CADTH. Rapid Response Report: Peer-Reviewed Summary with Critical Appraisal. Canadian Agency for Drugs and Technologies in Health

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1 Canadian Agency for Drugs and Technologies in Health Agence canadienne des médicaments et des technologies de la santé Rapid Response Report: Peer-Reviewed Summary with Critical Appraisal CADTH Intracameral Antibiotics for the Prevention of Endophthalmitis Post-Cataract Surgery: Review of Clinical and Cost-Effectiveness and Guidelines October 2010 Supporting Informed Decisions

2 Until April 2006, the Canadian Agency for Drugs and Technologies in Health (CADTH) was known as the Canadian Coordinating Office for Health Technology Assessment (CCOHTA). Publications can be requested from: CADTH Carling Avenue Ottawa ON Canada K1S 5S8 Tel.: Fax: or downloaded from CADTH s website: Cite as: Ndegwa S, Cimon K, Severn M. Intracameral Antibiotics for the Prevention of Endophthalmitis Post-Cataract Surgery: Review of Clinical and Cost-Effectiveness and Guideline [Internet]. Ottawa: Canadian Agency for Drugs and Technologies in Health; 2010 (Rapid Response Report: Peer-Reviewed Summary with Critical Appraisal). [cited ]. Available from: Production of this report is made possible by financial contributions from Health Canada and the governments of Alberta, British Columbia, Manitoba, New Brunswick, Newfoundland and Labrador, Northwest Territories, Nova Scotia, Nunavut, Prince Edward Island, Saskatchewan, and Yukon. The Canadian Agency for Drugs and Technologies in Health takes sole responsibility for the final form and content of this report. The views expressed herein do not necessarily represent the views of Health Canada, or any provincial or territorial government. Reproduction of this document for non-commercial purposes is permitted provided appropriate credit is given to CADTH. CADTH is funded by Canadian federal, provincial, and territorial governments. Legal Deposit 2010 Library and Archives Canada ISSN: (print) ISSN: (online) M0019 October 2010 PUBLICATIONS MAIL AGREEMENT NO RETURN UNDELIVERABLE CANADIAN ADDRESSES TO CANADIAN AGENCY FOR DRUGS AND TECHNOLOGIES IN HEALTH CARLING AVENUE OTTAWA ON K1S 5S8

3 Canadian Agency for Drugs and Technologies in Health Intracameral Antibiotics for the Prevention of Endophthalmitis Post-Cataract Surgery: Sarah Ndegwa, BScPharm 1 Karen Cimon 1 Melissa Severn, MISt 1 October Canadian Agency for Drugs and Technologies in Health, Ottawa, ON

4 Health technology assessment (HTA) agencies face the challenge of providing quality assessments of medical technologies in a timely manner to support decision-making. Ideally, all important deliberations would be supported by comprehensive health technology assessment reports, but the urgency of some decisions often requires a more immediate response. The Health Technology Inquiry Service (HTIS) provides Canadian health care decision-makers with health technology assessment information, based on the best available evidence, in a quick and efficient manner. Inquiries related to the assessment of health care technologies (drugs, devices, diagnostic tests, and surgical procedures) are accepted by the service. Information provided by the HTIS is tailored to meet the needs of decision-makers, taking into account the urgency, importance, and potential impact of the request. Consultations with the requestor of this HTIS assessment indicated that a review of the literature would be beneficial. The research question and selection criteria were developed in consultation with the requestor. The literature search was carried out by an information specialist using a standardized search strategy. The review of evidence was conducted by one internal HTIS reviewer. The draft report was internally reviewed and externally peer-reviewed by two or more peer reviewers. All comments were reviewed internally to ensure that they were addressed appropriately.

5 Reviewers These individuals kindly provided comments on this report: Ken Bassett, MD, PhD Professor University of British Columbia Vancouver, BC Dena S. Hammoudi, MD Resident, Postgraduate Year 5 University of Toronto Toronto, ON W.E.S Connolly, MD, FRCSC Associate Professor McGill University Montreal, QC Industry: The following manufacturers were provided with an opportunity to comment on an earlier version of this report: Sandoz Canada Inc., Allergan Inc., and Alcon Canada Inc. All comments that were received were considered when preparing the final report. This report is a review of existing public literature, studies, materials, and other information and documentation (collectively the source documentation ) that are available to CADTH. The accuracy of the contents of the source documentation on which this report is based is not warranted, assured, or represented in any way by CADTH, and CADTH does not assume responsibility for the quality, propriety, inaccuracies, or reasonableness of any statements, information, or conclusions contained in the source documentation. CADTH takes sole responsibility for the final form and content of this report. The statements and conclusions in this report are those of CADTH and not of reviewers. This document is prepared by the Health Technology Inquiry Service (HTIS), an information service of the Canadian Agency for Drugs and Technologies in Health (CADTH). The service is provided to those involved in planning and providing health care in Canada. HTIS responses are based on a comprehensive and systematic search of literature available to CADTH at the time of preparation. The intent is to provide a summary and critical appraisal of the best evidence on the topic that CADTH could identify using all reasonable efforts within the time allowed. This response has been peer-reviewed by clinical experts. The information in this document is intended to help Canadian health care decision-makers make wellinformed decisions and thereby improve the quality of health care services. HTIS responses should be considered along with other types of information and health care considerations. This report should not be used as a substitute for the application of clinical judgment in respect of the care of a particular patient or other professional judgment in any decision-making process, or as a substitute for professional medical advice. Readers are also cautioned that a lack of good-quality evidence does not necessarily mean a lack of effectiveness, particularly in the case of new and emerging health technologies for which little information can be found, but which may in the future prove to be effective. While CADTH has taken care in the preparation of the document to ensure that its contents are accurate, complete, and up to date as of the date of publication, CADTH does not make any guarantee to that effect. CADTH does not guarantee and is not responsible for the quality, currency, propriety, accuracy, or reasonableness of any statements, information, or conclusions contained in the source documentation. CADTH is not responsible for any errors or omissions or injury, loss, or damage arising from or relating to the use (or misuse) of any information, statements, or conclusions contained in or implied by the information in this document or in any of the source documentation. i

