Dohlman by 209 U.S. surgeons and 159 international surgeons. The endophthalmitis et al. 1974; Cardona & DeVoe 1977; cumulative mean incidence declined from 12% during its first decade of use to Barnham & Roper-Hall 1983). The about 3% during its second decade in the Unites States and about 5% internationally reason for this slow progress has pri- during the second decade. There remains a large incidence range both in the United marily been the risk of infectious end- States (1–12.5%) and internationally (up to 17%). Poor compliance with daily ophthalmitis that can destroy the eye topical antibiotics is an important risk factor. While Gram-positive organisms virtually overnight. Thus, artificial cor- remained dominant, fungal infections emerged during the second decade. nea surgery has been viewed as being Conclusions: Daily prophylactic topical antibiotics have dramatically reduced the extremely risky and rarely successful endophthalmitis incidence. Although Gram-positive organisms are the most common over time, but there has been substan- aetiology, antimicrobials must be inclusive of Gram-negative organisms. Selection of tial progress in reducing the infection prophylactic regimens should be tailored to local antibiotic susceptibility patterns, be rate over the past few decades (Dohl- cost-effective, and should not promote the emergence of antimicrobial resistance. An man & Doane 1994; Alvarez de Toledo example of a broad-spectrum, low-cost prophylactic option for non-autoimmune et al. 1999; Mannis & Dohlman 1999; patients includes trimethoprim/polymyxinB once daily. Falcinelli et al. 2005). The Boston keratoprosthesis Key words: Boston keratoprosthesis – endophthalmitis – ocular infections – ocular prophylaxis (B-KPro; FDA approved, 1992) is an artificial cornea of collar button design Acta Ophthalmol. composed of medical grade poly (methyl methylacrylate) (PMMA) with the opti- ª 2014 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd cal stem implanted through a corneal doi: 10.1111/aos.12309 graft transplanted into the patient’s eye *These authors contributed equally. similar to a penetrating keratoplasty

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(Doane et al. 1996). It can restore sight 2011). During the 1990s and later, it Library at the MEEI to identify all in eyes that are not candidates for was realized that low-dose prophylactic published reports pertaining to endoph- corneal transplantation. Type I design topical antibiotic regimens, given daily thalmitis associated with the Boston is most frequently used for non-autoim- for life, were markedly effective in keratoprosthesis. International data- mune graft failure patients with good reducing the risk of endophthalmitis bases (PubMed (National Library of tear and lid function (Fig. 1). Type II is in B-KPros patients (Dohlman 1993; Medicine), EMBASE, Web of Science, indicated for patients with cicatrizing Nouri et al. 2001). During 1999, several BIOSIS Previews, Cumulative Index to corneal diseases with very poor or changes in postoperative management Nursing and Allied Health Literature absent tear function such as Stevens– were introduced including (i) large soft (CINAHL), Cochrane Database of Johnson syndrome (SJS), ocular cicatri- contact lenses to be worn around the Systemic Reviews, Clinicaltrials.gov, cial pemphigoid (OCP), severe chemical clock to protect the underlying corneal Guidelines.gov, Latin American and burns; it has an additional 2-mm-long tissue from dehydration and epithelium Caribbean Center on Health Sciences anterior optical nub attached to the defects (Dohlman et al. 2002) and (ii) Information (LILACS), African Index collar button enabling it to protrude topical vancomycin in combination Medicus, WHO Library and Informa- through the upper lid. with broad-spectrum fluoroquinol- tion Networks for Knowledge Data- As with any indwelling or implant- ones, particularly for patients with base (WHOLIS), Index Medicus for the able medical device that traverses from autoimmune diseases, resulting in a Eastern Mediterranean Region, Index the normal microbial flora on the dramatic decline in bacterial endoph- Medicus for the South-East Asian ocular (or skin) surface into a sterile thalmitis rates (Durand & Dohlman Region, Western Pacific Region Index site (anterior chamber, blood), any 2009). With these developments, fungal Medicus, NLM Gateway, EU Clinical keratoprosthesis is at high risk for keratitis and endophthalmitis have Trials Register, and WHO Interna- infection (Fig. 2; Behlau & Gilmore been reported (Barnes et al. 2007). tional Clinical Trials Registry Platform) 2008), with autoimmune patients at the Sterile vitritis post-B-KPro implanta- were searched on 17 February 2012 and greatest risk (Nouri et al. 2001; Yagho- tion has also been identified (Nouri updated 24–29 January 2013 without uti et al. 2001). Most indwelling or et al. 2005). language restrictions. Additional stud- implantable device infections involve The main aims of this study are to ies were identified by a manual search of biofilms that are naturally resistant to assess the true risk of vision-threaten- the bibliographies and reference lists of antimicrobials. Their role in chronic ing endophthalmitis following B-KPro original relevant articles and published inflammation is only beginning to be implantations (Robert et al. 2012b) proceedings. recognized (Behlau & Gilmore 2008; and to recommend antibiotic prophy- Behlau et al. 2011a,b; de la Cruz et al. laxis combinations and frequencies that Selection criteria are safe, efficacious, and cost-effective Inclusion criteria included (i) human (Behlau 2012; Behlau et al. 2012). cases, (ii) Boston keratoprosthesis and (iii) endophthalmitis occurrence and/or Methods infection of the aqueous humour and/or vitreous fluid, even if zero. Articles The Human Studies Committee at the examined included clinically diagnosed Massachusetts Eye and Ear Infirmary culture-positive and culture-negative (MEEI), Boston, MA approved this cases. We did not exclude (i) cases that study. had other implantable devices (glaucoma shunts) or other surgical proce- dures (filtering blebs; Taban et al. 2005), Literature review study design even if those devices might be the source Fig. 1. Photograph of the modern Boston Search methods of infection and (ii) reports that we keratoprosthesis (B-KPro) type I composed A systematic review of the literature disagreed with their clinical and/or of poly (methyl methylacrylate) (PMMA). was performed through the Howe microbiological diagnosis of endophthalmitis. On the other hand, investiga- tor reports of suspected ‘sterile vitritis’ without vision loss were excluded in the calculation of infectious endophthalmitis rates.

