ARTICLE
Corneal endothelial changes after intracameral vancomycin injection in cataract surgery Jose L. Perez-Canales, MD, Juan J. Perez-Santonja, MD, FEBO, Ezequiel Campos-Mollo, MD, PhD
PURPOSE: To evaluate corneal endothelial changes after intracameral injection of vancomycin at the end of routine cataract surgery. SETTING: Department of Ophthalmology, Hospital Virgen de los Lirios, Alcoy, Alicante, Spain. DESIGN: Prospective comparative case series. METHODS: Eyes received an intracameral injection of vancomycin (1 mg/0.1 mL) or cefuroxime (1 mg/0.1 mL) at the end of surgery. The visual acuity, corneal clarity, pachymetry, anterior chamber reaction, endothelial cell density (ECD), coefficient of variation (CoV), and hexagonality were evaluated at baseline and 1 week, 1 month, and 3 months after surgery. RESULTS: Sixty eyes (42 patients), 30 in each group, were enrolled. In the vancomycin group, there was a significant decrease in ECD 1 week after surgery (P Z .000), after which the ECD stabilized. There were no statistically significant changes in postoperative CoV values between preoperatively and postoperatively, although there was a transient decrease in hexagonality 1 week after surgery (P Z .006). In the cefuroxime group, the ECD significantly decreased 1 week after surgery (P Z .000) and then stabilized. There was a statistically significantly decrease in the CoV between preoperatively and 3 months postoperatively (P Z .014). No changes were noted in hexagonality. The postoperative ECD, CoV, and hexagonality values were not significantly different between the vancomycin group and the cefuroxime group. CONCLUSIONS: Endothelial cell changes observed after intracameral vancomycin were similar to those observed after intracameral cefuroxime in cataract surgery. The results indicate that intracameral vancomycin is safe for use in cataract surgery. Financial Disclosure: No author has a financial or proprietary interest in any material or method mentioned. J Cataract Refract Surg 2015; 41:126–134 Q 2015 ASCRS and ESCRS
Postoperative infectious endophthalmitis is one of the most severe complications of cataract surgery. Fortunately, it is a relatively rare event, with a reported incidence ranging from 0.06% to 0.49% in the United States and Europe.1,2 To prevent its devastating effects, the use of prophylactic measures in cataract surgery has been significantly expanded. Several preoperative, intraoperative, and postoperative strategies have been developed over the years, although there is still no consensus on the best method and regimen of administration. Preoperative antiseptics and antibiotics are usually administered to reduce bacterial colonization of the 126
Q 2015 ASCRS and ESCRS Published by Elsevier Inc.
ocular surface. To that end, the use of preoperative povidone–iodine 5.0% in the conjunctival sac remains the most accepted method and is now considered the standard of care in cataract surgery.3 In contrast, the role of preoperative topical antibiotics is controversial, with some studies showing no significant effect on anterior chamber contamination.4 Intraoperatively, subconjunctival injections of antibiotics have been progressively replaced by intracameral injections, mainly as a result of the generalized adoption of topical anesthesia in cataract surgery. A multinational clinical trial by the European Society of Cataract and Refractive Surgeons (ESCRS)2
http://dx.doi.org/10.1016/j.jcrs.2014.05.033 0886-3350
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consistently showed the effectiveness of intracameral instillation of cefuroxime (1 mg in 0.1 mL) in addition to preoperative povidone–iodine antisepsis, reporting a 5-fold reduction in the risk for developing endophthalmitis. In contrast, the administration of topical antibiotics (levofloxacin 0.5%) after surgery led to no significant decrease in the incidence of postoperative infections. Intracameral vancomycin is commonly administered after cataract surgery in European countries and is currently considered a second-line drug in patients allergic to cephalosporins. However, the safety profile of intracameral vancomycin in terms of corneal endothelial toxicity has not been fully evaluated. To date, studies have been limited to animals and in vitro analysis of human corneas.5,6 The aim of this study was to assess corneal endothelial changes after intracameral injection of vancomycin as a prophylactic measure for postoperative endophthalmitis in cataract surgery. To our knowledge, this is the first study to evaluate in vivo corneal endothelial changes after intracameral injection of vancomycin. PATIENTS AND METHODS This prospective comparative case series, performed from September 2012 to October 2013, comprised eyes in which phacoemulsification cataract surgery was performed at Virgen de los Lirios Hospital, Alcoy, Spain. Eligible patients were aged 65 to 80 years with senile cataract and no concomitant disease that would prevent a postoperative corrected distance visual acuity (CDVA) of 20/40 or better. Exclusion criteria included a history of ocular surgery or trauma, corneal disease, glaucoma, uveitis, vitreous opacities, retinopathy, and visual pathway defects. Other exclusion criteria were current treatment with systemic steroids, immunosuppressants, anticoagulants, or prostaglandin analogue eyedrops. Patients with intraoperative complications or extended surgical time were also excluded. After informed consent was obtained, consecutive patients with a history of allergy to penicillin were assigned to the vancomycin group. An equal number of patients matched for age, sex, and laterality were selected and assigned to the control group (cefuroxime group). Patients in the vancomycin group received an intracameral injection of
Submitted: March 23, 2014. Final revision submitted: May 7, 2014. Accepted: May 8, 2014. From the Departments of Ophthalmology, Hospital Virgen de los Lirios (Perez-Canales, Campos-Mollo), Alcoy, and Alicante University General Hospital (Perez-Santonja), Alicante, and the Cornea Unit (Perez-Santonja), Oftalvist Group, Alicante, Spain. Corresponding author: Jose L. Perez-Canales, MD, Hospital General Universitario de Alicante, Departamento de Oftalmologıa, Avenida Pintor Baeza 12, 03010, Alicante, Spain. E-mail: [email protected].
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vancomycin (1 mg in 0.1 mL), whereas those in the cefuroxime group received an intracameral injection of cefuroxime (1 mg in 0.1 mL). The antibiotic dilutions were performed by the operating room nursing staff. The vancomycin injection was prepared from a commercially available vancomycin hydrochloride 500 mg powder and diluted with sterile normal saline to a 1 mg/0.1 mL solution. The vancomycin solution had a pH of 6.42 and an osmolality of 313 mOsm/kg. The cefuroxime injection was prepared from cefuroxime 750 mg powder and diluted to a 1 mg/0.1 mL solution. This solution had a pH of 7.28 and an osmolality of 366 mOsm/kg. Pupils were dilated with repeated doses of tropicamide 1.0% and phenylephrine 10.0%. Preoperative prophylactic measures consisted of skin preparation with povidone– iodine 10.0% (Betadine) and instillation of povidone–iodine 5.0% into the conjunctival sac at the operating site at least 5 minutes before surgery. A combination of topical tetracaine 1.0% and oxybuprocaine 4.0% was used for anesthesia. The same surgeon (J.J.P.-S.) performed all surgeries using a standard phaco-chop technique. A hydrophobic acrylic intraocular lens (IOL) (Acrysof SN60WF, Alcon Laboratories, Inc.) was implanted in all cases. After the ophthalmic viscosurgical device was removed and the surgeon ensured that the corneal incisions were adequately sealed, the antibiotic agent was injected via the side port into the capsular bag using a 27-gauge cannula. All patients received a standard postoperative regimen of topical ofloxacin 0.3% (Exocin) 4 times daily for 1 week and dexamethasone 0.1% (Maxidex) 4 times daily for the first week and then 3 times daily for the next 3 weeks.