6 Copyright: CADTH (October 2010). You are permitted to make copies of this document for non-commercial purposes provided it is not modified when reproduced and appropriate credit is given to CADTH. Links: This document may contain links to other information available on the websites of third parties on the Internet. CADTH does not have control over the content of such sites. Use of third-party sites is governed by the owners own terms and conditions set out for such sites. CADTH does not make any guarantee with respect to any information contained on such third-party sites and CADTH is not responsible for any injury, loss, or damage suffered as a result of using such third-party sites. ii

7 ACRONYMS AND ABBREVIATIONS CI ESCRS MRSA OR RCT RR confidence interval European Society of Cataract and Refractive Surgeons methicillin-resistant Staphylococcus aureus odds ratio randomized controlled trial relative risk iii

8 TABLE OF CONTENTS ACRONYMS AND ABBREVIATIONS...iii EXECUTIVE SUMMARY CONTEXT AND POLICY ISSUES RESEARCH QUESTIONS METHODS Literature search Article selection SUMMARY OF FINDINGS Randomized controlled trials Intracameral cefuroxime Intracameral moxifloxacin Intracameral vancomycin and gentamicin Observational studies Intracameral cefuroxime Intracameral vancomycin Intracameral cefazolin Intracameral moxifloxacin Economic evaluations Guidelines and recommendations Limitations CONCLUSIONS AND IMPLICATIONS FOR DECISION- OR POLICY-MAKING REFERENCES...13 APPENDIX 1: LITERATURE SEARCH STRATEGY...17 APPENDIX 2: SELECTION OF PUBLICATIONS...21 iv

9 TITLE: Intracameral Antibiotics for the Prevention of Endophthalmitis Post- Cataract Surgery: Review of Clinical and Cost-Effectiveness and Guidelines DATE: October 2010 EXECUTIVE SUMMARY Context and Policy Issues Endophthalmitis is a rare complication that can occur after routine cataract surgery. It is often associated with a poor prognosis and may result in severe, permanent vision loss. Despite advances in medical technologies and treatments, there is evidence that the incidence of post-operative endophthalmitis is increasing. There is significant variation among surgeons with respect to antibiotic prophylaxis for postoperative endophthalmitis. The intracameral injection of antibiotics has been investigated for the benefit of delivering an instantaneous, high concentration of antibiotic to the anterior chamber of the eye at the end of surgery. The exposure of intraocular tissues to high antibiotic concentrations may increase the risk of toxic effects, including macular edema and toxic anterior segment syndrome. This report reviews the evidence on the clinical effectiveness, safety, and cost-effectiveness of using intracameral antibiotics for the prevention of endophthalmitis after cataract surgery. Current evidence-based guidelines for the use of intracameral antibiotics are also presented. Research Questions 1. What is the clinical effectiveness of intracameral antibiotics for the prevention of endophthalmitis post-cataract surgery? 2. What is the cost-effectiveness of intracameral antibiotics for the prevention of endophthalmitis post-cataract surgery? 3. What are the guidelines for the use and preparation of intracameral antibiotics? Methods A literature search was conducted on health technology assessment resources, including Ovid MEDLINE, Ovid MEDLINE(R) In- Process & Other Non-Indexed Citations, PubMed, Embase, The Cochrane Library (Issue 5, 2010), the University of York Centre for Reviews and Dissemination (CRD) databases, EuroScan, international health technology agencies, and a focused Internet search. The search was limited to English language articles that were published between January 1, 2005 and May 17, Regular alerts are current to July 22, No filters were applied to limit the retrieval by study type for research questions 1 and 2. A filter was applied to research question 3 to limit the retrieval to guidelines. Two independent reviewers screened articles using pre-defined criteria. Summary of Findings Intracameral cefuroxime In a randomized controlled trial (RCT), the European Society of Cataract and Refractive Surgeons (ESCRS) assessed the clinical effectiveness of using intracameral cefuroxime with or without perioperative topical levofloxacin for the prevention of endophthalmitis after routine phacoemulsification cataract surgery. The study was halted early when a preliminary analysis of 16,211 patients showed that the absence of prophylactic intracameral cefuroxime was associated with a statistically significant increase in the risk of presumed infectious post-operative endophthalmitis. The absence of perioperative topical levofloxacin did not significantly increase the risk of post-operative endophthalmitis. The results of six observational studies support the superiority of using intracameral cefuroxime over alternatives, including topical antibiotics and subconjunctival cefuroxime, for the prophylaxis of postoperative endophthalmitis. No anaphylactic reactions or signs of toxicity were reported in two RCTs and one observational study. Intracameral moxifloxacin One RCT and one observational study evaluated the safety of using intracameral moxifloxacin compared with intracameral balanced salt solution. No drug-related adverse events occurred, and there were no statistically 1