Worldwide endophthalmitis surveillance survey The ﬁrst part of a two-step surveillance survey sent to 368 surgeons who implanted Boston KPros from 1990 through December 2010 contained the following queries: (i) B-KPro surgery Fig. 2. Acute bacterial endophthalmitis (Streptococcus pneumoniae) in a B-KPro type I patient start year, (ii) number of keratoprosthe- with Stevens–Johnson syndrome. ses implanted and (iii) number of

2 Acta Ophthalmologica 2014 deidentified endophthalmitis cases, if Statistical analysis racharya et al. 2012; Chan & Holland any. Surveys were sent via email, fax, 2012; Iyer et al. 2012; Kamyar et al. Literature review postal mail, telephone calls and online 2012; Kang et al. 2012; Kiang et al. We provide a descriptive analysis of survey repeatedly to all surgeons that 2012; Patel et al. 2012; Ramchandran endophthalmitis with associated pro- had been shipped a B-KPro until a et al. 2012; Robert et al. 2012b; phylactic antibiotic regimens, aetiolo- response was obtained during 2011 Magalhaes et al. 2013) was predomi- gies and susceptibilities when available. through 2012. The number of implanted nantly retrospective, institutional chart Due to limited information, we were B-KPros through 31 December 2010 reviews. There were four case reports, unable to reliably perform a meta- was determined by invoice records and several case series restricted to a specific analysis study at this time. confirmed for accuracy by the reporting patient population and one quasi-pro- surgeon. Implanted B-KPros prior to spective/retrospective multicenter vol- Global surveillance survey 1990 and after 31 December 2010 were unteer series. There was only one We calculated a cumulative incidence excluded. prospective (non-randomized, non- of endophthalmitis by counting the blinded) case–control study in the number of reported cases of endoph- Boston keratoprosthesis literature com- Single-surgeon endophthalmitis-associated thalmitis divided by the total number paring corneal carrier grafts (Robert B-KPro experience of implanted B-KPro per each decade. et al. 2012a). There were no prospective This is a retrospective single surgeon studies with randomization methods. Single-surgeon experience (Claes H. Dohlman) reporting of The United States had the highest Herein, we report both new cases of endophthalmitis cases associated with number of studies reported (36), while endophthalmitis and previously B-KPro implantation from a continu- international studies comprised twelve. reported cases divided per decade. ous surgical case log maintained over a There were 19 U.S. B-KPro surgeons Additionally, selective prophylactic 20-year period (March 1990 through reporting, accounting for 9.1% of all antibiotics and dosing frequency from January 2010) at the Massachusetts U.S. B-KPro surgeons, and 12 interna- forty consecutive B-KPro patients Eye and Ear Infirmary, Boston, MA. tional surgeons (including two U.S. (non-autoimmune, non-burn) receiving Prior literature reports (Dohlman & surgeons operating internationally), implantations between 2007 and 2010, Doane 1994; Dohlman & Terada 1998; accounting for 6.9% of 159 interna- with 3-year follow-up, were reviewed. Nouri et al. 2001, 2005; Yaghouti et al. tional B-KPro surgeons. Overall, this Duration on particular antibiotics with 2001; Dohlman et al. 2002, 2010; Ray represents 8.1% of B-KPro surgeons. their respective cumulative time peri- et al. 2002; Barnes et al. 2007; Sayegh One surgeon had 13 reports and the ods was recorded. et al. 2008; Durand & Dohlman 2009; largest case series (255; Durand & Rivier et al. 2009; Cade et al. 2011) Dohlman 2009). Two surgeons reported and new endophthalmitis cases were five times either singularly or in combi- assessed. Results nation representing sequential, longitudinal retrospective studies. Determination Yield from literature search of the true cumulative endophthalmitis Definition of endophthalmitis The combined electronic database incidence has been complicated by the Acute endophthalmitis is easily identified 135 unique citations. Manual lack of referencing previously reported defined by a sudden onset of eye pain, search of bibliographies resulted in 11 patients (Robert et al. 2012b). abrupt decreased vision and intraocu- additional unique citations for a total The number of B-KPros implanted lar inflammation. Acute endophthalm- 146 articles. From these, 46 met our in eyes reflects 35% of the total United itis in the setting of a KPro can be criteria for review. Two articles States and 24% of the total interna- clinically divided into two visual out- required translation. The literature tional implanted B-KPros. The inci- come groups: one with disastrous (Dohlman & Doane 1994; Dohlman & dence of endophthalmitis associated outcome and the other, benign with Terada 1998; Nouri et al. 2001; Yagho- with B-KPro implanted prior to 2000 the original vision restored. This study uti et al. 2001; Dohlman et al. 2002; was 13.9% (15/108) in the United focuses on endophthalmitis associated Ray et al. 2002; Aquavella et al. 2005, States and 100% international (4/4; with vision loss. The authors recognize 2006, 2007; Nouri et al. 2005; Javadi Javadi et al. 2006). Notably, the cumu- the challenges of distinguishing et al. 2006; Zerbe et al. 2006; lative incidence with design and post- chronic endophthalmitis with low-viru- Akpek et al. 2007; Barnes et al. 2007; operative management changes for lent, slow-growing micro-organisms Sayegh et al. 2008; Stolz et al. 2008; B-KPros implanted after 2000 through versus sterile inflammation. Any clini- Aldave et al. 2009; Bradley et al. 2009; 2010 (few reports extending into 2011) cally suspected infectious endophthalm- Fintelmann et al. 2009; Chew et al. was 4.8% (53/1211) in the United itis reported case (even coagulase- 2009; de la Cruz & McMahon 2009; States, while the international inci- negative staphylococci (CNS), uncul- Durand & Dohlman 2009; Truax et al. dence (with a shorter follow-up time) tured, or culture-negative) was included. 2009; Rivier et al. 2009; Dohlman et al. was also 4.8% (14/289). There was a ‘Sterile vitritis’ with a sudden decrease in 2010; Dunlap et al. 2010; Georgalas large incidence range with the maxi- vision with little erythema or pain, with et al. 2010; Tsui et al. 2010; Cade et al. mum up to 12.5% in the United States restoration of pre-event vision with the 2011; Greiner et al. 2011; Gevorgyan (Chew et al. 2009; Fintelmann et al. use of corticosteroids alone (Nouri et al. et al. 2011; Guell et al. 2011; Li et al. 2009; Greiner et al. 2011; Li et al. 2011) 2005), was not included in the calcula- 2011; Verdejo-Gomez et al. 2011; Utine and up to 17% (Gevorgyan et al. 2011; tion of incidence. et al. 2011a,b; Aldave et al. 2012; Baj- Aldave et al. 2012) internationally in