Patient Examinations Postoperative examinations were performed at 1 week, 1 month, and 3 months. Preoperative and postoperative examinations included uncorrected distance visual acuity (UDVA), refraction, CDVA, corneal clarity, anterior chamber reaction (cells and flare), pachymetry, intraocular pressure (IOP) by applanation tonometry, and endothelial specular microscopy (endothelial cell density [ECD], coefficient of variation [CoV] in cell size, and percentage of hexagonality). The data obtained before surgery were compared with those obtained after surgery within the 2 groups. Preoperative and postoperative data were also compared between groups. The postoperative examiner was masked to the group assignment. Visual acuity was measured using Snellen charts at 6 m. Corneal edema was evaluated by slitlamp biomicroscopy (BQ 900, Haag-Streit AG) and scored as follows: grade 0 Z no corneal edema; grade 1 Z corneal edema limited to incision area; grade 2 Z edema affecting less than 25% of the cornea without Descemet membrane folds; grade 3 Z edema affecting between 25% and 50% of the cornea or presence of Descemet membrane folds; grade 4 Z edema affecting more than 50% of the cornea. Central corneal thickness was measured using an ultrasonic pachymeter (Palmscan AP2000, Micromedical Devices, Inc.). The anterior chamber reaction was classified using a modification of the International Uveitis Study Group recommendations.7 The aqueous cell count was graded on a scale of 0 to 4 depending on the amount per slit-beam field (1.0 mm 1.0 mm) as follows: grade 0 Z fewer than 5 cells; grade 1 Z 6 to 15 cells; grade 2 Z 16 to 25 cells; grade 3 Z 26 to 50 cells; grade 4 Z more than 51 cells. The grading scheme
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for flare was grade 0 Z no flare; grade 1 Z barely detectable flare; grade 2 Z evident flare with iris details clearly visible; grade 3 Z marked flare and iris details not clearly visible; grade 4 Z plastic aqueous and fibrin presence in anterior chamber. In all eyes, noncontact wide-field specular microscopy of the central corneal endothelium was performed preoperatively and 1 week, 1 month, and 3 months postoperatively. The wide-field corneal specular microscope (Cellchek XL, Konan Medical, Inc.) was adapted to a digitization imageanalysis system (Cellchek Advanced Analysis Software, Konan Medical, Inc.). The specular microscopic images of the central portion of each cornea were taken using the specular microscope's built-in charge-coupled device camera and sent to the image-analysis system to be stored on a hard disk for subsequent digitization and analysis. At a later time, 3 images from each examination were digitized on the computer for analysis. The reviewer (J.L.P.-C.), who performed the image digitization, was unaware of the group status of the patient. The center of 150 cells (at least 50 cells per image) was digitized and analyzed using the “center method” of the image-analysis software. The endothelium was analyzed to calculate the mean cell density (cells per square millimeter), the CoV in cell size, and the percentage of hexagonal cells (cell shape). All these parameters were calculated automatically by the computer. The CoV provides a good quantitative assessment of cell size variability.8 The percentage of hexagonal cells was used as a measure of cell shape variability9 (reduction in the frequency of hexagonal cells results in greater variability). Data were encoded and analyzed using the SPSS software (version 21.0, SPSS, Inc.). Comparability in baseline demographic and clinical characteristics between groups was ensured. A paired Student t test was used to compare preoperative and postoperative continuous variables within groups. Comparisons between groups were performed using an unpaired Student t test for continuous variables and Mann-Whitney U test for ordinal and categorical variables. A P value less than 0.05 was determined to be significant. The results are given as the mean G SD.
Table 1. Between-group comparison of preoperative patient parameters and demographics.
Parameter
Vancomycin
Sex (n) Male 13 Female 13 Age (y) Mean G SD 73.23 G 5.83 Range 65, 80 CDVA (logMAR) Mean G SD 0.33 G 0.17 Range 0.15, 0.70 IOP (mm Hg) Mean G SD 14.85 G 2.63 Range 10, 22 Corneal thickness (mm) Mean G SD 538.96 G 39.52 Range 477, 605
Cefuroxime
P Value* .582
13 13 72.38 G 4.43 65, 79
.559
0.34 G 0.13 0.10, 0.70
.794
16.04 G 2.72 9, 20
.113
552.19 G 33.86 492, 606
.201
CDVA Z corrected distance visual acuity; IOP Z Intraocular pressure *Unpaired t test for continuous variables; chi-square test for categorical variables.
(preoperative: P Z .588; postoperative: P Z .268 at 1 week, P Z .124 at 1 month, and P Z .589 at 3 months). Anterior chamber inflammation resolved in all patients within the first week after surgery. The aqueous cell count was significantly higher in the vancomycin group than in the cefuroxime group 24 hours after surgery (P ! .02) (Figure 1). However, no differences in aqueous cells or flare were noted between the 2 groups at subsequent examinations.
RESULTS The vancomycin group and the cefuroxime group each comprised 30 eyes of 21 patients. Four eyes in the vancomycin group and 3 in the cefuroxime group were lost to follow-up because of unrelated adverse events or death. One eye in the cefuroxime group was withdrawn because the examiner was not able to analyze at least 150 endothelial cells at the postoperative examinations. Table 1 shows the patients' demographics. There were no significant differences in the preoperative mean age, sex, UDVA, refraction, CDVA, corneal pachymetry, IOP, ECD, CoV, or hexagonality between groups. Both groups had a statistically significant increase in UDVA and CDVA after surgery (P Z .000). At 3 months, all eyes had improved CDVA. Preoperative and postoperative CDVA values were comparable between groups
Figure 1. Aqueous cell count distribution 24 hours after surgery.
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24 hours after surgery (P Z .234). Corneal edema was absent in all patients at subsequent examinations. Central corneal thickness significantly increased in the vancomycin group and the cefuroxime group at the 1-week follow-up (P Z .000). However, the mean 1-month and 3-month corneal thickness did not differ from baseline values in either group (vancomycin: P Z .056 at 1 month and P Z .561 at 3 months; cefuroxime: P Z .344 at 1 month and P Z .647 at 3 months). Preoperative and postoperative values were similar in the 2 groups (preoperative: P Z .201; postoperative: P Z .973 at 1 week, P Z .411 at 1 month, and P Z .276 at 3 months) (Figure 2). Endothelial Cell Density
Figure 2. Changes in central corneal pachymetry over time.
There were 2 cases of posterior vitreous detachment in the vancomycin group and 2 cases in the cefuroxime group. No adverse drug reaction was reported over the 3-month follow-up.
Corneal Edema and Central Corneal Thickness Corneal edema was absent or limited to the area of incisions in 21 patients (80.7%) in the vancomycin group and 23 patients (88.4%) in the cefuroxime group
Table 2 shows the mean ECD, CoV, and hexagonality in both groups. The mean number of endothelial cells analyzed per patient was 286.29 (range 156 to 444) at baseline and 216.85 (range 151 to 479) at the postoperative examinations. In the vancomycin group, there was a significant decrease in the ECD from preoperatively to postoperatively (all comparisons P Z .000). However, the differences between the 1-week and 1-month mean values and between the 1-month and 3-month mean values were not statistically significant (P Z .847 and P Z .218, respectively). By 3 months postoperatively, the mean ECD had decreased by a mean of 13.30% from the preoperative values; the decrease was statistically significant (P Z .000).
Table 2. Endothelial changes over time by groups. Endothelial Cell Density (Cells/mm2) Group All eyes (N Z 52) Preoperative Postoperative 1 week 1 month 3 months Vancomycin (n Z 26) Preoperative Postoperative 1 week 1 month 3 months Cefuroxime (n Z 26) Preoperative Postoperative 1 week 1 month 3 months
Coefficient of Variation
Hexagonality
Mean G SD
P Value
Mean G SD
P Value
Mean G SD
P Value
2365.21 G 377.57
d
38.00 G 5.03
d
57.88 G 5.53
d
2056.04 G 459.68 2036.81 G 425.00 2065.81 G 440.80
000 .000 .000
37.37 G 5.36 36.36 G 4.51 36.23 G 4.48
.291 .015 .008
54.85 G 6.34 56.23 G 5.53 56.00 G 6.58
.001 .066 .077
2289.12 G 394.75
d
38.38 G 5.81
d
57.42 G 6.28
d
1957.19 G 443.48 1952.27 G 395.74 1984.58 G 417.25
.000 .000 .000
38.96 G 6.34 36.41 G 5.40 37.27 G 4.52
.412 .065 .228
54.15 G 6.85 55.88 G 5.33 54.73 G 5.94
.006 .255 .052
2441.31 G 350.64
d
37.62 G 4.20
d
58.35 G 4.74
d
2154.88 G 462.66 2121.35 G 443.84 2147.04 G 464.51
.000 .000 .000
35.77 G 3.62 36.31 G 3.51 35.19 G 4.27
.056 .122 .014
55.54 G 5.84 56.58 G 5.81 57.27 G 7.05
.067 .149 .514
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Figure 3. Changes over time in ECD and morphometric parameters.