10 significant differences in safety parameters between the two groups. A second observational study evaluating the safety of using intracameral moxifloxacin showed no statistically significant differences between pre- and post-surgical measurements of safety parameters. Intracameral vancomycin One RCT found no statistically significant differences in macular edema or visual acuity when intracameral vancomycin plus gentamicin was compared with no antibiotics. One observational study showed a statistically significant reduction in the incidence of postoperative endophthalmitis when intracameral vancomycin plus topical fusidic acid was compared with topical fusidic acid alone. Intracameral cefazolin Two observational studies showed a statistically significant reduction in the rate of post-operative endophthalmitis with the use of intracameral cefazolin plus topical antibiotics compared with topical antibiotics alone. No toxic effects or anaphylactic reactions were reported in either study. Economic evaluations One US cost-effectiveness analysis conducted from a societal perspective determined that intracameral cefuroxime was more cost-effective than intracameral moxifloxacin or topical antibiotics for the prevention of endophthalmitis after cataract surgery. Conclusions and Implications for Decision- or Policy-Making There is consistent evidence that the use of intracameral cefuroxime reduces the risk of post-operative endophthalmitis without significant safety issues. An economic analysis determined that the use of intracameral cefuroxime was more cost-effective than intracameral moxifloxacin or topical antibiotics in the prevention of post-operative endophthalmitis. Based on the identified literature, there is insufficient evidence to support the use of the other intracameral antibiotics that were evaluated in the included studies. The included studies did not support the routine use of topical fluoroquinolones over intracameral cefuroxime. Despite these findings, most guidelines leave the choice of prophylactic antibiotic and mode of administration to the individual surgeon s discretion, and many surgeons favor the use of topical moxifloxacin or gatifloxacin. Until more information is available, the strengths and limitations of the available evidence, clinical experience, changes in microbial resistance, emergence of new pathogens, and institution-specific budgets may be considerations regarding the choice of antibiotic and mode of administration for the prophylaxis of post-operative endophthalmitis. Guidelines and recommendations Two international guidelines recommend the use of intracameral antibiotics for the prophylaxis of post-operative endophthalmitis. One guideline does not specify the choice of antibiotic, and the other guideline recommends the use of intracameral cefuroxime, but not intracameral vancomycin. Two North American guidelines leave the choice of prophylactic antibiotic and mode of administration to the individual surgeon s discretion. 2

11 1 CONTEXT AND POLICY ISSUES Endophthalmitis is a rare complication that can occur after routine cataract surgery. 1 It is often associated with a poor prognosis and may result in severe, permanent vision loss. 1 Gram-positive bacteria, including Staphylococcus epidermidis (S. epidermis) and Staphylococcus aureus, account for more than 90% of post-operative endophthalmitis infections. 1,2 Infections due to other gram-positive bacteria (including various Streptococci and Enterococci species) and gramnegative bacteria have also been reported. 1,2 Several studies have estimated the incidence of post-operative endophthalmitis to be between 0.043% and 0.15% in Canada. 3-6 Despite advances in medical technologies and treatments, there is evidence that the incidence of post-operative endophthalmitis is increasing. 7 Changes in surgical techniques, incision type, and an aging population may be some of the factors that are driving this trend. 5,7,8 Furthermore, recent data show that the number of cataract procedures performed in Canada continues to increase. 9 A total of 255,800 cataract surgeries were performed nationally between 2007 and 2008, representing a 15% increase from the number of surgeries that were performed between 2004 and Because of the health and economic burden associated with endophthalmitis, prophylaxis with antibiotics has been introduced to prevent infection. 10 There is significant variation among surgeons with respect to choice of the antibiotic and the administration route. 3,4,11-14 Intracameral injection has been investigated for the benefit of delivering an instantaneous, high concentration of antibiotic to the anterior chamber of the eye at the end of surgery. 15 However, the exposure of intraocular tissues to high antibiotic concentrations may increase the risk of toxic effects, including macular edema (swelling of the central portion of the retina resulting in visual distortion) and toxic anterior segment syndrome (a noninfectious inflammatory reaction with signs and symptoms that mimic endophthalmitis infection). 15,16 In light of the significant morbidity that is associated with endophthalmitis, an assessment of different prophylactic options is needed. This report reviews evidence on the clinical effectiveness, safety, and cost-effectiveness of using intracameral antibiotics for the prevention of endophthalmitis after cataract surgery. Current evidence-based guidelines for the use of intracameral antibiotics are also presented. 2 RESEARCH QUESTIONS 1. What is the clinical effectiveness of intracameral antibiotics for the prevention of endophthalmitis post-cataract surgery? 2. What is the cost-effectiveness of intracameral antibiotics for the prevention of endophthalmitis post-cataract surgery? 3. What are the guidelines for the use and preparation of intracameral antibiotics? 3 METHODS 3.1 Literature search Peer-reviewed literature searches were conducted to obtain published literature for this review. All search strategies were developed by the information specialist with input from the project team. The following bibliographic databases were searched through the Ovid interface: MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, and EMBASE. Parallel searches were run in PubMed and The Cochrane Library (Issue 5, 2010). The search strategy comprised controlled vocabulary, such as the National Library of Medicine s MeSH (Medical Subject Headings) and keywords. No filters were applied to limit the retrieval by study type for research questions 1 and 2. A filter was applied to research question 3 to limit the retrieval to guidelines. The detailed search strategies appear in Appendix 1. The search was restricted to English language articles that were published between January 1, 3