3 Acta Ophthalmologica 2014 the second decade. Four total case Surgeons by geographical locations are skewed the overall distribution to the reports without patient denominators not shown due to confidentiality and left with the lower quartile (Q25) at 5.5 were included in these calculations anonymity. and the upper quartile (Q75)at30.3 (Georgalas et al. 2010; Tsui et al. months. The median time for bacterial 2010; Bajracharya et al. 2012; Robert endophthalmitis was 13 months with Single-surgeon experience et al. 2012b). Q25 = 4.8 and Q75 = 34, while for fun- Table 2 reports the largest retrospec- gal endophthalmitis the median time Comparison of endophthalmitis to ocular tive single-surgeon case series spanning was 18.5 months with Q25 = 14.5 and diseases over two decades with a minimum Q75 = 26 months. The percentages of During the first decade, the dominant 2-year follow-up. In the first decade, cases that occurred within the first ocular diseases in the United States the incidence of severe bacterial end- 12 months were 47.8% and 28%, res- (Nouri et al. 2001) and internationally ophthalmitis was high, particularly in pectively, within the first 24 months (Javadi et al. 2006) were autoimmune autoimmune patients (Nouri et al. 60.9% and 71.4%, respectively, and only in 37% and 34% and chemical burn in 2001), while no fungal infections were within 36 months did 82.6% bacterial 26% and 59%, respectively. After seen. In the second decade, there was a cases and 100% of fungal cases occur. 2000, the predominant patient popula- dramatic decline to 1.7% in severe Glaucoma drainage devices (GDD) tion in the United States had shifted bacterial endophthalmitis cases, how- were present in 20 of 30 patients with dramatically to non-autoimmune, non- ever, a rise in fungal endophthalmitis B-KPros at the time of endophthalm- chemical burn patients (Nouri et al. to 2.4%. Of the seven reported cases of itis. A trabeculectomy-associated ble- 2005; Durand & Dohlman 2009), while fungal infection, four were cured with bitis was the source of infection in one in some developing countries chemical minimal visual loss. Two cases (0.7%) B-KPro patient (Dohlman et al. 2002). burn remained a dominant clinical of atypical mycobacterial endoph- Similar to others’ (Al-Torbak et al. diagnosis (Stolz et al. 2008). thalmitis also emerged. 2005; Zerbe et al. 2006; Bradley et al. The mean (average) time from 2009; Kim & Chen 2011; Li et al. 2011), Comparison of endophthalmitis to prophy- B-KPro implantation to all types of conjunctival dehiscence over the tube or lactic antibiotics endophthalmitis cases was 20 months, erosion over the trabeculectomy lead- During the first decade, there were while the median was 14.3 months. ing to infection was implicated or several antibiotic regimens in use (often This large difference was due to late contributory in 40% of GDD/BKPro- in rotation), with trimethoprim-poly- onset bacterial endophthalmitis often associated endophthalmitis cases. myxinB (TMP-PMB) or ofloxacin the related to non-compliance. Frequent Antibiotic non-compliance occurred most commonly prescribed antibiotics. early bacterial endophthalmitis events in one-fourth of the patients in the first Of note, there were no reports of fungal endophthalmitis or ‘sterile vitritis’ dur- Table 1. Boston keratoprosthesis-associated endophthalmitis worldwide surveillance survey. ing this first decade. As of late 1999s Reports are for Boston keratoprostheses implanted from 1990 through 31 December 2010, with through the second decade, with the a minimum 1-year follow-up. Endophthalmitis incidence includes both bacterial and fungal introduction of bandage contact lenses, aetiologies. broad-spectrum fourth-generation fluoroquinolone either as single agent or United States International in combination with vancomycin, 1990–2010 2002 –2010 (while TMP-PMB fell out of favour), Total B-KPro surgeons 209 159 cases of fungal endophthalmitis were B-KPro surgeons response rate 95.2% 66.7% reported (Barnes et al. 2007; Rivier Number of implanted B-KPros 3501 1228 et al. 2009; Utine et al. 2011a; Chan % Implanted B-KPros accounted 99.5% 86.2% & Holland 2012). Number of endophthalmitis cases 111 65 Cumulative incidence of endophthalmitis 3.2% 5.0% Incidence of endophthalmitis per decade (1990–2000) 12.0% NA Global surveillance survey Incidence of endophthalmitis per decade (2001–2010) 2.9% 5.0% This retrospective self-reporting survey was sent to all surgeons who implanted Table 2. Single-surgeon experience in Boston of B-KPro-associated endophthalmitis over a B-KPros between 1990 through Decem- 20-year period. The total period is divided into a first decade (March 1990–Dec 1999) and second ber 2010 as shown in Table 1. In the decade (Jan 2000–Jan 2010). The second decade coincides with design changes, bandage contact United States, there was a dramatic lens and vancomycin use; minimum 2-year follow-up. decline in the incidence of endophthalm- 1990–1999 2000–2010 itis from the first decade of use (12%) compared to the second decade (2.9%). Total number of B-KPro implantations 113 291 The international incidence of endoph- Autoimmune % 42 32 thalmitis from the first decade was not Chemical or thermal burn % 29 12 calculated due to the absence of reliable Graft failure or other (non-autoimmune, non-burn) % 29 56 reports. In the second decade, a higher Severe endophthalmitis cumulative incidence of endophthalm- Bacterial % 10.1 1.7 Atypical mycobacteria % 0 0.7 itis was seen internationally (5%) Fungal % 0 2.4 compared to U.S. surgeons (2.9%).