Similarly, the ECD decreased significantly in the cefuroxime group from preoperatively to postoperatively (all comparisons P Z .000). The difference between the 1-week ECD and 1-month ECD was not significant (P Z .065), although there was a significant increase in ECD at 3 months over the ECD at 1 month (P Z .044). By 3 months after surgery, the mean ECD had decreased by a mean of 12.05%; the decrease was statistically significant (P Z .000). The preoperative mean ECD was similar in the 2 groups (P Z .148). Postoperatively, the ECD remained similar (P Z .122 at 1 week, P Z .153 at 1 month, and P Z .191 at 3 months) (Figure 3, A). Coefficient of Variation In the vancomycin group, there were no significant differences between the preoperative CoV value and the postoperative CoV value (P Z .412 at 1 week, P Z .065 at 1 month, and P Z .228 at 3 months). However, the mean CoV was statistically significantly lower 1 month after surgery than at 1 week (P Z .016). The difference between 1 month and 3 months was not statistically significant (P Z .271). By 3 months, the CoV had decreased by a mean of 2.89%; the change was not statistically significant. In the cefuroxime group, the CoV values were not significantly different from baseline values 1 week or 1 month after surgery (P Z .056 and P Z .122, respectively). However, there was a statistically significant decrease between preoperatively and 3 months postoperatively (P Z .014). The difference was not statistically significant between any 2 postoperative time points (P Z .471, 1 week versus 1 month; P Z .158, 1 month versus 3 month). The mean CoV decrease was 6.46% at the 3-month follow-up; the change was statistically significant (P Z .014).
The preoperative and postoperative CoV values were slightly higher in the vancomycin group than in the cefuroxime group (Figure 3, B), although the difference was statistically significant at the 1-week postoperative visit only (preoperative: P Z .587; postoperative: P Z .031 at 1 week, P Z .937 at 1 month, and P Z .095 at 3 months). Hexagonality In the vancomycin group, there was a statistically significant decrease in the percentage of hexagonal cells 1 week after surgery (P Z .006). However, no statistically significant differences were found between the preoperative value and the 1-month or 3-month postoperative values (P Z .255 and P Z .052, respectively). Similarly, there were no statistically significant differences in the postoperative hexagonality values (P Z .087, 1-week versus 1-month values; P Z .291, 1-month versus 3-month values). The mean decrease in hexagonality in the vancomycin group was 4.68% at the 3-month follow-up. In the cefuroxime group, there was no statistically significant difference in the percentage of hexagonal cells between preoperatively and postoperatively (P Z .067 at 1 week, P Z .149 at 1 month, and P Z .514 at 3 months). Moreover, the differences in hexagonality values were not statistically significant between any 2 postoperative time points (P Z .380, 1 week versus 1 month; P Z .618, 1 month versus 3 months). By 3 months postoperatively, hexagonality had decreased by a mean of 1.85%. The preoperative and postoperative hexagonality values were not statistically significantly different between the vancomycin group and the cefuroxime group (preoperative: P Z .552; postoperative: P Z .436 at 1 week, P Z .656 at 1 month, and P Z .167 at 3 months) (Figure 3, C).
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DISCUSSION In the wake of concerns about increasing rates of postoperative endophthalmitis and antibiotic resistance, efforts to find the most effective method for preventing postoperative infections continue. Despite this, endophthalmitis continues to be one of the most devastating complications of cataract surgery. Several factors are proposed to be involved in this process; these include the surgical technique, intraoperative contamination of the anterior chamber, and increasing age of patients having phacoemulsification. Intraocular contamination is known to occur during cataract extraction or within the first hours after surgery. Anterior chamber aspirates obtained during phacoemulsification show contamination rates ranging from 2% to 43%.10,11 Coagulase-negative Staphylococcus, Propionibacterium acnes, and other conjunctival flora are the most commonly isolated microorganisms. The number of bacterial isolates in preoperative conjunctival cultures in patients older than 75 years old seems to be significantly higher than in younger patients,12 suggesting a correlation between age and bacterial load. Several advantages have been attributed to the use of intracameral injections over traditional topical drop regimens. Achieving intraocular drug levels above the minimum inhibitory concentration (MIC) against conjunctival flora pathogens is of primary importance because of the absence of vascular structures in the cornea and aqueous humor and to avoid the development of bacterial resistance. This is better accomplished with intracameral injections because ocular penetration of topical antibiotics is mostly restricted by the corneal epithelium and lacrimal drainage system. An antibiotic delivered directly into the anterior chamber provides high initial intracameral levels immediately after the injection. These aqueous humor levels should be enough to eradicate intracameral bacteria at the end of the surgery and the first hours of the postoperative period. Another relevant issue is the need to ensure prolonged intraocular levels of antibiotics after the injection; these levels are directly related to the antibiotic's half-life and to aqueous humor turnover. The half-life of intracameral cefuroxime has been reported to be approximately 1 to 2 hours, with drug levels above the MIC for at least 4 hours.13 On the other hand, the half-life of vancomycin has been estimated to range from 2 to 3 hours.13,14 Based on these observations, vancomycin levels in aqueous humor should exceed the MIC for most common microorganisms for a longer period than cefuroxime. Despite this, it has been reported that vancomycin requires a long contact time to achieve its bactericidal effect, making comparisons difficult.15 This longer half-life could be in part responsible for
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the intensity of the anterior chamber reaction observed in the vancomycin group 24 hours after surgery in our study. Since the ESCRS study2 evaluated the effectiveness of intracameral cefuroxime and established the clinical benefits of a dose of 1 mg cefuroxime after cataract extraction, the use of intracameral antibiotics has gained worldwide acceptance. Vancomycin is one of the most commonly used alternatives to cefuroxime. Its mechanism of action is based on the inhibition of bacterial cell-wall synthesis by blocking peptidoglycan crosslinking, thus being almost 100% effective against gram-positive organisms involved in endophthalmitis.16 In the U.S., a 2007 American Society of Cataract and Refractive Surgery member survey17 showed that of surgeons using intracameral injections after cataract extraction, 61% used vancomycin regularly. In Europe, vancomycin is frequently administered in patients with documented allergies to penicillin or cephalosporins because the use of intracameral cefuroxime in these cases remains a matter of controversy. In that respect, although it has been advocated that the absence of mast cells in the anterior chamber protects it from immunoglobulin E–mediated reactions,13 there is concern that a breakdown in the blood–aqueous barrier caused by postoperative inflammation will lead to an anaphylactic reaction. A literature search showed that only 2 cases of possible anaphylactic reactions after intracameral injection of cefuroxime have been reported. However, most surgeons prefer the use of an alternative to cefuroxime. Numerous studies have assessed the safety of intracameral injections of cefuroxime in terms of endothelial toxicity and ocular inflammation. Montan et al.18 found no significant difference in endothelial cell loss between 45 patients receiving 1 mg intracameral cefuroxime and 45 patients who did not receive intracameral prophylaxis. Even higher doses of cefuroxime did not significantly damage the corneal endothelium, although injections of 40 mg to 50 mg, instead of the recommended 1 mg, were associated with transient macular edema and serous retinal detachment.19 Recent studies consistently showed that intracameral injections of moxifloxacin, a fourth-generation fluoroquinolone, in cataract surgery as an alternative to cefuroxime is safe for the corneal endothelium and anterior segment structures. Lane et al.20 used a moxifloxacin 0.5% ophthalmic solution for intracameral use as the last step of phacoemulsification. The mean endothelial cell loss, IOP, corneal thickness, and aqueous flare were not significantly different in patients who received intracameral moxifloxacin and those who received an equal volume of a balanced salt solution. In a study by Espiritu et al.,21 there was no significant difference in the mean ECD between