12 2005 and May 17, Regular alerts were established on Embase and MEDLINE, and information that was retrieved through alerts was current to July 22, Grey literature (literature that is not commercially published) was identified by searching the websites of health technology assessment and related agencies, professional associations, and other specialized databases. Google and other Internet search engines were used to search for additional information. These searches were supplemented by handsearching the bibliographies and abstracts of key papers, and through contacts with appropriate experts and agencies. 3.2 Article selection Two independent reviewers (SN, KC) screened the titles and abstracts of the retrieved publications. The same two reviewers independently evaluated the full-text publications for final article selection. The criteria for inclusion were: Population Patients undergoing cataract surgery. Intervention Comparator Outcomes Study design Intracameral antibiotics for the prevention of endophthalmitis. Other prophylactic therapies or no prophylaxis. Clinical effectiveness, safety, costs, cost-effectiveness, guidelines. Systematic reviews, systematicreview-based meta-analyses, randomized controlled trials (RCTs), controlled clinical trials, observational studies, economic studies, evidencebased guidelines. The criteria for exclusion were: in vitro studies experimental animal model studies. 4 SUMMARY OF FINDINGS Of the 334 citations that were identified in the literature search, 283 were excluded after screening of titles and abstracts, and 51 were retrieved for full-text screening. Four relevant publications were identified in the grey literature search. Twenty publications were included in this review, and the remaining 35 articles were excluded (Appendix 2). Four RCTs, observational studies, 8,21-30 one economic evaluation, 31 and four evidence-based guidelines were identified. The literature search did not identify any health technology assessments, systematic reviews, meta-analyses, or controlled clinical trials. 4.1 Randomized controlled trials Intracameral cefuroxime The European Society of Cataract and Refractive Surgeons (ESCRS) study was a multicentre, double-blind, placebo-controlled, partially masked RCT. 17 Twenty-four European ophthalmology units and eye clinics assessed the clinical effectiveness of using intracameral cefuroxime with or without perioperative topical levofloxacin for the prevention of endophthalmitis after routine phacoemulsification cataract surgery. Patients who were allergic to penicillins or cephalosporins; those in long-term nursing homes, those who were pregnant, those who had severe thyroid disease, or those who were younger than 18 years old; and all groups who were severely at risk for infection, including those with severe atopic keratoconjunctivitis or active blepharitis, were excluded from the study. The majority (58%) of participants were women with a median age of 73 years to 75 years. Approximately 14% of the study population had diabetes. The random allocation divided patients into four treatment groups based on a 2 x 2 factorial design. Two of the four groups were treated with intracameral cefuroxime (1 mg in 0.1 ml normal saline solution) at the end of 4

13 surgery. Two groups (one treated with intracameral cefuroxime, one untreated) received perioperative topical levofloxacin 0.5% in a standard regimen. The study was masked for levofloxacin but not for intracameral cefuroxime. All groups also received povidoneiodine 5% preoperatively and topical levofloxacin 0.5% four times daily postoperatively for six days. The primary study end points were the overall number of patients with presumed infectious post-operative endophthalmitis and the number of patients with infectious post-operative endophthalmitis proven using culture, Gram stain, or polymerase chain reaction. The outcomes of the four groups appear in Table 1. The researchers planned to randomize 32,000 patients but the study was stopped early, after analysis of the available data from 16,211 patients showed that the incidence of endophthalmitis in the groups not receiving intracameral cefuroxime was statistically significantly higher than that in the groups receiving intracameral cefuroxime. A total of 29 cases of post-operative endophthalmitis were reported, 20 of which had a proven infectious cause. Five of the 29 reported cases occurred in groups receiving intracameral cefuroxime. Of these five cases, three had a proven infectious cause (two cases of S. epidermis in the group receiving intracameral cefuroxime and one case of Staphylococcus warneri in the group receiving intracameral cefuroxime and topical levofloxacin). Toxic anterior segment syndrome was not believed to be the cause of the presenting signs and symptoms in the two remaining unproven cases. The incidence of post-operative endophthalmitis was lower in patients receiving intracameral cefuroxime and perioperative topical levofloxacin than intracameral cefuroxime alone (0.049% versus 0.074%). The statistical significance was not calculated. A logistic regression analysis showed that the absence of prophylactic intracameral cefuroxime was associated with a statistically significant increase in the risk of presumed infectious post-operative endophthalmitis (odds ratio [OR] 4.92; 95% confidence interval [CI] 1.87 to 12.9; P = 0.001). The absence of topical levofloxacin was not associated with a statistically significant increase in risk of presumed infectious post-operative endophthalmitis (OR 1.41; 95% CI 0.67 to 2.95, P = 0.368). No cases of anaphylaxis were observed in the patients receiving intracameral cefuroxime. No other safety outcomes were reported. Based on these findings, the authors concluded that an intracameral injection of cefuroxime reduces the risk of infectious postoperative endophthalmitis after phacoemulsification cataract surgery. In a single-centre, double-masked RCT, Gupta et al. investigated whether intracameral cefuroxime increases the risk of macular edema. 18 Patients were randomized to receive intracameral cefuroxime (1 mg of cefuroxime in 0.1 ml normal saline solution) (34 patients) or an equal volume of intracameral balanced salt solution (28 patients) after phacoemulsification cataract surgery. Macular edema was measured using ocular coherence tomography. There were no significant differences between groups in demographic or surgical characteristics. The results showed there were no statistically significant differences between groups in macular edema four to six weeks after surgery. The use of intracameral cefuroxime did not affect post-operative visual acuity. The authors concluded that these results support the safety of using intracameral cefuroxime in routine cataract surgery. 5