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decade. In the second decade, antibiotic non-compliance in two of ﬁve

92 patients precipitated severe bacterial –

Gentamicin or Tobramycin endophthalmitis with complete vision – – † loss remarkably in a brief 3 5 days. In the other three patients, partial non- compliance (not taking one of the two antibiotics) appeared to lead to 99 90 9899 95 87 not done. > > > destructive endophthalmitis in just a = few days. Information on antibiotic susceptibility was limited because two-thirds of the endophthalmitis events occurred in patients who lived or travelled to areas distant from our site. Antibiotic resis- Trimethoprim/ Sulphamethoxazole Polymyxin B ibilities (Clinical Microbiology, Newton-Wellesley tance (all fluoroquinolone resistance) was identified in five cases involving CNS and Streptococcus pneumoniae infection; both organisms are associ- 9 100 Tetracycline or Doxycycline – moxifloxacin and gatifloxacin, ND ated with a 30 40% resistance

= (Table 3). Both cases of atypical mycobacteria (M. abscessus) were fluoroquinolone resistant (de la Cruz et al. 2007). All seven fungal and the two † atypical mycobacterial cases were on both vancomycin and 4-FQ at the time of the endophthalmitis, and 50% of these infections were in non-autoimmune, non-burn patients (Fig. 3). To offer insight into safe and cost- effective antibiotic regimens, we reviewed sequential medical records for non-burn/non-autoimmune patients 729028 6468 74 38 61 99 99 94 98 96 95 98 90 99 99 98 77 R R R R 98 99 97 91 86 R Rwho received R aB-KPro R from 2007 – – – – –

Ciproﬂoxacin- Levoﬂox-4FQ Clindamycin Chloramphenicol through January 2010 and calculated naturally resistant or susceptibility is 0%, 4-FQ the number of years on a prophylactic = antibiotic regimen. Since 2007, there has .R been a deliberate shift back to TMP- 2012. Numbers are percent susceptible based on Clinical & Laboratory Standards Institute (CLSI) guidelines.

