Background Current practice methods are unclear as to the most safe and effective prophylactic pharmacotherapy and method of delivery to reduce postoperative endophthalmitis occurrence.
Methods A systematic review and meta-analysis using Meta-analysis of Observational Studies in Epidemiology guidelines was performed to compare the efficacy of intracameral cefuroxime, moxifloxacin and vancomycin in preventing postphacoemulsification cataract surgery endophthalmitis. A safety analysis of intracameral antibiotics was concurrently performed.
Data sources BIOSIS Previews, CINAHL, ClinicalTrials.gov, Cochrane Library, Dissertations & Theses, EMBASE, PubMed, ScienceDirect and Scopus were searched from inception to January 2017. Data were pooled using a random effects model. All articles were individually reviewed and data were extracted by two independent reviewers. Funnel plot, risk of bias and quality of evidence analyses were performed.
Results Seventeen studies with over 900 000 eyes were included, which favoured the use of intracameral antibiotics at the end of cataract surgery (OR 0.20; 95% CI 0.13 to 0.32; P<0.00001). The average weighted postoperative endophthalmitis incidence rates with intracameral cefuroxime, moxifloxacin and vancomycin were 0.0332%, 0.0153% and 0.0106%, respectively. Secondary analyses showed no difference in efficacy between intracameral plus topical antibiotics versus intracameral alone (P>0.3). Most studies had low to moderate risk of bias. The safety analysis showed minimal toxicity for moxifloxacin. Dosing errors led to the majority of toxicities with cefuroxime. Although rare, vancomycin was associated with toxic retinal events.
Conclusion Intracameral cefuroxime and moxifloxacin reduced endophthalmitis rates compared with controls with minimal or no toxicity events at standard doses. Additionally, intracameral antibiotics alone may be as effective as intracameral plus topical antibiotics.
- treatment medical
- treatment surgery
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Endophthalmitis is a sight-threatening inflammation of the eye. For patients and surgeons alike, one of the most feared complications of cataract surgery is acute postoperative endophthalmitis (POE).1 With over 10 million cataract surgeries performed worldwide every year,1 2 effective POE prophylaxis is necessary. Povidone-iodine solution has historically been the standard for POE prophylaxis,3 but other modalities include intracameral (IC), topical, subconjunctival and oral antibiotics. Of the identified risk factors for POE, many authors state that both the route of administration and the type of antibiotic are important factors for risk mitigation,4–6 which has led to an increased number of IC antibiotic studies. Currently, although IC administration is widely accepted, there is no consensus on the best prophylactic therapy or route of administration for POE prevention.6 7 However, antibiotics including cephalosporins, fluoroquinolones and vancomycin have been tested for effective POE prevention.
The aim of this study was to evaluate the safety and efficacy of intracameral cefuroxime (ICC) intracameral moxifloxacin (ICM) and intracameral vancomycin (ICV) as prophylactic pharmacotherapy for prevention of POE.
Eligibility criteria for considering studies for this review
We conducted a systematic review and meta-analysis of relevant literature using the Meta-analysis of Observational Studies in Epidemiology guidelines.8 The methods are described in detail in online supplementary eMethods. We considered randomised controlled trials (RCT) and observational studies that evaluated patients undergoing phacoemulsification cataract surgery with a minimum sample size of 500 eyes. Interventions included IC antibiotics (ie, cefuroxime, moxifloxacin or vancomycin) at the end of cataract surgery. Comparisons included non-IC antibiotics (topical, subconjunctival or non-specified) at the end of cataract surgery. The primary outcome was the incidence of postcataract surgery endophthalmitis. Secondary analyses examined the effects of geographic location, and the addition of topical antibiotics on POE incidence. Studies were excluded if they included extracapsular cataract extraction (ECCE) surgeries that could not be separated from phacoemulsification surgery data. Culture results from POE cases were reviewed to determine the spectrum of microorganisms causing endophthalmitis in this population.
Supplementary file 1
We also reviewed studies within our literature search that reported safety or toxicity data with ICC, ICM and ICV. Eligible studies included animal models or postoperative humans who underwent phacoemulsification cataract surgery. Toxicity to the cornea, anterior chamber (AC), or retina, or a change in intraocular pressure (IOP) or visual acuity (VA) were analysed.