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preoperatively and postoperatively in patients receiving intracameral moxifloxacin 0.5 mg/mL. Yoeruek et al.6 suggest that the toxicity of cefuroxime and vancomycin to endothelial cells is dose dependent. They harvested human endothelial cells from donor eyes and exposed them to various concentrations of cefuroxime and vancomycin (0.15 to 15.0 mg/mL). Vancomycin concentrations higher than 5.0 mg/mL and cefuroxime concentrations higher than 2.75 mg/mL led to a significant reduction in the number of viable cells. However, clinically used concentrations (1 mg diluted in 0.1 mL) did not have € toxic effects. Ozlem et al.22 evaluated the risk for corneal edema, anterior chamber reaction, and endothelial cell damage after intracameral injections of cefuroxime and vancomycin (1 mg/0.1 mL) in a rabbit model. No corneal edema or anterior chamber reaction was detected 6 hours after injection in either group. To our knowledge, the present study is the first to evaluate the in vivo corneal endothelial changes in humans after intracameral injection of vancomycin. Unlike cefuroxime, vancomycin and moxifloxacin have not been approved for intracameral use by the European Medicines Agency. According to the ESCRS guidelines for prevention of endophthalmitis, both are justifiable options in cases of suspicion of cephalosporin allergy; however, their widespread use is discouraged for 2 reasons.23 First, vancomycin remains an extremely effective drug in the treatment of resistant gram-positive infections and there is controversy about whether its routine use in cataract surgery will promote resistance. Second, no randomized clinical trials have evaluated the efficacy of intracameral moxifloxacin or vancomycin in lowering postoperative endophthalmitis rates. Our primary objective was to evaluate corneal endothelial changes after intracameral injections of vancomycin as an adjunct to povidone–iodine prophylaxis in preventing postoperative endophthalmitis. In physiologic conditions, the ECD decreases with age at an average rate of approximately 0.3% to 0.6% per year because in vivo proliferative potential of human endothelial cells is almost absent.24 However, the corneal endothelium might be exposed to additional damage from corneal disorders, systemic diseases such as diabetes, and toxic exposure. Cataract surgery is a common iatrogenic cause of endothelial damage, especially in patients with a low preoperative ECD. Unlike other tissues, the corneal endothelium wound-healing process is achieved through mechanisms of cell–cell interaction. Peripheral cells interact with each other and promote cell enlargement and migration, restoring a similar pattern when possible. This process induces irreversible cell loss and alters the uniformity of endothelial cell population
(polymegathism) and cell shape (polymorphism). Therefore, the ECD tends to decrease after significant endothelial trauma and is considered a reliable indicator of endothelium injury. However, endothelial cell morphometric analysis combined with an endothelial cell count is a more sensible index of endothelial damage and functional reserve than ECD alone.25 The CoV is an estimation of the variance in cell area across a region of the corneal endothelium. A traumatized endothelium will be expected to have a high CoV as an early sign of endothelial cell loss. Likewise, the percentage of hexagonality reflects cell pleomorphism and complements the CoV as an index of endothelium remodeling. It is usual to find an inverse correlation between hexagonality and the CoV. Specular microscopy is based on the emission of a magnified reflection of light on the endothelium and is the most reliable method available in clinical practice and medical trials for endothelium evaluation. However, a small cell-counting error can have a large effect on the final ECD, CoV, or hexagonality. To minimize sampling errors in our study, 3 measurements were taken and at least 150 cells were analyzed at the preoperative and postoperative examinations. There was a significant decrease in ECD after surgery in both groups in our study, with minimal or no change in the CoV or hexagonality. The mean ECD decreased 1 week after surgery in all patients and then stabilized, which may reflect endothelial damage exerted by the phacoemulsification procedure, as previously reported. According to some studies, the mean endothelial cell loss after modern phacoemulsification can vary from 9% to 14% depending on factors such as age and hardness of the cataract.26,27 In our study, there was minimal evidence of cell density recovery 3 months after surgery in both groups. No significant differences were found in ECD or hexagonality between groups at any time postoperatively, and the CoV values were different at 1 week only. These results suggest that vancomycin and cefuroxime induce comparable corneal endothelial changes and trigger a similar healing process. The potential risk for endothelial toxicity has also been associated with the chemical composition, osmolality, pH, and concentration of the drug solution in the anterior chamber.28 Our cefuroxime and vancomycin dilutions exhibited pH and osmolality values within safe ranges for humans.29 Nevertheless, the pH value of the vancomycin solution was on the lower end of the suitable range for intracameral injection. Based on our findings, intracameral vancomycin seems to be a safe alternative to cefuroxime in terms of corneal endothelial toxicity. No significant differences in the overall percentage of endothelial cell loss, CoV, or hexagonality between vancomycin and
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cefuroxime were observed. No signs of persistent anterior segment toxicity were registered, and no significant differences were noted in IOP or pachymetry changes between the 2 groups 1 week, 1 month, and 3 months after surgery. These results, along with those in previous studies of animal models, support the safety profile of intracameral injections of vancomycin at a dose of 1 mg in 0.1 mL. We decided to analyze the data 3 months after surgery because similar studies evaluating the safety profile of intracameral antibiotics had a follow-up period of 1 to 3 months.20,21 In summary, our findings support the safety of intracameral vancomycin in terms of corneal endothelial damage and anterior chamber inflammation. Although further studies are needed to confirm our observations and determine its retinal safety, vancomycin appears to be a safe alternative to cefuroxime as a prophylaxis method for postoperative endophthalmitis.
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WHAT WAS KNOWN The use of intracameral vancomycin after cataract surgery is effective in preventing postoperative endophthalmitis. Based on in vitro observations and studies in animal models, intracameral injections of vancomycin seem to be safe in terms of corneal endothelial toxicity.
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11.
12.
WHAT THIS PAPER ADDS
13.
Based on specular microscopy analysis, intracameral vancomycin after cataract surgery appears to be as safe as intracameral cefuroxime in terms of corneal endothelial toxicity and anterior segment inflammation in humans.
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REFERENCES
16.
1. Taban M, Behrens A, Newcomb RL, Nobe MY, Saedi G, Sweet PM, McDonnell PJ. Acute endophthalmitis following cataract surgery; a systematic review of the literature. Arch Ophthalmol 2005; 123:613–620. Available at: http://archopht.jam anetwork.com/data/Journals/OPHTH/9940/ecs40117.pdf. Accessed October 9, 2014 2. ESCRS Endophthalmitis Study Group. Prophylaxis of postoperative endophthalmitis following cataract surgery: results of the ESCRS multicenter study and identification of risk factors. J Cataract Refract Surg 2007; 33:978–988 3. Ciulla TA, Starr MB, Masket S. Bacterial endophthalmitis prophylaxis for cataract surgery; an evidence-based update. Ophthalmology 2002; 109:13–24 4. Chitkara DK, Manners T, Chapman F, Stoddart MG, Hill D, Jenkins D. Lack of effect of preoperative norfloxacin on bacterial contamination of anterior chamber aspirates after cataract surgery. Br J Ophthalmol 1994; 78:772–774. Available at: http://