– PMB use in this non-inﬂammatory group. We report 30 cumulative years S. aureus of TMP-PMB alone use without adverse events except due to non-compliance in one patient (Fig. 3). One patient while on ﬂuoroquinolone alone (Fig. 3) expe- Erythromycin or Azithromycin Vancomycin rienced CNS vitritis 1-week post-Ah- med shunt placement and 5 months methicillin-resistant post-B-KPro implantation (2009); he = regained full vision. Of note, no patients 98 R R 95 R 92 97 R R 86 R S 75 89 – – have developed fungal keratitis or Cefazolin, Ceftriaxone*, or Ceftazidime

, MRSA endophthalmitis while on TMP-PMB. Discussion S. aureus

MA State median susceptibilities reported (2011), MA Dept of Public Health, Jamaica Plain, MA). The present study is a descriptive syn- thesis of three reporting methodologies to assess the cumulative incidence of RR95 R R 99 R R 87 172266 71%51 ND 66% 43 R 88 89 43 100 60 100 69 100 66 100 88 95* 84 82 R ND 79 R 100 R R 95 R S R 95 R 89 B-lactams Penicillin or Ampicillin Oxacillin endophthalmitis and to assess the eﬃ- cacy of diﬀerent antibiotic prophylactic methicillin-sensitive

Boston area community-based hospitals antibiotic susceptibilities regimens for prevention of endoph- total = thalmitis associated with the Boston keratoprosthesis. The challenges in this MSSAMRSA 24 R 100 R 57 10 100 100 87 26 marcesans aureus- staphlyococci pneumoniae coli mirablilis aeruginosa Streptococus pneumoniae Data are derived from the literature. Serratia Staphylococcus Coag-negative Streptococcus Escherichia Proteus Pseudomonas Gram-positives Gram-negatives Table 3. Organisms MSSA † Sources are from the PorterHospital, Bacteriology Newton, Laboratory, Massachusetts MA Eye (2010). and* Ear Inﬁrmary, Boston, MA, with the exception of chloramphenicol suscept study are those inherent in retrospective

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continue to face are microbiologically unsafe water, medical access and compliance. We suspect that the difference between the literature review and the surveillance survey in the United States is a reporting bias that favours publication of ‘positive’ findings (endophthalmitis). The paradigm shift in endophthalmitis incidence is best exemplified from one surgeon’s long-term practice in Boston where the overall severe bacterial endophthalmitis incidence fell from 10% in the 1990s to less than 2% in 2000–2010 period (Table 2), with a similar number of autoimmune patients represented in the two decades. Similar results in the literature and by unpublished surgeons’ reports during the surveillance survey have been achieved (Table 1). Several pos- tulates for this drastic improvement Fig. 3. Boston keratoprosthesis-associated endophthalmitis microbial spectrum timeline. This include design changes improving single-surgeon timeline over 20-year period reflects device interventions, introduction of bandage nutrition to the corneal graft, thera- contact lens and changes in prophylactic antibiotic usage. peutic contact lens to minimize drying- associated epithelial damage and the systematic introduction of vancomycin literature reviews and surveillance sur- To assess accurately the cumulative to the prophylactic repertoire (espe- veys in which criteria and diagnostic global incidence of endophthalmitis, cially in the vulnerable autoimmune methods to diagnose endophthalmitis we used two methodologies. The first patients), all in the late 1999s (Fig. 3; are not predefined and could be poten- was a systematic literature review, Nouri et al. 2001; Durand & Dohlman tially subjects for recall bias. Incomplete inclusive of case reports, in which we 2009). The efficacy of vancomycin in reporting of prophylactic antimicrobial found the cumulative incidence to be combination with a fluoroquinolone regimens and microbiologic details fur- no more than 4.8% in both the United was compared to a fluoroquinolone ther limits this study. States and internationally during the alone concluding that combination For the purpose of this study, the second decade of B-KPro implanta- therapy was superior to single fluor- definition of endophthalmitis is tion. The discrepancy from other liter- oquinolone therapy (Durand & Dohl- involvement of the posterior (vitreous) ature reviews (Robert et al. 2012b) man 2009). Of note, vancomycin was of the eye – not keratitis alone or reflect that we evaluated (i) the inci- neither combined with another non- anterior chamber reaction alone. A dence by implantation study years and fluoroquinolone antibiotic nor was a sudden infection with redness, severe not by publication year, (ii) later pub- comparison made to another antibiotic pain and positive culture, leading to a lications by the same surgeon(s) to combination regimen such as TMP- dramatic reduction of final vision is avoid duplicate reporting and (iii) all PMB. Importantly, reports of fungal the main focus of this study. How- electronic databases without language infections (keratitis and endophthalm- ever, in other cases, the vision loss restrictions. The second method we itis) and uncommon organisms (Barnes may be sudden and drastic, but the employed was the ‘door-to-door’ glo- et al. 2007; Chan & Holland 2012) only subsequent course mild and with little bal surveillance survey (Table 1) often occurred after introduction of these pain, tenderness or redness and with a viewed as the most accurate, albeit changes (Fig. 3). final recovery to most or all of the labour intensive. Herein, we report that Over the past two decades, there pre-existing visual acuity. The latter the overall cumulative incidence in the have been widely different management presentation can represent a sterile United States of Boston keratopros- patterns and outcomes from different (possibly immune-mediated) vitritis thesis-associated endophthalmitis was institutions both in the United States (Nouri et al. 2005), or it can result 3.2% spanning over two decades of and internationally, and they offer from infection with a low-virulent use. The international incidence was valuable clues that may lead to organism (e.g. CNS) – the distinction higher at 5% during the second decade improved and standardized postopera- may be clinically difficult; cultures can despite shorter follow-up periods. As tive prophylaxis. The use of vancomy- be ambiguous (Ormerod et al. 1993a, might be expected, countries with cin mono-prophylaxis by Mannis and b; Bannerman et al. 1997), and there- greater economic and medical coworkers (Bradley et al. 2009; Greiner fore, exact aetiology can remain in resources have lower endophthalmitis et al. 2011; Li et al. 2011) dramatically doubt. The first severe group with rates than less developed countries, shifted infections to Gram-negatives poor visual outcome is the subject of where most of the corneal blind dwell. and yeast (even in non-autoimmune, this study. The challenges these latter countries non-burn eyes) and demonstrated that