Search methods for identifying studies
We identified published studies from BIOSIS Previews (ISI Web of Knowledge), CINAHL (EBSCOhost), ClinicalTrials.gov, Cochrane Library (Wiley Interscience), Dissertations & Theses Global (ProQuest), EMBASE (Embase.com), PubMed (National Library of Medicine), ScienceDirect (Elsevier) and Scopus (Elsevier) from inception to January 2017. There were no language restrictions. To optimise search criteria, we developed a detailed and comprehensive search strategy with an information specialist (MM) for each electronic database (online supplementary eMethods). EndNote V.X7 was used for deduplication (EndNote, Thomson Reuters).
Each article was independently reviewed by two reviewers. The titles and abstracts (if available) were screened. Full-text copies were obtained for all potentially relevant articles and reviewed for inclusion and data collection. Disagreements in selection were reconciled by a separate reviewer. Language interpreters assisted in reviewing non-English articles, resulting in a single person reviewing these articles. References in full-text articles were screened for relevance and added if they met inclusion criteria. We contacted authors as needed for additional study details to assist in the data analysis.
Data collection and risk of bias assessment
We extracted the following: type of study, IC antibiotic used, country of origin, incidence of POE with and without IC antibiotics, dose of antibiotic, use of topical antibiotics, location of toxicity and microorganisms isolated in POE. Two risk of bias tools were used. For the efficacy analysis, we used a Cochrane Risk of Bias Assessment Tool: For Non-Randomized Studies of Interventions. For the safety analysis, we used the Office of Health Assessment and Translation Risk of Bias Rating Tool for Human and Animal Studies. Funnel plots were evaluated using Review Manager V.5.3 (RevMan V.5.3).9 Additionally, we used the GRADEprofiler (V.3.6.1) to assess the quality of evidence.
Data synthesis and analysis
We used RevMan V.5.39 for the statistical analysis. Studies were stratified by the antibiotic used post surgery. As the primary outcome was dichotomous, OR estimates and corresponding 95% CIs were calculated for each study. OR estimates were combined using the random effects Mantel-Haenszel method. Summary of OR estimates was given for each stratum and collection of studies. ORs compared IC versus non-IC antibiotics. Heterogeneity was assessed by the Q and I2 statistics, calculated for each stratum and for the full collection of studies. Results were displayed using forest plots. Funnel plots enabled evaluation of publication bias.9 Secondary analyses examined the effect of geographic location (Europe vs non-Europe) on the risk of POE while stratifying by antibiotic type. Similarly, the effect on POE of topical antibiotics in conjunction with the primary IC antibiotic was examined and stratified by antibiotic type. The number and percent of microorganisms identified in POE cases as well as the safety analysis were tabulated as descriptive statistics.
Results for the efficacy of IC antibiotics
We reviewed 4849 titles and abstracts; for 70 of these, the full text was evaluated (figure 1). Seventeen articles met the inclusion criteria.4 7 10–25 The European Society of Cataract & Refractive Surgeons (ESCRS) study was the only RCT4; 16 were observational studies (15 retrospective cohort studies10–13 15–23 25 and 1 case–control study7). Within the 16 observational studies, 9 compared ICC 1 mg/0.1 mL (4 ICC only and 5 ICC with topical antibiotics),10–13 15–18 24 6 compared ICM 100–500 mcg/0.1 mL (with 1 study ranging from 5 to 50 mcg/0.1 mL)19 (2 ICM only and 4 ICM with topical antibiotics),7 11 19 20 24 25 and 5 compared ICV 1 mg/0.1 mL (1 ICV only and 4 ICV with topical antibiotics)7 11 21–23 against their corresponding controls (ie, postoperative topical, subconjunctival or oral antibiotics). One study did not define the antibiotic doses administered.7 The 16 observational studies enrolled 909 582 eyes and the 1 RCT enrolled 16 211 eyes (online supplementary eTable 1).