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www.ncbi.nlm.nih.gov/pmc/articles/PMC504932/pdf/brjopthal 00034-0040.pdf. Accessed October 9, 2014 Kodjikian L, Couprie J, Hachicha W, Timour Q, Devouassoux M, Builles N, Hartmann D, Fessi H. Experimental intracameral injection of vancomycin microparticles in rabbits. Invest Ophthalmol Vis Sci 2010; 51:4125–4132. Available at: http://www.iovs. org/content/51/8/4125.full.pdf. Accessed October 9, 2014 Yoeruek E, Spitzer MS, Saygili O, Tatar O, Biedermann T, Yoeruek E, Bartz-Schmidt KU, Szurman P. Comparison of in vitro safety profiles of vancomycin and cefuroxime on human corneal endothelial cells for intracameral use. J Cataract Refract Surg 2008; 34:2139–2145 Bloch-Michel E, Nussenblatt RB. International Uveitis Study Group recommendations for the evaluation of intraocular inflammatory disease [letter]. Am J Ophthalmol 1987; 103:234–235 Rao GN, Waldron WR, Aquavella JV. Morphology of graft endothelium and donor age. Br J Ophthalmol 1980; 64:523–527. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/ PMC1043751/pdf/brjopthal00199-0056.pdf. Accessed October 9, 2014 Mardelli PG, Piebenga LW, Matta CS, Hyde LL, Gira J. Corneal endothelial status 12 to 55 months after excimer laser photorefractive keratectomy. Ophthalmology 1995; 102:544–548; discussion by PS Binder, 548–549 Baillif S, Roure-Sobas C, Le-Duff F, Kodjikian L. Aqueous humor contamination during phacoemulsification in a university teaching hospital. J Fr Ophtalmol 2012; 35:153–156 Dickey JB, Thompson KD, Jay WM. Anterior chamber aspirate cultures after uncomplicated cataract surgery. Am J Ophthalmol 1991; 112:278–282 Rubio EF. Influence of age on conjunctival bacteria of patients undergoing cataract surgery. Eye 2006; 20:447–454. Available at: http://www.nature.com/eye/journal/v20/n4/pdf/6701899a. pdf. Accessed October 9, 2014 Montan PG, Wejde G, Koranyi G, Rylander M. Prophylactic intracameral cefuroxime; efficacy in preventing endophthalmitis after cataract surgery. J Cataract Refract Surg 2002; 28:977– 981 Hachicha W, Kodjikian L, Fessi H. Preparation of vancomycin microparticles: importance of preparation parameters. Int J Pharm 2006; 324:176–184 Kodjikian L, Renaud FNR, Roques C, Roques C, Garweg JG, Pellon G, Freney J, Burillon C. In vitro influence of vancomycin on adhesion of a staphylococcus epidermidis strain encoding intercellular adhesion locus ica to intraocular lenses. J Cataract Refract Surg 2005; 31:1050–1058 Zhanel GG, Calic D, Schweizer F, Zelenitsky S, Adam H, -Wiens PRS, Rubinstein E, Gin AS, Hoban DJ, Lagace Karlowsky JA. New lipoglycopeptides; a comparative review of dalbavancin, oritavancin and telavancin. Drugs 2010; 70:859– 886; erratum 2011; 71:526 Chang DF, Braga-Mele R, Mamalis N, Masket S, Miller KM, Nichamin LD, Packard RB, Packer M; for the ASCRS Cataract Clinical Committee. Prophylaxis of postoperative endophthalmitis after cataract surgery: results of the 2007 ASCRS member survey. J Cataract Refract Surg 2007; 33:1801–1805 €m C. Montan PG, Wejde G, Setterquist H, Rylander M, Zetterstro Prophylactic intracameral cefuroxime; evaluation of safety and kinetics in cataract surgery. J Cataract Refract Surg 2002; 28:982–987 Delyfer M-N, Rougier M-B, Leoni S, Zhang Q, Dalbon F, Colin J, Korobelnik J-F. Ocular toxicity after intracameral injection of very high doses of cefuroxime during cataract surgery. J Cataract Refract Surg 2011; 37:271–278
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20. Lane SS, Osher RH, Masket S, Belani S. Evaluation of the safety of prophylactic intracameral moxifloxacin in cataract surgery. J Cataract Refract Surg 2008; 34:1451–1459 21. Espiritu CRG, Caparas VL, Bolinao JG. Safety of prophylactic intracameral moxifloxacin 0.5% ophthalmic solution in cataract surgery patients. J Cataract Refract Surg 2007; 33:63–68 € € €lsen Y, Ays‚e NB, Firdevs O. 22. Ozlem TY, Necati DM, Fatma YM, Gu Are cefuroxime and vancomycin really safe on the corneal endothelial cells? Graefes Arch Clin Exp Ophthalmol 2010; 248:415–420 s L, Gardner S. ESCRS Guidelines for Preven23. Barry P, Cordove tion and Treatment of Endophthalmitis Following Cataract Surgery: Data, Dilemmas and Conclusions. Dublin, Ireland, European Society of Cataract and Refractive Surgeons, 2013. Available at: http://www.escrs.org/downloads/EndophthalmitisGuidelines.pdf. Accessed October 7, 2014 24. Bourne WM, Nelson LR, Hodge DO. Central corneal endothelial cell changes over a ten-year period. Invest Ophthalmol Vis Sci 1997; 38:779–782. Available at: http://www.iovs.org/cgi/ reprint/38/3/779. Accessed October 9, 2014 25. Waring GO III, Bourne WM, Edelhauser HF, Kenyon KR. The corneal endothelium; normal and pathologic structure and function. Ophthalmology 1982; 89:531–590 26. Bourne RRA, Minassian DC, Dart JKG, Rosen P, Kaushal S, Wingate N. Effect of cataract surgery on the corneal endothe-
lium; modern phacoemulsification compared with extracapsular cataract surgery. Ophthalmology 2004; 111:679–685 27. Ravalico G, Tognetto D, Palomba MA, Lovisato A, Baccara F. Corneal endothelial function after extracapsular cataract extraction and phacoemulsification. J Cataract Refract Surg 1997; 23:1000–1005 28. Mamalis N. Intracameral medication: is it worth the risk? [editorial] J Cataract Refract Surg 2008; 34:339–340 29. Trinkaus-Randall V, Edelhauser HF, Leibowitz HM, Freddo TF. Corneal structure and function. In: Leibowitz HM, Waring GO III, eds, Corneal Disorders; Clinical Diagnosis and Management, 2nd ed. Philadelphia, PA, WB Saunders, 1998; 21–27
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First author: Jose L. Perez-Canales, MD Department of Ophthalmology, Hospital Virgen de los Lirios, Alcoy, Spain
Corneal endothelial changes after intracameral vancomycin injection in cataract surgery Jose L. Perez-Canales, MD, Juan J. Perez-Santonja, MD, FEBO, Ezequiel Campos-Mollo, MD, PhD
PURPOSE: To evaluate corneal endothelial changes after intracameral injection of vancomycin at the end of routine cataract surgery. SETTING: Department of Ophthalmology, Hospital Virgen de los Lirios, Alcoy, Alicante, Spain. DESIGN: Prospective comparative case series. METHODS: Eyes received an intracameral injection of vancomycin (1 mg/0.1 mL) or cefuroxime (1 mg/0.1 mL) at the end of surgery. The visual acuity, corneal clarity, pachymetry, anterior chamber reaction, endothelial cell density (ECD), coefficient of variation (CoV), and hexagonality were evaluated at baseline and 1 week, 1 month, and 3 months after surgery. RESULTS: Sixty eyes (42 patients), 30 in each group, were enrolled. In the vancomycin group, there was a significant decrease in ECD 1 week after surgery (P Z .000), after which the ECD stabilized. There were no statistically significant changes in postoperative CoV values between preoperatively and postoperatively, although there was a transient decrease in hexagonality 1 week after surgery (P Z .006). In the cefuroxime group, the ECD significantly decreased 1 week after surgery (P Z .000) and then stabilized. There was a statistically significantly decrease in the CoV between preoperatively and 3 months postoperatively (P Z .014). No changes were noted in hexagonality. The postoperative ECD, CoV, and hexagonality values were not significantly different between the vancomycin group and the cefuroxime group. CONCLUSIONS: Endothelial cell changes observed after intracameral vancomycin were similar to those observed after intracameral cefuroxime in cataract surgery. The results indicate that intracameral vancomycin is safe for use in cataract surgery. Financial Disclosure: No author has a financial or proprietary interest in any material or method mentioned. J Cataract Refract Surg 2015; 41:126–134 Q 2015 ASCRS and ESCRS
Postoperative infectious endophthalmitis is one of the most severe complications of cataract surgery. Fortunately, it is a relatively rare event, with a reported incidence ranging from 0.06% to 0.49% in the United States and Europe.1,2 To prevent its devastating effects, the use of prophylactic measures in cataract surgery has been significantly expanded. Several preoperative, intraoperative, and postoperative strategies have been developed over the years, although there is still no consensus on the best method and regimen of administration. Preoperative antiseptics and antibiotics are usually administered to reduce bacterial colonization of the 126
Q 2015 ASCRS and ESCRS Published by Elsevier Inc.