6 Acta Ophthalmologica 2014 even high-dose vancomycin was insuf- fourth-generation fluoroquinolones, or for patients and can invite fungal or ficient to ward off Staphylococcus vancomycin in combination with a other opportunistic infections. Given aureus infections in exposed situations. fluoroquinolone (FQ) heavily selects that S. pneumoniae infections of the Thus, their report provides supportive for colonizing yeast, fungi and uncom- eye almost always leads to devastating evidence that coverage of Gram-nega- mon FQ-resistant bacteria (including loss of vision, we also recommend tive bacteria is important in prophy- atypical mycobacteria; Chew et al. prevention with the newer pneumococ- laxis and that the effects of vancomycin 2009; Fintelmann et al. 2009; Utine cal vaccines. Cultures at the time of on commensal ocular microflora is et al. 2011a; Chan & Holland 2012; surgery to screen for resistant organ- profound. Additionally, there has been Patel et al. 2012). In our single-surgeon isms or when there is a clinical change concern that high-dose vancomycin experience (Fig. 3), we see the effect of are encouraged. may lead to epithelial cytotoxicity (Yu vancomycin for selection of these same An additional factor in achieving & Huang 2011). uncommon pathogens. Evidently, our success with endophthalmitis prophy- Fluoroquinolones, particularly the prophylactic choices do appear to have laxis is the patient’s compliance with fourth generation, have also been used a profound effect on the ocular the regimen – for life. As we and others as a single agent for prophylaxis. The surface’s protective indigenous micro- have witnessed, even after years of longitudinal experience of Aquavella biota. KPro stability, the patient must under- and coworkers provides the most It may seem counter-intuitive that stand that a lapse over a few days can insight. Combined vancomycin and such a small dose of antibiotics, if given result in the devastating loss of the eye, fluoroquinolones resulted in no infec- daily, can protect an eye with a and this message deserves to be tions in their early reports (Aquavella penetrating device from infection. The repeated at every patient visit. Under et al. 2005, 2006; Aquavella et al. 2007; result of prophylaxis cannot be the any circumstances, it seems that the Akpek et al. 2007; Dunlap et al. 2010). total elimination of the indigenous greatest threat to long-term safety of As he and others changed to fluoroqu- microbiota, but prevention of infection the operated eye lies in laxity of steady, inolone use alone (Chew et al. 2009; by opportunistic pathogenic bacteria, daily compliance with the antibiotic Fintelmann et al. 2009; Robert et al. while not promoting antibiotic resis- prophylaxis. 2012a,b; Ramchandran et al. 2012), tance and maintaining some protective Tied into the compliance issue are vitritis with CNS emerged with greater commensal microflora. the cost of antibiotics and the com- than 50% CNS documented to be With judicious prophylactic antibi- plexity of purchase. Expensive drugs resistant to fluoroquinolones (FQ-R), otic usage, we have seen no cases of requiring compounding in a pharmacy along with two other FQ-R species marked adverse reaction, on the sur- and also shipment can be discouraging (Ramchandran et al. 2012). Fluoroqu- face or inside the eye. On the other to the point of non-compliance. Diffi- inolone resistance has been well docu- hand, we would caution against using culties of medication access may be mented even in ocular isolates over combinations of powerful antibacteri- playing a significant role in the higher the past two decades (Table 4; Ocular als in too frequent doses such as four endophthalmitis rates seen internation- Microbiology, Bascom Palmer Eye times a daily. Such a high concentra- ally (Table 1; Gevorgyan et al. 2011). Institute (2012); Schimel et al. 2012). tion and frequent prophylactic dosing Table 4 illustrates the cost aspect of Reports have been accumulating over long times can lead to ocular antibiotic combinations in the Boston that vancomycin as a single agent, toxicity (Bezwada et al. 2008; Etminan area that will have to be put into the frequent dosing of broad-spectrum et al. 2012), is challenging and costly context of what is available on the

Table 4. Topical ophthalmic antibiotic retail cost in the United States 2012. Prices are retail prices per Massachusetts Eye and Ear Inﬁrmary (MEEI) suppliers unless noted.