Common reasons for excluding studies included the lack of a control or comparison group, and the inability to separate ECCE from phacoemulsification data. Of the 17 studies, 8 were based in Europe (including the RCT),4 10 12 13 15–17 21 2 were based in Canada,7 11 2 in the USA,22 24 2 in India,18 25 and 1 each was based in Japan,19 Australia23 and Colombia.20 The Matsuura et al’s study used a bag and chamber flushing technique.19 All other studies used a small volume injection at the end of surgery. Rudnisky et al were contacted and calculation of values from their published study was performed for the groups who received ICM and ICV.7
The 17 included studies had mild to moderate risk of bias (online supplementary eFigures 1 and 2). Confounding variables were most common as some observational studies did not control for preoperative antibiotic regimen, use of steroid drops, surgical incision site, phacoemulsification method, surgical complications or patient comorbidities. However, studies that recognised these variables controlled their risk of bias through matching and analytical tests. The remaining sources of bias were determined to be low risk for most studies, which included selection of participants, departure from intended interventions, missing data, measurement of outcomes and reporting. Random effect analysis funnel plots of the 17 included studies reflected only minimal bias (online supplementary eFigure 3).
Using GRADEprofiler, the overall quality of evidence for the included observational studies was moderate (online supplementary eTable 2). Quality was downgraded by one level to account for the risk of bias due to confounding in multiple studies. Quality was upgraded due to the large effect found in the pooled data for observational studies. The overall quality of the RCT was graded as high due to the study design, low risk of bias, large measure of effect and direct comparisons.
The overall pooled data favoured the use of IC antibiotics at the end of phacoemulsification cataract surgery (OR, 0.20; 95% CI 0.13 to 0.32; P<0.00001). Within ICC groups, a lower incidence of endophthalmitis in the treatment group was observed (OR, 0.26; 95% CI 0.15 to 0.45; P<0.00001). These data are similar to the RCT (OR, 0.21; 95% CI 0.08 to 0.54; P=0.001).4 A lower incidence of endophthalmitis in treatment groups was also observed for ICM (OR, 0.30; 95% CI 0.13 to 0.67; P=0.004) and ICV (OR, 0.09; 95% CI 0.02 to 0.42; P=0.002) (figure 2).
In secondary analyses, there was no statistically significant difference in POE rates between patients treated with IC antibiotics plus topical antibiotics and patients treated with IC antibiotics alone within the cefuroxime (χ2=0.04; df=1; P=0.85), vancomycin (χ2=0.31; df=1; P=0.58) and moxifloxacin groups (χ2=0.78; df=1; P=0.38) (online supplementary eFigure 4).
Geographic forest plot analysis showed statistical significance in favour of IC antibiotics regardless of location. The average weighted POE incidence of ICC in Europe was 0.0366% compared with 0.0303% in non-European countries. For ICV, the incidence was 0.0079% compared with 0.0113%, respectively. There were no moxifloxacin studies performed in Europe for comparison (online supplementary eFigure 5).
Results for the safety analysis of IC antibiotics
Thirty-three studies met the inclusion criteria for the safety and toxicity analysis. Of these studies, there were 7 animal studies, 7 case series, 15 cohort studies, 2 cohort and animal studies, and 2 RCTs. Animal studies included rabbit and rat eyes. Eleven studies discussed the safety of ICC,26–36 3 discussed ICV safety37–39 and 15 discussed ICM safety.19 40–52 Three studies compared ICC versus ICV53–55 and one study compared ICV versus ICM.56 Cefuroxime doses ranged from 1 to 10 mg/0.1 mL, vancomycin doses ranged from 0.0375 to 1 mg/0.1 mL, and moxifloxacin doses ranged from 15 to 500 mcg/0.1 mL. Postoperative follow-up ranged from 1 day to 12 months.
Of the 33 studies analysed for risk of bias, the principal causes of moderate to high bias were confounding variables and protocol deviations. Selection, attrition and reporting bias were determined to be low to moderate risk of bias (online supplementary eFigures 6–8). Lack of homogeneity between studies (eg, differences in study methods, species and antibiotic concentrations) was the greatest challenge in comparing studies.