ocular surface. To that end, the use of preoperative povidone–iodine 5.0% in the conjunctival sac remains the most accepted method and is now considered the standard of care in cataract surgery.3 In contrast, the role of preoperative topical antibiotics is controversial, with some studies showing no significant effect on anterior chamber contamination.4 Intraoperatively, subconjunctival injections of antibiotics have been progressively replaced by intracameral injections, mainly as a result of the generalized adoption of topical anesthesia in cataract surgery. A multinational clinical trial by the European Society of Cataract and Refractive Surgeons (ESCRS)2
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consistently showed the effectiveness of intracameral instillation of cefuroxime (1 mg in 0.1 mL) in addition to preoperative povidone–iodine antisepsis, reporting a 5-fold reduction in the risk for developing endophthalmitis. In contrast, the administration of topical antibiotics (levofloxacin 0.5%) after surgery led to no significant decrease in the incidence of postoperative infections. Intracameral vancomycin is commonly administered after cataract surgery in European countries and is currently considered a second-line drug in patients allergic to cephalosporins. However, the safety profile of intracameral vancomycin in terms of corneal endothelial toxicity has not been fully evaluated. To date, studies have been limited to animals and in vitro analysis of human corneas.5,6 The aim of this study was to assess corneal endothelial changes after intracameral injection of vancomycin as a prophylactic measure for postoperative endophthalmitis in cataract surgery. To our knowledge, this is the first study to evaluate in vivo corneal endothelial changes after intracameral injection of vancomycin. PATIENTS AND METHODS This prospective comparative case series, performed from September 2012 to October 2013, comprised eyes in which phacoemulsification cataract surgery was performed at Virgen de los Lirios Hospital, Alcoy, Spain. Eligible patients were aged 65 to 80 years with senile cataract and no concomitant disease that would prevent a postoperative corrected distance visual acuity (CDVA) of 20/40 or better. Exclusion criteria included a history of ocular surgery or trauma, corneal disease, glaucoma, uveitis, vitreous opacities, retinopathy, and visual pathway defects. Other exclusion criteria were current treatment with systemic steroids, immunosuppressants, anticoagulants, or prostaglandin analogue eyedrops. Patients with intraoperative complications or extended surgical time were also excluded. After informed consent was obtained, consecutive patients with a history of allergy to penicillin were assigned to the vancomycin group. An equal number of patients matched for age, sex, and laterality were selected and assigned to the control group (cefuroxime group). Patients in the vancomycin group received an intracameral injection of
Submitted: March 23, 2014. Final revision submitted: May 7, 2014. Accepted: May 8, 2014. From the Departments of Ophthalmology, Hospital Virgen de los Lirios (Perez-Canales, Campos-Mollo), Alcoy, and Alicante University General Hospital (Perez-Santonja), Alicante, and the Cornea Unit (Perez-Santonja), Oftalvist Group, Alicante, Spain. Corresponding author: Jose L. Perez-Canales, MD, Hospital General Universitario de Alicante, Departamento de Oftalmologıa, Avenida Pintor Baeza 12, 03010, Alicante, Spain. E-mail: [email protected].
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vancomycin (1 mg in 0.1 mL), whereas those in the cefuroxime group received an intracameral injection of cefuroxime (1 mg in 0.1 mL). The antibiotic dilutions were performed by the operating room nursing staff. The vancomycin injection was prepared from a commercially available vancomycin hydrochloride 500 mg powder and diluted with sterile normal saline to a 1 mg/0.1 mL solution. The vancomycin solution had a pH of 6.42 and an osmolality of 313 mOsm/kg. The cefuroxime injection was prepared from cefuroxime 750 mg powder and diluted to a 1 mg/0.1 mL solution. This solution had a pH of 7.28 and an osmolality of 366 mOsm/kg. Pupils were dilated with repeated doses of tropicamide 1.0% and phenylephrine 10.0%. Preoperative prophylactic measures consisted of skin preparation with povidone– iodine 10.0% (Betadine) and instillation of povidone–iodine 5.0% into the conjunctival sac at the operating site at least 5 minutes before surgery. A combination of topical tetracaine 1.0% and oxybuprocaine 4.0% was used for anesthesia. The same surgeon (J.J.P.-S.) performed all surgeries using a standard phaco-chop technique. A hydrophobic acrylic intraocular lens (IOL) (Acrysof SN60WF, Alcon Laboratories, Inc.) was implanted in all cases. After the ophthalmic viscosurgical device was removed and the surgeon ensured that the corneal incisions were adequately sealed, the antibiotic agent was injected via the side port into the capsular bag using a 27-gauge cannula. All patients received a standard postoperative regimen of topical ofloxacin 0.3% (Exocin) 4 times daily for 1 week and dexamethasone 0.1% (Maxidex) 4 times daily for the first week and then 3 times daily for the next 3 weeks.
Patient Examinations Postoperative examinations were performed at 1 week, 1 month, and 3 months. Preoperative and postoperative examinations included uncorrected distance visual acuity (UDVA), refraction, CDVA, corneal clarity, anterior chamber reaction (cells and flare), pachymetry, intraocular pressure (IOP) by applanation tonometry, and endothelial specular microscopy (endothelial cell density [ECD], coefficient of variation [CoV] in cell size, and percentage of hexagonality). The data obtained before surgery were compared with those obtained after surgery within the 2 groups. Preoperative and postoperative data were also compared between groups. The postoperative examiner was masked to the group assignment. Visual acuity was measured using Snellen charts at 6 m. Corneal edema was evaluated by slitlamp biomicroscopy (BQ 900, Haag-Streit AG) and scored as follows: grade 0 Z no corneal edema; grade 1 Z corneal edema limited to incision area; grade 2 Z edema affecting less than 25% of the cornea without Descemet membrane folds; grade 3 Z edema affecting between 25% and 50% of the cornea or presence of Descemet membrane folds; grade 4 Z edema affecting more than 50% of the cornea. Central corneal thickness was measured using an ultrasonic pachymeter (Palmscan AP2000, Micromedical Devices, Inc.). The anterior chamber reaction was classified using a modification of the International Uveitis Study Group recommendations.7 The aqueous cell count was graded on a scale of 0 to 4 depending on the amount per slit-beam field (1.0 mm 1.0 mm) as follows: grade 0 Z fewer than 5 cells; grade 1 Z 6 to 15 cells; grade 2 Z 16 to 25 cells; grade 3 Z 26 to 50 cells; grade 4 Z more than 51 cells. The grading scheme
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for flare was grade 0 Z no flare; grade 1 Z barely detectable flare; grade 2 Z evident flare with iris details clearly visible; grade 3 Z marked flare and iris details not clearly visible; grade 4 Z plastic aqueous and fibrin presence in anterior chamber. In all eyes, noncontact wide-field specular microscopy of the central corneal endothelium was performed preoperatively and 1 week, 1 month, and 3 months postoperatively. The wide-field corneal specular microscope (Cellchek XL, Konan Medical, Inc.) was adapted to a digitization imageanalysis system (Cellchek Advanced Analysis Software, Konan Medical, Inc.). The specular microscopic images of the central portion of each cornea were taken using the specular microscope's built-in charge-coupled device camera and sent to the image-analysis system to be stored on a hard disk for subsequent digitization and analysis. At a later time, 3 images from each examination were digitized on the computer for analysis. The reviewer (J.L.P.-C.), who performed the image digitization, was unaware of the group status of the patient. The center of 150 cells (at least 50 cells per image) was digitized and analyzed using the “center method” of the image-analysis software. The endothelium was analyzed to calculate the mean cell density (cells per square millimeter), the CoV in cell size, and the percentage of hexagonal cells (cell shape). All these parameters were calculated automatically by the computer. The CoV provides a good quantitative assessment of cell size variability.8 The percentage of hexagonal cells was used as a measure of cell shape variability9 (reduction in the frequency of hexagonal cells results in greater variability). Data were encoded and analyzed using the SPSS software (version 21.0, SPSS, Inc.). Comparability in baseline demographic and clinical characteristics between groups was ensured. A paired Student t test was used to compare preoperative and postoperative continuous variables within groups. Comparisons between groups were performed using an unpaired Student t test for continuous variables and Mann-Whitney U test for ordinal and categorical variables. A P value less than 0.05 was determined to be significant. The results are given as the mean G SD.
Table 1. Between-group comparison of preoperative patient parameters and demographics.
Parameter
Vancomycin
Sex (n) Male 13 Female 13 Age (y) Mean G SD 73.23 G 5.83 Range 65, 80 CDVA (logMAR) Mean G SD 0.33 G 0.17 Range 0.15, 0.70 IOP (mm Hg) Mean G SD 14.85 G 2.63 Range 10, 22 Corneal thickness (mm) Mean G SD 538.96 G 39.52 Range 477, 605
Cefuroxime
P Value* .582
13 13 72.38 G 4.43 65, 79
.559
0.34 G 0.13 0.10, 0.70
.794
16.04 G 2.72 9, 20
.113
552.19 G 33.86 492, 606
.201
CDVA Z corrected distance visual acuity; IOP Z Intraocular pressure *Unpaired t test for continuous variables; chi-square test for categorical variables.