Microbial spectrum Antibiotics Quantity (ml) Cost per ml (U.S. dollars)

Gram-Positives Vancomycin 14 mg/ml* 4 8 Azithromycin 1% (AzaSite) 2.5 41 Cefazolin 133 mg/ml* 4 8 Levofloxacin 0.5% 5 16 Ofloxacin 0.3% 5 3 Chloramphenicol 0.5%† 10 8 Doxycycline 0.1%† 10 5 Trimethoprim/Polymyxin B (Polytrim) 10 1 Gatifloxacin 0.5% (Zymaxid) 2.5 49 Moxifloxacin 0.3% (Vigamox) 3 36 Ciprofloxacin 0.3% 2.5 10 Ceftazidime 50 mg/ml* 4 9 Gentamicin 3 mg/ml* 7 4 Tobramycin 3 mg/ml* 7 6

Gram-Negatives

* MEEI compounding patient cost (non-retail). † Leiter’s compounding pharmacy (preservative-free formulations).

7 Acta Ophthalmologica 2014 market in any specific country. Given fungal keratitis leading to endoph- prevent both colonization and infec- the increasing fluoroquinolone resis- thalmitis may be prevented. Often, cure tion of the B-KPro itself (Behlau et al. tance, a particularly effective broad- requires longer antifungal treatment 2011a,b). spectrum combination antibiotic at low and eventual KPro exchange. In coun- cost seems to be TMP-PMB (Tables 3 tries with warm, humid climates and Acknowledgements and 4); it is now favoured by us in our agricultural exposures, prophylactic non-autoimmune patients with rela- antifungals may perhaps be given We are most grateful to Rhonda Wal- tively normal tear and blink mecha- together with antibacterials after KPro cott-Harris whose assistance has been nisms with only one drop instilled per surgery. Also, the benefits of economical invaluable and Roberto Pineda II, day (Table 5). In autoimmune patients, 5% povidone-iodine wash at each clinic MD, for advice on infection prevention on the other hand, 1.4% vancomycin is visit (Table 5) are not yet evidence based recommendations in the International added once or twice per day to either but appear promising, especially in B-KPro protocol. We would also like TMP-PMB or fluoroquinolone (Table 5). high-risk patients and environments to thank Laura Collins (MEEI Howe Perhaps an only eye and chemical burn (Pineda R and Behlau I, unpublished Library, Boston, MA); Rick P. Boody, eyes would also fall in this latter cate- data; Ament et al. 2009; Magalhaes MT(AMT), Elizabeth Leonard MT gory. Since this shift in practice, the et al. 2013). Additionally, short ‘bursts’ (ASCP), MPH, Therese F. Labrecque emergence of inherently resistant yeast, of antifungals (e.g. amphotericin B M(ASCP), M. Susan Parker (deceased) fungi and atypical organisms in non- drops twice daily for a week every MT(ASCP), Nancy Sutcliffe, MT autoimmune patients appears to have 2–3 months) appear beneficial in some (ASCP) (MEEI Henry Whittier Porter abated (Behlau I and Dohlman CH, autoimmune or burn patients, especially Bacteriology Laboratory); Susan Man- unpublished data; Table 5, Fig. 3). in those with prior fungal infections or ning, MT(ASCP) for Newton-Welles- Compared to aggressive bacteria heavy colonization. The cost and the ley Hospital (Clinical Microbiology that can slide along the KPro stem availability of antifungal treatments Laboratory, Newton-Wellesley Hospi- and rapidly infect the anterior cham- may be limiting in some locations. tal, Newton, MA); Debbie Rich, RN ber, fungal infections are usually slower The reported results are clearly (Infection Control, MEEI, Boston, and can be contained if recognized. important for the proper positioning MA); Larisa Gelfand, Mary Lou They usually start as a keratitis in the of the B-KPro in the stepladder of Moar, Ludmilla Menelau Cavalcanti graft, manifested as a whitish sheen in worldwide surgical treatment options (KPro Research, MEEI, Boston, MA), the tissue around the stem and progress of corneal opacities. Our hope is that John Graney and Susan Kinnean (JG relatively slowly. Still of the cases of the global bacterial infection rate Machine Co, Wilmington, MA); James endophthalmitis reported in Table 2, post-B-KPro (over the patient’s life- Chodosh, MD, MPH, Rony Sayegh, six were ascribed fungal aetiology but time) can be reduced to one per cent MD, Eleftherios Pascalis, PhD, Borja of these, only two patients lost vision in or less with thoughtful and compul- Salvador Culla, MD (B-KPro Research, the operated eye. With more attention, sive management while awaiting MEEI, Boston, MA) and Andrew education and rapid intervention, newer antimicrobial approaches to Wright, PhD (Molecular Biology and

Table 5. Examples of daily prophylactic antibacterial regimens. Double antibiotic regimens are recommended to prevent the emergence of resistance. Antibiotic selection should be based on local susceptibility patterns. Alternative I is currently preferred by us.