In the cefuroxime group, a total of 503 eyes were analysed for safety and toxicity of ICC (table 1). Of these, 69 (14%) eyes were reported to have toxic effects from the antibiotic; 23 had corneal oedema (CE),29 32 53 6 had endothelial cell death,57 17 developed toxic anterior segment syndrome (TASS),33 13 had cell or fibrin formation in the AC,32 34 14 had elevated IOP,29 32 18 had macular oedema31 32 36 and 15 had poor VA.29 32 36
In the vancomycin group, 171 eyes were analysed for safety and toxicity of ICV (table 2). None of the studies comparing vancomycin with control groups found any significant changes in IOP, endothelial cell density, AC inflammation, CE or macular oedema.37 38 53–56 However, a case series showed 36 eyes with vancomycin-associated haemorrhagic occlusive retinal vasculitis (HORV) resulting in VA worse than 20/200 in 22 of the eyes.39
In the moxifloxacin group, 1243 eyes were analysed for safety and toxicity of ICM (table 3). Fifty-five eyes treated previously with penetrating keratoplasty had increased central corneal thickness (P<0.05) and decreased endothelial cell density (P<0.05).43 At 500 mcg/0.1 mL, Akal et al 50 found 8 of 10 rat eyes with elevated caspase-3 and 9 of 10 eyes with elevated caspase-8 indicating increased apoptotic activity (P>0.05). Matsuura et al reported that 15 mcg/0.1 mL was safe and provided concentrations above MIC90 (minimum inhibitory concentration to inhibit 90% of organisms) for 2 hours for most of the resistant pathogens.45
Analysis of microorganisms identified in POE cases
The data for causative infectious agents of POE were extracted from the 17 included studies. Ten studies provided data,4 12 13 16–25 which included 145 endophthalmitis cases. The predominant microorganisms causing POE in postphacoemulsification cataract surgeries were coagulase-negative Staphylococcus (S. epidermatis, S. hominis, S. saprophyticus, S. warneri) (33 of 145; 22.8%). The second most common group was unspecified gram-negative rods (15 of 145; 10.3%). Other common organisms were Staphylococcus aureus (7 of 145; 4.8%), gram-positive organisms (unspecified) (7 of 145; 4.8%) and Streptococcus pneumoniae (8 of 145; 5.5%). In addition, one case of Aspergillus fumagatus (0.7%), four cases of Pseudomonas aeruginosa (2.8%) and three cases of methicillin-resistant Staphylococcus aureus (MRSA) (2.1%) were also reported. A large fraction of cases yielded no growth (56 of 145; 38.6%) (online supplementary eFigure 9).
An effective and safe prophylactic treatment at the end of cataract surgery is needed to prevent serious sight-threatening endophthalmitis. In this meta-analysis, we identified nearly two decades of POE data from 909 582 eyes (observational studies) and 16 211 eyes (RCT), giving this analysis sufficient power to detect very small differences in rare outcomes such as endophthalmitis. Overall pooled data favoured the use of IC antibiotics to reduce POE rates when compared with controls (figure 2). ICC findings were consistent with the ESCRS findings.4 Additionally, χ2 analysis showed no difference between IC plus topical antibiotics compared with IC antibiotics alone, which suggests that postoperative topical antibiotics may provide no additional benefit.14 24 58 Pooled weighted averages for POE incidence favour ICM or ICV with incidences of 0.0153% and 0.0106%, respectively, compared with ICC (0.0332%). Quality of studies was graded at moderate to high with predominately low to moderate risk of bias.
Our systematic review of IC antibiotic safety suggests that ICC is relatively safe, but has had more complications with contamination, dilution errors and TASS along with macular toxicity compared with vancomycin and moxifloxacin (tables 1–3). ICV at 1 mg/0.1 mL showed no significant corneal or AC toxicities.37 38 53–55 However, ICV has more recently been associated with rare cases of HORV.39 Two studies with ICM 500 mcg/0.1 mL suggest decreased corneal cell density and increased apoptotic markers of the cornea. However, the majority of studies suggest no significant toxicities to the cornea, AC, retina or VA.41 42 44–49 52 56 58
IC antibiotic selection
ICC is the only IC antibiotic that has been analysed for efficacy by an RCT and has the most observational studies of the three antibiotics. From a phone survey of 250 ESCRS members, over 90% of surgeons would use cefuroxime if an approved product were commercially available.59 Although Aprokam is approved in Europe, a product which likely overcomes the risks associated with dilution error preparations, it remains unavailable in some nations and has not been approved by the Food and Drug Administration. Challenges to cefuroxime use include the potential for allergic reactions in patients with beta-lactam allergies,60 61 overdosing risks associated with preparation in areas where Aprokam is not available, and poor coverage of methicillin-resistant, penicillin-resistant gram-positive bacteria or multiresistant enterococci and some gram-negative species such as Pseudomonas.62