14 Group A Intervention Placebo vehicle drops 5* No intracameral injection Table 1: Results of ESCRS Study 17 Group B Intervention Placebo vehicle drops 5* Intracameral cefuroxime 1 mg Endophthalmitis incidence rates Intent-to-treat (n = 4,054) Total: 14 (0.345%; 95% CI 0.119% to 0.579%) Proven: 10 (0.247%; 95% CI 0.118% to 0.453%) Per-Protocol (n = 3,990) Total: 13 (0.326%; 95% CI 0.174% to 0.557%) Proven: 9 (0.226%; 95% CI 0.103% to 0.428%) Group C Intervention Levofloxacin drops 0.5% 5* No intracameral injection Endophthalmitis incidence rates Intent-to-treat (n = 4,049) Total: 10 (0.247%; 95% CI 0.119% to 0.454%) Proven: 7 (0.173%; 95% CI 0.070% to 0.356%) Per-Protocol (n = 3,984) Total: 10 (0.251%; 95% CI 0.120% to 0.461%) Proven: 7 (0.176%; 95% CI 0.071% to 0.362%) Endophthalmitis incidence rates Intent-to-treat (n = 4,056) Total: 3 (0.074%; 95% CI 0.015% to 0.216%) Proven: 2 (0.049%; 95% CI 0.006% to 0.178%) Per-Protocol (n = 3,997) Total: 3 (0.075%; 95% CI 0.016% to 0.219%) Proven: 2 (0.050%; 95% CI 0.006% to 0.181%) Group D Intervention Levofloxacin drops 0.5% 5* Intracameral cefuroxime 1 mg Endophthalmitis incidence rates Intent-to-treat (n = 4,052) Total: 2 (0.049%; 95% CI 0.006% to 0.178%) Proven: 1 (0.025%; 95% CI 0.001% to 0.137%) Per-Protocol (n = 4,000) Total: 2 (0.050%; 95% CI 0.006% to 0.181%) Proven: 1 (0.025%; 95% CI 0.001% to 0.139%) CI=confidence interval; ESCRS = European Society of Cataract and Refractive Surgeons. *Two drops given preoperatively and three drops given post-operatively. All groups also received povidone-iodine 5% preoperatively and topical levofloxacin 0.5% four times daily post-operatively for six days Intracameral moxifloxacin In a multicentre, open-label RCT, Lane et al. evaluated the safety of intracameral moxifloxacin. 19 Participants were randomized to receive an intracameral injection of a 250 g/0.050 ml dose of undiluted moxifloxacin 0.5% ophthalmic solution (26 eyes) or an equal volume of balanced salt solution (31 eyes) at the end of routine phacoemulsification cataract surgery. The two study groups were comparable at baseline for demographic and clinical characteristics. The mean age of participants was 74 years 9.3 years (range 51 years to 88 years), and most (59.6%) were women. The safety parameters that were assessed included macular edema, visual acuity, intraocular pressure, effects on the cornea (endothelial cell density and thickness, corneal clarity, and edema), inflammation in the anterior chamber (aqueous cell count), and effects on the bloodaqueous barrier (aqueous flare). The results showed that there were no statistically significant differences between the two groups in safety parameters preoperatively or at followup visits at one day, two to four weeks, or three months post-operatively. No study-related adverse events occurred. The authors concluded that an intracameral injection of a commercially available moxifloxacin ophthalmic solution appears to be safe for the prophylaxis of endophthalmitis after cataract surgery Intracameral vancomycin and gentamicin In a single-centre, evaluator-blinded RCT, Ball et al. investigated whether the use of 6 Intracameral Antibiotics for Prevention of Endophthalmitis Post-Cataract Surgery:

15 vancomycin and gentamicin increases the risk of macular edema after phacoemulsification cataract surgery. 20 Forty-one patients (25 eyes in each group) were randomized to receive no antibiotics or vancomycin (20 g/ml) and gentamicin (8 g/ml) in the infusion fluid at the time of cataract surgery. There were no significant differences between groups in preoperative or surgical factors. The mean age was 70.2 years in the control group and 68.5 years in the antibiotic group, and most (56%) of the participants were male. The results showed no statistically significant differences in macular edema or visual acuity between groups five weeks post-operatively. Based on these findings, the authors concluded that the use of intracameral vancomycin and gentamicin in the infusion fluid at the time of cataract surgery does not increase the risk of macular edema or negatively affect visual function postoperatively. 4.2 Observational studies Intracameral cefuroxime In a single-centre, 10-year (January 1999 to December 2008) study, Garcia-Sáenz et al. prospectively evaluated the effectiveness of using intracameral cefuroxime for the prevention of endophthalmitis in patients who underwent cataract surgery. 21 Before the introduction of intracameral cefuroxime, 6,595 patients received topical ofloxacin 0.3% four times daily for a week after surgery. In 2005, antibiotic prophylaxis in 7,057 patients was switched to intracameral injection cefuroxime (1.0 mg in 0.1 ml normal saline) at the end of cataract surgery. The incidence in post-operative endophthalmitis was statistically significantly higher in the group who received topical ofloxacin compared with those who received intracameral cefuroxime (0.590% versus 0.043% respectively; relative risk [RR] 0.072; 95% CI to 0.231; P < 0.05). The causative organisms in the cases of endophthalmitis occurring after the introduction of intracameral cefuroxime could not be identified using culture. No safety outcomes were reported. In a single-centre, retrospective (October 2001 to April 2007) chart review of patients undergoing phacoemulsification cataract surgery, Sobaci et al. evaluated the effectiveness of using intracameral cefuroxime. 22 Before the introduction of intracameral cefuroxime, 3,075 patients received topical ofloxacin 0.3% four times daily for one week after surgery, which was then tapered and stopped after two weeks. In 2004, the intracameral injection of cefuroxime (1.0 mg in 0.1 ml normal saline) was added to the prophylactic regimen in 3,024 surgeries. The incidence of post-operative endophthalmitis was statistically significantly higher in patients who received topical ofloxacin alone compared with patients who also received intracameral cefuroxime (0.42% versus 0.13% respectively; OR 3.20; 95% CI 1.04 to 9.84; P = 0.031). Three of the four cases of endophthalmitis occurring in the group receiving intracameral cefuroxime had a proven infectious cause (one case each of Aspergillus fumigatus, Pseudomonas aeruginosa, and Streptococcus pneumonia). No signs of toxicity, including toxic anterior segment syndrome or anaphylactic reactions, were documented in the intracameral cefuroxime group. In a single-centre retrospective (January 2000 to December 2006) database analysis, Yu-Wai- Man et al. evaluated the clinical effectiveness of using intracameral cefuroxime (1 mg in 0.1 ml normal saline) in 17,318 procedures compared with the use of subconjunctival cefuroxime (50 mg in 0.5 ml normal saline) in 19,425 procedures, for the prevention of endophthalmitis after phacoemulsification cataract surgery. 23 The incidence of presumed infectious endophthalmitis was statistically significantly higher in the subconjunctival cefuroxime group than in the intracameral cefuroxime group (0.139% versus 0.046% respectively; OR 3.01; 95% CI 1.37 to 6.63; P = ). No safety outcomes were reported. Two multicentre studies used prospective data from the Swedish National Cataract Register to assess the risk factors for the development of endophthalmitis after cataract surgery. 8,24 The first study collected data between 1999 and Surgeries using intracameral antibiotics 7