Alternative I Alternative II Alternative III

Low risk Trimethoprim sulphate Vancomycin 1.4% Chloramphenicol 1%* (low inﬂammation) 0.1%-Polymyxin B (TMP-PMB) plus plus 19 per Day Fluoroquinolone Fluoroquinolone 1–29 per Day 1–29 per Day High risk (autoimmune, chemical Vancomycin 1.4% Vancomycin 1.4% Chloramphenicol 1%* burn, only eye, epithelium defects) plus plus plus TMP-PMB Fluoroquinolone Fluoroquinolone 1–29 per Day OR OR TMP-PMB TMP-PMB plus plus Fluoroquinolone Choramphenicol 1%* 1–29 per Day 1–29 per Day

Additional recommendations to be considered:Preoperative: (1) Pneumococcal vaccine (conjugate (PCV-13) or polysaccharide (PPSV-23)) (2) Baseline cultures: a) MRSA nasal screen and b) conjunctival and/or corneal culture with sensitivities Routine clinic visit: (1) Reinforce antibiotic adherence and availability (2) Povidone-iodine 5%; wash per clinic visit (3) Consider contact lens exchange or cleaning (if deposits or every 3 months) * Chloramphenicol is not commercially available in the United States. Vancomycin must be specially prepared. Fluoroquinolones (FQ): ofloxacin, ciprofloxacin, levofloxacin, moxifloxacin, gatifloxacin.

8 Acta Ophthalmologica 2014

Microbiology, Tufts School of Medi- version_id=5816016 (Accessed August 15, thesis type I implantation. Cornea 31: 339– cine, Boston, MA). We would also like 2009). 467. to express our gratitude to the hundreds Aquavella JV, Qian Y, McCormick GJ & Chew HF, Ayres BD, Hammersmith KM, of Boston keratoprosthesis surgeons Palakuru JR (2005): Keratoprosthesis: the Rapuano CJ, Laibson PR, Myers JS, Jin YP Dohlman-Doane device. Am J Ophthalmol & Cohen EJ (2009): Boston keratoprosthesis around the world who have responded 140: 1032–1037. outcomes and complications. Cornea 28: to our survey and generously shared Aquavella JV, Qian Y, McCormick GJ & 989–996. their experiences. Palakuru JR (2006): Keratoprosthesis: cur- de la Cruz J & McMahon T (2009): Surveil- rent techniques. Cornea 25: 656–662. lance cultures of contact lenses of patients Aquavella JV, Gearinger MD, Akpek EK & with Boston kpro type I keratoprosthesis. Authors Contribution McCormick GJ (2007): Pediatric kerato- EVER 330: Oct 2, 2009. IB, KVM and JNM have full access to prosthesis. Ophthalmology 114: 989–994. de la Cruz J, Behlau I & Pineda R (2007): Case all of the data in the study and take Bajracharya L, Gurung R & Tabin F (2012): report: atypical mycobacteria keratitis after Keratoprosthesis, Dohlman type I device for laser in situ keratomileusis unresponsive to responsibility for the integrity of the a patient with repeated corneal graft failure. fourth generation fluoroquinolone therapy. data. IB and ENN take responsibility Nepal J Ophthalmol 4: 165–169. J Cataract Refract Surg 33: 1318–1321. for the data analysis. Bannerman TL, Rhoden DL, McAllister SK, de la Cruz J, Cortina MS, Chang J-H & Azar DT Miller JM & Wilson LA (1997): The source (2011): Scanning electron microscopy analysis of coagulase-negative staphylococci in the of explanted keratoprostheses. ARVO; D861. Funding Endophthalmitis Vitrectomy Study. A com- Doane MG, Dohlman CH & Bearse G (1996): This work was made possible by the parison of eyelid and intraocular isolates Fabrication of a keratoprosthesis. Cornea – generous support of Fight for Sight using pulsed-field electrophoresis. Arch 15: 179 184. – Grant-In-Aid (IB) and MEEI B-KPro Ophthalmol 115: 357 361. Dohlman CH (1993): Postoperative regimen Barnes SD, Dohlman CH & Durand ML and repair of complications after keratopros- Fund. (2007): Fungal colonization and infection in thesis surgery. Refract Corneal Surg 9:197–198. Boston keratoprosthesis. Cornea 26:9–15. Dohlman CH & Doane MG (1994): Some Conflict of Interest Barnham JJ & Roper-Hall MJ (1983): Kera- factors influencing outcome after kerato- toprosthesis: a long-term view. Br J Oph- prosthesis surgery. Cornea 13: 214–218. The MEEI B-KPro Fund is supported thalmol 67: 468–474. Dohlman CH & Terada H (1998): Keratopros- by sale of the Boston keratoprosthesis. Behlau I (2012):Boston keratoprosthesis-asso- thesis in pemphigoid and Stevens-Johnson The Boston keratoprosthesis is mar- ciated endophthalmitis: recommendations syndrome. Adv Exp Med Biol 438:1021–1025. keted under the auspices of the Mas- for prevention. Miami, Fl: 8th kPro Study Dohlman CH, Schneider HA & Doane MG Group, May 12, 2012. (1974): Prosthokeratoplasty. Am J Ophthal- sachusetts Eye and Ear Infirmary, Behlau I & Gilmore MG (2008): Microbial mol 77: 694–700. Boston, MA. biofilms in ophthalmology and infectious Dohlman CH, Dudenhoefer EJ, Khan BF & diseases. Arch Ophthalmol 126: 1572–1581. Morneault S (2002): Protection of the ocular Behlau I, Mukherjee K, Todani A et al. surface after keratoprosthesis surgery: the (2011a): Assessment of biocompatibility and role of soft contact lenses. CLAO J 28:72–74. 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