In our study, the incidence and OR of POE for ICV were the lowest; however the total population size was the smallest of the three groups. Vancomycin has superior MRSA coverage but does not cover gram-negative bacteria. This may be meaningful as only 2% of POE cases in this study were caused by MRSA versus 10% caused by gram-negative bacteria. The risk of vancomycin-resistant bacteria is also an important consideration.63
There are currently no RCTs that have evaluated the efficacy of ICM for POE prevention. In our study, the average weighted incidence of POE with ICM was lower than ICC but higher than ICV. The predominant dose concentration used in included studies was 100 mcg/0.1 mL vs undiluted 500 mcg/0.1 mL.7 20 25 64 Analysis suggests 500 mcg/0.1 mL may be more effective than 100 mcg/0.1 mL; however, this is based on only four studies.7 20 25 64 Literature review showed a low postoperative toxicity profile for ICM, possibly due to its self-sterilising properties which negates addition of potentially harmful preservatives in solution.65 66 Moxifloxacin also provides broader antimicrobial coverage of bacteria that have been isolated in POE compared with cefuroxime and vancomycin.67 68
Study strengths and limitations
Other reviews and meta-analyses on this topic leave the question as to the added value of this study.69 70 Given that ECCE is known to have increased POE rates,71 this study aims to represent the most current practice methods with only phacoemulsification cases. Additionally, this study compared IC alone to IC plus topical postoperative antibiotics to assess the impact on POE incidence. Most importantly, this study provides a novel systematic review comparing the safety and toxicity of ICC, ICM and ICV. Limitations of this analysis include the lack of RCTs for ICM and ICV. Only one RCT has been performed analysing IC antibiotics.4 All other studies included were observational studies, which have a higher risk of bias. As study cohorts were not evaluated concurrently, this can lead to bias as surgical techniques improve over time. Furthermore, variability in techniques such as lens type,4 incision type and location,72 complications,73 and experience and age of the surgeon4 73 could not be adjusted in this analysis. However, we attempted to reduce risk of bias by only including phacoemulsification cataract surgeries, which we believe makes the data more robust as evidence suggests ECCE has a higher rate of endophthalmitis.71 Consequently, many large studies that could not separate ECCE or meet other inclusion criteria were excluded from this study, specifically, several studies from France, Sweden, Israel and Iran.72 74–79 These studies reported an ICC POE incidence range from 0.05% to 0.023%, which approximates our study finding of 0.0332%. Lastly, this study targeted IC antibiotics and therefore leaves the question of whether IC antibiotics are superior to postoperative, topical antibiotics alone. It has been suggested that the primary POE reducing element is the antibiotic type (eg, fourth-generation fluoroquinolones), despite the route of administration.7 Conversely, the ESCRS study strongly favoured IC use of cefuroxime over topical third-generation fluoroquinolones.4 A future analysis with focused search criteria for this question is needed.
Our study assessed two decades of POE incidence from over 900 000 eyes reported in 17 studies. The average weighted incidence rates of POE were 0.0332% (ICC), 0.0153% (ICM) and 0.0106% (ICV). Additionally, IC antibiotics alone may be as effective as IC plus postoperative topical antibiotics; however, the lack of direct comparison and the variety of topical antibiotics could suggest an alternative interpretation. These data showed that although very rare, ICV has been associated with HORV. ICC had minimal toxicity events at standard doses. ICM was the most studied antibiotic for safety and found to have a low toxicity profile at all studied concentrations. Future direct comparison studies of IC antibiotics as well as an RCT for ICM efficacy and tolerance would add to the current literature.
We thank Melissa L Rethlefsen, MSLS, who provided guidance in using the MOOSE guidelines for the meta-analysis and supervised the data presentation for the systematic review.
Contributors All authors contributed to the design or acquisition of data, analysis or interpretation of data, and contributed to drafting or critically revising the article for important intellectual content and final approval of the version to be published.
Funding This investigation was supported by the University of Utah Study Design and Biostatistics Center, with funding in part from the National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health, through grant 8UL1TR000105 (formerly UL1RR025764), National Institutes of Health (EY014800), and an unrestricted grant from Research to Prevent Blindness, New York, to the Department of Ophthalmology and Visual Sciences, University of Utah.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.