16 for prophylaxis were compared with surgeries not using intracameral antibiotics (151,874 versus 6,805 surgeries respectively). Intracameral cefuroxime was used in 98.5% of patients. Intracameral infusion of gentamicin and vancomycin was used in the remaining 1.5% of patients. The frequency of post-operative endophthalmitis was statistically significantly higher in patients who had not received intracameral antibiotics (OR 3.649; 95% CI to 5.812; P < 0.001). The second study 8 collected data between January 2002 and December 2004 and compared 223,156 surgeries using intracameral cefuroxime with 2,315 surgeries not using intracameral cefuroxime for prophylaxis. The frequency of post-operative endophthalmitis was statistically significantly higher in patients who had not received intracameral cefuroxime (OR 7.236; 95% CI 3.71 to 14.11; P < 0.001). Using multiple regression analyses, both studies showed that not receiving intracameral cefuroxime was an independent predictor for the development of post-operative endophthalmitis (P < 0.001). In a single-centre, retrospective, case-control study, Wejde et al. assessed risk factors for the development of endophthalmitis among 46,292 cataract surgeries that were performed between January 1994 and December Fifty-nine cases of endophthalmitis in the study group were compared with 235 control cases that were selected at random. A statistically significantly lower risk of post-operative endophthalmitis was found when prophylaxis with intracameral cefuroxime (1.0 mg in 0.1 ml normal saline) was used in addition to preoperative topical gentamicin 0.3% drops (OR 4.6; 95% CI 2.5 to 8.5; P < 0.001) compared with topical gentamicin alone. Multiple logistic regression analyses showed that prophylaxis using topical gentamicin alone was an independent risk factor for the development of post-operative endophthalmitis (OR 5.7; 95% CI 2.8 to 11.9; P < 0.001) Intracameral vancomycin In a single-centre retrospective (January 1998 to December 2008) study, Anijeet et al. compared the incidence of endophthalmitis before and after the introduction of intracameral vancomycin. 26 Before the introduction of intracameral vancomycin, patients received topical fusidic acid for 10 days post-operatively (3,904 surgeries). In 2001, vancomycin (1 mg in 0.1 ml normal saline) injected intracamerally into the capsular bag after surgery was added to the antibiotic prophylaxis protocol (12,702 surgeries). The results showed a statistically significant reduction in the incidence of postoperative endophthalmitis after the introduction of intracameral vancomycin compared with topical fusidic acid alone (0.008% versus 0.3% respectively; P < ; RR 38; 95% CI 7 to 252). The absolute risk reduction with the use of intracameral vancomycin was calculated to be 292 cases per 100,000 cataract surgeries. The one case of endophthalmitis occurring after the introduction of intracameral vancomycin was negative on Gram stain or culture. No safety outcomes were reported Intracameral cefazolin In a single-centre retrospective (January 2002 to December 2007) study, Garat et al. assessed the clinical effectiveness of using intracameral cefazolin for the prevention of post-operative endophthalmitis after phacoemulsification cataract surgery. 27 The cumulative incidence of post-operative endophthalmitis occurring before (5,930 surgeries) and after (12,649 surgeries) the addition of intracameral cefazolin (2.5 mg in 0.1 ml normal saline) was compared. All patients also received post-operative topical ofloxacin 0.3% drops and tobramycin-dexamethasone drops four times daily for a week postoperatively. The results showed a statistically significant reduction in the rate of endophthalmitis with the use of intracameral cefazolin compared with topical prophylaxis alone (0.047% versus 0.422% respectively; P < ), corresponding to an RR reduction of 88.7% (95% CI 72.6% to 95.4%). Four of the six cases of endophthalmitis occurring with the use of intracameral cefazolin were proven on Gram stain or culture (two cases of Streptococcus oralis and one case each of S. epidermis and Proteus mirabilis). No adverse events including post-operative inflammation or negative changes in visual acuity were observed. 8