(preoperative: P Z .588; postoperative: P Z .268 at 1 week, P Z .124 at 1 month, and P Z .589 at 3 months). Anterior chamber inflammation resolved in all patients within the first week after surgery. The aqueous cell count was significantly higher in the vancomycin group than in the cefuroxime group 24 hours after surgery (P ! .02) (Figure 1). However, no differences in aqueous cells or flare were noted between the 2 groups at subsequent examinations.
RESULTS The vancomycin group and the cefuroxime group each comprised 30 eyes of 21 patients. Four eyes in the vancomycin group and 3 in the cefuroxime group were lost to follow-up because of unrelated adverse events or death. One eye in the cefuroxime group was withdrawn because the examiner was not able to analyze at least 150 endothelial cells at the postoperative examinations. Table 1 shows the patients' demographics. There were no significant differences in the preoperative mean age, sex, UDVA, refraction, CDVA, corneal pachymetry, IOP, ECD, CoV, or hexagonality between groups. Both groups had a statistically significant increase in UDVA and CDVA after surgery (P Z .000). At 3 months, all eyes had improved CDVA. Preoperative and postoperative CDVA values were comparable between groups
Figure 1. Aqueous cell count distribution 24 hours after surgery.
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24 hours after surgery (P Z .234). Corneal edema was absent in all patients at subsequent examinations. Central corneal thickness significantly increased in the vancomycin group and the cefuroxime group at the 1-week follow-up (P Z .000). However, the mean 1-month and 3-month corneal thickness did not differ from baseline values in either group (vancomycin: P Z .056 at 1 month and P Z .561 at 3 months; cefuroxime: P Z .344 at 1 month and P Z .647 at 3 months). Preoperative and postoperative values were similar in the 2 groups (preoperative: P Z .201; postoperative: P Z .973 at 1 week, P Z .411 at 1 month, and P Z .276 at 3 months) (Figure 2). Endothelial Cell Density
Figure 2. Changes in central corneal pachymetry over time.
There were 2 cases of posterior vitreous detachment in the vancomycin group and 2 cases in the cefuroxime group. No adverse drug reaction was reported over the 3-month follow-up.
Corneal Edema and Central Corneal Thickness Corneal edema was absent or limited to the area of incisions in 21 patients (80.7%) in the vancomycin group and 23 patients (88.4%) in the cefuroxime group
Table 2 shows the mean ECD, CoV, and hexagonality in both groups. The mean number of endothelial cells analyzed per patient was 286.29 (range 156 to 444) at baseline and 216.85 (range 151 to 479) at the postoperative examinations. In the vancomycin group, there was a significant decrease in the ECD from preoperatively to postoperatively (all comparisons P Z .000). However, the differences between the 1-week and 1-month mean values and between the 1-month and 3-month mean values were not statistically significant (P Z .847 and P Z .218, respectively). By 3 months postoperatively, the mean ECD had decreased by a mean of 13.30% from the preoperative values; the decrease was statistically significant (P Z .000).
Table 2. Endothelial changes over time by groups. Endothelial Cell Density (Cells/mm2) Group All eyes (N Z 52) Preoperative Postoperative 1 week 1 month 3 months Vancomycin (n Z 26) Preoperative Postoperative 1 week 1 month 3 months Cefuroxime (n Z 26) Preoperative Postoperative 1 week 1 month 3 months
Coefficient of Variation
Hexagonality
Mean G SD
P Value
Mean G SD
P Value
Mean G SD
P Value
2365.21 G 377.57
d
38.00 G 5.03
d
57.88 G 5.53
d
2056.04 G 459.68 2036.81 G 425.00 2065.81 G 440.80
000 .000 .000
37.37 G 5.36 36.36 G 4.51 36.23 G 4.48
.291 .015 .008
54.85 G 6.34 56.23 G 5.53 56.00 G 6.58
.001 .066 .077
2289.12 G 394.75
d
38.38 G 5.81
d
57.42 G 6.28
d
1957.19 G 443.48 1952.27 G 395.74 1984.58 G 417.25
.000 .000 .000
38.96 G 6.34 36.41 G 5.40 37.27 G 4.52
.412 .065 .228
54.15 G 6.85 55.88 G 5.33 54.73 G 5.94
.006 .255 .052
2441.31 G 350.64
d
37.62 G 4.20
d
58.35 G 4.74
d
2154.88 G 462.66 2121.35 G 443.84 2147.04 G 464.51
.000 .000 .000
35.77 G 3.62 36.31 G 3.51 35.19 G 4.27
.056 .122 .014
55.54 G 5.84 56.58 G 5.81 57.27 G 7.05
.067 .149 .514
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Figure 3. Changes over time in ECD and morphometric parameters.
Similarly, the ECD decreased significantly in the cefuroxime group from preoperatively to postoperatively (all comparisons P Z .000). The difference between the 1-week ECD and 1-month ECD was not significant (P Z .065), although there was a significant increase in ECD at 3 months over the ECD at 1 month (P Z .044). By 3 months after surgery, the mean ECD had decreased by a mean of 12.05%; the decrease was statistically significant (P Z .000). The preoperative mean ECD was similar in the 2 groups (P Z .148). Postoperatively, the ECD remained similar (P Z .122 at 1 week, P Z .153 at 1 month, and P Z .191 at 3 months) (Figure 3, A). Coefficient of Variation In the vancomycin group, there were no significant differences between the preoperative CoV value and the postoperative CoV value (P Z .412 at 1 week, P Z .065 at 1 month, and P Z .228 at 3 months). However, the mean CoV was statistically significantly lower 1 month after surgery than at 1 week (P Z .016). The difference between 1 month and 3 months was not statistically significant (P Z .271). By 3 months, the CoV had decreased by a mean of 2.89%; the change was not statistically significant. In the cefuroxime group, the CoV values were not significantly different from baseline values 1 week or 1 month after surgery (P Z .056 and P Z .122, respectively). However, there was a statistically significant decrease between preoperatively and 3 months postoperatively (P Z .014). The difference was not statistically significant between any 2 postoperative time points (P Z .471, 1 week versus 1 month; P Z .158, 1 month versus 3 month). The mean CoV decrease was 6.46% at the 3-month follow-up; the change was statistically significant (P Z .014).
The preoperative and postoperative CoV values were slightly higher in the vancomycin group than in the cefuroxime group (Figure 3, B), although the difference was statistically significant at the 1-week postoperative visit only (preoperative: P Z .587; postoperative: P Z .031 at 1 week, P Z .937 at 1 month, and P Z .095 at 3 months). Hexagonality In the vancomycin group, there was a statistically significant decrease in the percentage of hexagonal cells 1 week after surgery (P Z .006). However, no statistically significant differences were found between the preoperative value and the 1-month or 3-month postoperative values (P Z .255 and P Z .052, respectively). Similarly, there were no statistically significant differences in the postoperative hexagonality values (P Z .087, 1-week versus 1-month values; P Z .291, 1-month versus 3-month values). The mean decrease in hexagonality in the vancomycin group was 4.68% at the 3-month follow-up. In the cefuroxime group, there was no statistically significant difference in the percentage of hexagonal cells between preoperatively and postoperatively (P Z .067 at 1 week, P Z .149 at 1 month, and P Z .514 at 3 months). Moreover, the differences in hexagonality values were not statistically significant between any 2 postoperative time points (P Z .380, 1 week versus 1 month; P Z .618, 1 month versus 3 months). By 3 months postoperatively, hexagonality had decreased by a mean of 1.85%. The preoperative and postoperative hexagonality values were not statistically significantly different between the vancomycin group and the cefuroxime group (preoperative: P Z .552; postoperative: P Z .436 at 1 week, P Z .656 at 1 month, and P Z .167 at 3 months) (Figure 3, C).