17 In a single-centre retrospective (January 2001 to December 2004) study, Romero et al. evaluated the use of prophylactic intracameral cefazolin for the prevention of endophthalmitis after cataract surgery. 28 The cumulative incidence of post-operative endophthalmitis occurring before (3,650 surgeries) and after (3,618 surgeries) the addition of intracameral cefazolin (1 mg in 0.1 ml of normal saline) was compared. All patients also received post-operative tobramycindexamethasone drops every four hours. The results showed a statistically significant reduction in the rate of endophthalmitis with the use of intracameral cefazolin compared with topical prophylaxis alone (0.055% versus 0.63%; P < ). The bacteria that were cultured for the two cases of endophthalmitis occurring with the use of intracameral cefazolin were Klebsiella and Corynebacterium. No patients in the intracameral cefazolin group showed signs of toxic effects to the cornea or retina, and no anaphylactic reactions were reported Intracameral moxifloxacin In a single-centre retrospective chart review, Arbisser assessed the safety of an intracameral injection of moxifloxacin after cataract surgery. 29 The safety outcomes among 141 patients receiving moxifloxacin 0.5% drops diluted with balanced salt solution to a 100 g/0.1 ml dose were compared with those of 50 randomly selected patients who had cataract surgery before the implementation of intracameral moxifloxacin. All patients also received topical moxifloxacin 0.5% drops four times daily for two days preoperatively and then four times daily for a week post-operatively. No statistically significant differences were noted between groups in anterior chamber inflammation (aqueous cell counts) at one week post-operatively. No post-operative epithelial defects or stromal edema was observed in the intracameral moxifloxacin group. A prospective analysis of 18 patients was done to measure macular edema. Ocular coherence tomography measurements at six weeks post-operatively did not show any statistically significant differences in macular edema compared with preoperative measurements. No drug-related adverse effects were observed. In a single-centre, prospective study, Espiritu et al. investigated the safety of using intracameral moxifloxacin in 65 patients undergoing phacoemulsification cataract surgery. 30 Undiluted moxifloxacin 0.5% drops at a dose of 500 g/0.1 ml was used. The safety parameters that were assessed were inflammation in the anterior chamber (aqueous cells), effects on the cornea (endothelial cell density and thickness), and effects on the blood-aqueous barrier (aqueous flare). The results at one month postoperatively did not show any statistically significant changes in endothelial cells or corneal thickness compared with preoperative measurements. No eye showed signs of significant anterior chamber inflammation one week post-operatively or lost a line of visual acuity. 4.3 Economic evaluations Sharifi et al. determined the cost-effectiveness from a societal perspective in the US of different antibiotic regimens for the prevention of endophthalmitis after cataract surgery. 31 The modes of administration for the antibiotics were intracameral (cefuroxime or moxifloxacin), topical (sulfacetamide, polymyxin/trimethoprim, ciprofloxacin, ofloxacin, moxifloxacin, or gatifloxacin), and subconjunctival (gentamicin or cefazolin). A combination regimen of intracameral cefuroxime, subconjunctival gentamicin, subconjunctival cefazolin, and topical sulfacetamide was also assessed. The different prophylactic therapies were compared with no intervention. A decision-analytic model for a hypothetical cohort of 100,000 patients aged 70 years and older undergoing cataract surgery was used. The analysis used a six week time horizon. Clinical effectiveness estimates were derived from the ESCRS study 17 and the authors assumptions. The risk of endophthalmitis in the absence of any intervention was estimated to be 0.247% (95% CI 0.208% to 0.288%). The risk of endophthalmitis when intracameral cefuroxime or the four antibiotic combination regimen was 9

18 used was estimated to be 0.045% (95% CI 0.036% to 0.054%). Because no clinical data were available, the economic model assumed 100% prevention of endophthalmitis with all other options. The economic analysis included the costs of each antibiotic and the treatment of endophthalmitis or toxic anterior segment syndrome. The cost per case of endophthalmitis was estimated to be US$3,793. The productivity losses due to endophthalmitis were excluded in the cost analysis. Intracameral cefuroxime was used as a reference standard in the analysis because it was the only method that had been studied. A threshold effectiveness (the number of endophthalmitis cases prevented) at which point a given antibiotic would achieve the same costeffectiveness ratio as intracameral cefuroxime was calculated. The results appear in Table 2. Four options (intracameral cefuroxime, subconjunctival gentamicin, subconjunctival cefazolin, and topical sulfacetamide) were associated with savings in net costs. Intracameral cefuroxime yielded a net cost savings of approximately US$480,000 in the cohort because of the endophthalmitis cases that were averted. When the treatment costs saved from prevented cases of endophthalmitis were excluded, the cost-effectiveness ratio of intracameral cefuroxime over no intervention was US$1,403 per case of post-operative endophthalmitis prevented. None of the fluoroquinolones (ciprofloxacin, ofloxacin, moxifloxacin, or gatifloxacin) were cost saving, even after assuming that all potential cases of endophthalmitis were averted after their use. A near five-fold increase in clinical effectiveness of intracameral moxifloxacin over intracameral cefuroxime was needed to achieve the same cost-effectiveness ratio. An eight-fold increase in clinical effectiveness of the least expensive topical fluoroquinolone, ciprofloxacin, was needed over intracameral cefuroxime to achieve the same cost-effectiveness ratio. The most expensive topical fluoroquinolones, gatifloxacin and moxifloxacin, needed to be at least 19 times more effective than intracameral cefuroxime to achieve cost-effective equivalence. For all regimens, except topical sulfacetamide and subconjunctival gentamicin, the number of cases that would need to be prevented exceeded the number of cases expected without treatment (247 per 100,000 patients). Sensitivity analyses varying the cost of antibiotics, cost of endophthalmitis treatment, risk of infection, and degree of complications from intracameral injections (anaphylaxis or toxic anterior segment syndrome) confirmed the robustness of these findings. The authors concluded that the use of intracameral cefuroxime was more cost-effective than that of commonly used topical antibiotics for the prevention of endophthalmitis after cataract surgery. 4.4 Guidelines and recommendations The Canadian Ophthalmological Society published practice guidelines for cataract surgery in The recommendations are based on a non-systematic literature review. In the absence of direct evidence, the recommendations reflect a unanimous consensus of the Expert Committee. The guidelines state that surgeons should be aware of their personal and institutional risk of endophthalmitis, and if the rate of endophthalmitis is higher than published norms or the risk is higher because of intraoperative complications, intracameral antibiotics may be considered (based on consensus). No details regarding the choice of antibiotic are provided. 10

19 Antibiotic Prophylaxis Table 2: Results of Cost-Effectiveness Analysis of Antibiotic Prophylaxis 31 Cost per Person (US$) Cohort Net Cost* (US$ millions) Cost- Effectiveness Ratio Threshold Effectiveness Ratio Compared with Intracameral Cefuroxime (number of prevented cases) Intracameral Cefuroxime Cost saving NA Moxifloxacin , (984) Subconjunctival Gentamicin Cost saving 1.04 (210) Cefazolin Cost saving 1.26 (254) Topical Sulfacetamide Cost saving 0.81 (164) Polymyxin/ , (881) trimethoprim Ciprofloxacin , (1,775) Ofloxacin , (2,405) Moxifloxacin , (3,920) Gatifloxacin , (4,105) Four antibiotic combination , (831) NA = not applicable *Net cost in a cohort of 100,000 eyes includes cost savings of prevented infections. Includes cost saving from averted endophthalmitis. Intracameral cefuroxime, subconjunctival gentamicin, subconjunctival cefazolin, and topical sulfacetamide. The Scottish Intercollegiate Guidelines Network released a guideline for antibiotic prophylaxis in surgery in The guideline is based on a systematic literature review. The guideline recommends intracameral antibiotic prophylaxis to reduce the risk of developing endophthalmitis after cataract surgery (level of evidence A; based on at least one high quality meta-analysis, systematic review, or RCT with a very low risk of bias and directly applicable to the target population). No other details regarding the choice of antibiotic are provided in the guideline. Clinical practice guidelines for the management of post-operative infectious endophthalmitis were developed by the Ministry of Health Malaysia in The recommendations are based on a non-systematic literature review. The guidelines recommend intracameral cefuroxime (1 mg cefuroxime in 0.1 ml normal saline) at the end of surgery to prevent post-operative endophthalmitis (level of evidence A; based on at least one good quality meta-analysis, systematic review, or RCT and directly applicable to the target population). The guidelines note that careful dilution must be undertaken to prevent potential toxicity and provide steps to ensure the accurate preparation of cefuroxime for intracameral injection. The guidelines do not recommend the use of intracameral vancomycin in the irrigating solution, because of insufficient evidence for clinical effectiveness and the potential for retinal toxicity and antibiotic resistance (level of evidence C; based on expert committees reports, or opinions and/or clinical experiences of respected authorities). The American Academy of Ophthalmology released guidelines for the management of cataracts in The recommendations are based on a systematic literature review. The guidelines state that, given the absence of clear evidence for the benefit of prophylactic measures other than 5% povidone iodine, the individual ophthalmologist should decide on the use of a particular strategy, including Intracameral Antibiotics for Prevention of Endophthalmitis Post-Cataract Surgery: 11

20 intracameral antibiotics, for the prevention of endophthalmitis during the perioperative period (not graded for strength of evidence). 4.5 Limitations A limited literature search was conducted for this report. Potentially relevant evidence published before 2005 or of a non-english language may have been excluded. The ESCRS study reported a higher incidence of post-operative endophthalmitis in groups not receiving intracameral cefuroxime than that generally reported in the literature. 36 Hence, it is debatable whether findings from the ESCRS study can be generalized to Canadian settings with lower incidences of post-operative endophthalmitis. Furthermore, the estimate for the reduction of endophthalmitis with intracameral cefuroxime had a wide CI and should not be viewed as a precise estimate of the treatment effect. Early termination of the ESCRS study based on a beneficial outcome may have led to an overestimation of the treatment effect of intracameral cefuroxime. 37 Findings on the clinical effectiveness of intracameral antibiotics from observational studies may be subject to selection bias in the treatment groups. Studies assessing safety outcomes may have lacked a sufficient sample size to detect infrequent adverse events and excluded patients with significant comorbidities including diabetes and ocular pathologies, and those with intraoperative complications. It is unclear whether the findings of the US cost-effectiveness analysis can be generalized to the institution-specific costs and public health care funding of a Canadian setting. 5 CONCLUSIONS AND IMPLICATIONS FOR DECISION- OR POLICY-MAKING The ESCRS study 17 was the only identified RCT that evaluated the clinical effectiveness of using intracameral antibiotics for the prevention of endophthalmitis after cataract surgery. The results showed a near five-fold decrease in the risk of presumed infectious post-operative endophthalmitis after the use of intracameral cefuroxime. The ESCRS study also showed that intracameral cefuroxime was clinically superior to perioperative topical levofloxacin for the prevention of post-operative endophthalmitis. These findings are supported in several observational studies. 8,21,22,24,25 In addition, an observational study 23 indicated that the use of intracameral cefuroxime was superior for the prevention of post-operative endophthalmitis compared with subconjunctival cefuroxime. Despite evidence that the use of intracameral cefuroxime reduces the risk of post-operative endophthalmitis, many ophthalmologists favour topical fourth generation fluoroquinolones (moxifloxacin or gatifloxacin) over intracameral cefuroxime for prophylaxis. 3,11 A barrier to the uptake of intracameral cefuroxime in clinical practice appears to be the lack of a commercially available pre-formulated preparation for intracameral use. 11,12,36 Currently, intracameral cefuroxime is extemporaneously prepared using a product that is intended for intravenous administration. 38 The extemporaneous preparation of cefuroxime solution carries a risk of dilution errors that may result in toxic anterior segment syndrome. 15,38 Other limitations of using cefuroxime include restricted coverage against gram-negative bacteria, Enterococci, and methicillin-resistant Staphylococcus aureus (MRSA), and the potential for hypersensitivity reactions. 2,39 The results of observational studies indicate that intracameral cefazolin may be an effective alternative to intracameral cefuroxime for the 12