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DISCUSSION In the wake of concerns about increasing rates of postoperative endophthalmitis and antibiotic resistance, efforts to find the most effective method for preventing postoperative infections continue. Despite this, endophthalmitis continues to be one of the most devastating complications of cataract surgery. Several factors are proposed to be involved in this process; these include the surgical technique, intraoperative contamination of the anterior chamber, and increasing age of patients having phacoemulsification. Intraocular contamination is known to occur during cataract extraction or within the first hours after surgery. Anterior chamber aspirates obtained during phacoemulsification show contamination rates ranging from 2% to 43%.10,11 Coagulase-negative Staphylococcus, Propionibacterium acnes, and other conjunctival flora are the most commonly isolated microorganisms. The number of bacterial isolates in preoperative conjunctival cultures in patients older than 75 years old seems to be significantly higher than in younger patients,12 suggesting a correlation between age and bacterial load. Several advantages have been attributed to the use of intracameral injections over traditional topical drop regimens. Achieving intraocular drug levels above the minimum inhibitory concentration (MIC) against conjunctival flora pathogens is of primary importance because of the absence of vascular structures in the cornea and aqueous humor and to avoid the development of bacterial resistance. This is better accomplished with intracameral injections because ocular penetration of topical antibiotics is mostly restricted by the corneal epithelium and lacrimal drainage system. An antibiotic delivered directly into the anterior chamber provides high initial intracameral levels immediately after the injection. These aqueous humor levels should be enough to eradicate intracameral bacteria at the end of the surgery and the first hours of the postoperative period. Another relevant issue is the need to ensure prolonged intraocular levels of antibiotics after the injection; these levels are directly related to the antibiotic's half-life and to aqueous humor turnover. The half-life of intracameral cefuroxime has been reported to be approximately 1 to 2 hours, with drug levels above the MIC for at least 4 hours.13 On the other hand, the half-life of vancomycin has been estimated to range from 2 to 3 hours.13,14 Based on these observations, vancomycin levels in aqueous humor should exceed the MIC for most common microorganisms for a longer period than cefuroxime. Despite this, it has been reported that vancomycin requires a long contact time to achieve its bactericidal effect, making comparisons difficult.15 This longer half-life could be in part responsible for
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the intensity of the anterior chamber reaction observed in the vancomycin group 24 hours after surgery in our study. Since the ESCRS study2 evaluated the effectiveness of intracameral cefuroxime and established the clinical benefits of a dose of 1 mg cefuroxime after cataract extraction, the use of intracameral antibiotics has gained worldwide acceptance. Vancomycin is one of the most commonly used alternatives to cefuroxime. Its mechanism of action is based on the inhibition of bacterial cell-wall synthesis by blocking peptidoglycan crosslinking, thus being almost 100% effective against gram-positive organisms involved in endophthalmitis.16 In the U.S., a 2007 American Society of Cataract and Refractive Surgery member survey17 showed that of surgeons using intracameral injections after cataract extraction, 61% used vancomycin regularly. In Europe, vancomycin is frequently administered in patients with documented allergies to penicillin or cephalosporins because the use of intracameral cefuroxime in these cases remains a matter of controversy. In that respect, although it has been advocated that the absence of mast cells in the anterior chamber protects it from immunoglobulin E–mediated reactions,13 there is concern that a breakdown in the blood–aqueous barrier caused by postoperative inflammation will lead to an anaphylactic reaction. A literature search showed that only 2 cases of possible anaphylactic reactions after intracameral injection of cefuroxime have been reported. However, most surgeons prefer the use of an alternative to cefuroxime. Numerous studies have assessed the safety of intracameral injections of cefuroxime in terms of endothelial toxicity and ocular inflammation. Montan et al.18 found no significant difference in endothelial cell loss between 45 patients receiving 1 mg intracameral cefuroxime and 45 patients who did not receive intracameral prophylaxis. Even higher doses of cefuroxime did not significantly damage the corneal endothelium, although injections of 40 mg to 50 mg, instead of the recommended 1 mg, were associated with transient macular edema and serous retinal detachment.19 Recent studies consistently showed that intracameral injections of moxifloxacin, a fourth-generation fluoroquinolone, in cataract surgery as an alternative to cefuroxime is safe for the corneal endothelium and anterior segment structures. Lane et al.20 used a moxifloxacin 0.5% ophthalmic solution for intracameral use as the last step of phacoemulsification. The mean endothelial cell loss, IOP, corneal thickness, and aqueous flare were not significantly different in patients who received intracameral moxifloxacin and those who received an equal volume of a balanced salt solution. In a study by Espiritu et al.,21 there was no significant difference in the mean ECD between
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preoperatively and postoperatively in patients receiving intracameral moxifloxacin 0.5 mg/mL. Yoeruek et al.6 suggest that the toxicity of cefuroxime and vancomycin to endothelial cells is dose dependent. They harvested human endothelial cells from donor eyes and exposed them to various concentrations of cefuroxime and vancomycin (0.15 to 15.0 mg/mL). Vancomycin concentrations higher than 5.0 mg/mL and cefuroxime concentrations higher than 2.75 mg/mL led to a significant reduction in the number of viable cells. However, clinically used concentrations (1 mg diluted in 0.1 mL) did not have € toxic effects. Ozlem et al.22 evaluated the risk for corneal edema, anterior chamber reaction, and endothelial cell damage after intracameral injections of cefuroxime and vancomycin (1 mg/0.1 mL) in a rabbit model. No corneal edema or anterior chamber reaction was detected 6 hours after injection in either group. To our knowledge, the present study is the first to evaluate the in vivo corneal endothelial changes in humans after intracameral injection of vancomycin. Unlike cefuroxime, vancomycin and moxifloxacin have not been approved for intracameral use by the European Medicines Agency. According to the ESCRS guidelines for prevention of endophthalmitis, both are justifiable options in cases of suspicion of cephalosporin allergy; however, their widespread use is discouraged for 2 reasons.23 First, vancomycin remains an extremely effective drug in the treatment of resistant gram-positive infections and there is controversy about whether its routine use in cataract surgery will promote resistance. Second, no randomized clinical trials have evaluated the efficacy of intracameral moxifloxacin or vancomycin in lowering postoperative endophthalmitis rates. Our primary objective was to evaluate corneal endothelial changes after intracameral injections of vancomycin as an adjunct to povidone–iodine prophylaxis in preventing postoperative endophthalmitis. In physiologic conditions, the ECD decreases with age at an average rate of approximately 0.3% to 0.6% per year because in vivo proliferative potential of human endothelial cells is almost absent.24 However, the corneal endothelium might be exposed to additional damage from corneal disorders, systemic diseases such as diabetes, and toxic exposure. Cataract surgery is a common iatrogenic cause of endothelial damage, especially in patients with a low preoperative ECD. Unlike other tissues, the corneal endothelium wound-healing process is achieved through mechanisms of cell–cell interaction. Peripheral cells interact with each other and promote cell enlargement and migration, restoring a similar pattern when possible. This process induces irreversible cell loss and alters the uniformity of endothelial cell population
(polymegathism) and cell shape (polymorphism). Therefore, the ECD tends to decrease after significant endothelial trauma and is considered a reliable indicator of endothelium injury. However, endothelial cell morphometric analysis combined with an endothelial cell count is a more sensible index of endothelial damage and functional reserve than ECD alone.25 The CoV is an estimation of the variance in cell area across a region of the corneal endothelium. A traumatized endothelium will be expected to have a high CoV as an early sign of endothelial cell loss. Likewise, the percentage of hexagonality reflects cell pleomorphism and complements the CoV as an index of endothelium remodeling. It is usual to find an inverse correlation between hexagonality and the CoV. Specular microscopy is based on the emission of a magnified reflection of light on the endothelium and is the most reliable method available in clinical practice and medical trials for endothelium evaluation. However, a small cell-counting error can have a large effect on the final ECD, CoV, or hexagonality. To minimize sampling errors in our study, 3 measurements were taken and at least 150 cells were analyzed at the preoperative and postoperative examinations. There was a significant decrease in ECD after surgery in both groups in our study, with minimal or no change in the CoV or hexagonality. The mean ECD decreased 1 week after surgery in all patients and then stabilized, which may reflect endothelial damage exerted by the phacoemulsification procedure, as previously reported. According to some studies, the mean endothelial cell loss after modern phacoemulsification can vary from 9% to 14% depending on factors such as age and hardness of the cataract.26,27 In our study, there was minimal evidence of cell density recovery 3 months after surgery in both groups. No significant differences were found in ECD or hexagonality between groups at any time postoperatively, and the CoV values were different at 1 week only. These results suggest that vancomycin and cefuroxime induce comparable corneal endothelial changes and trigger a similar healing process. The potential risk for endothelial toxicity has also been associated with the chemical composition, osmolality, pH, and concentration of the drug solution in the anterior chamber.28 Our cefuroxime and vancomycin dilutions exhibited pH and osmolality values within safe ranges for humans.29 Nevertheless, the pH value of the vancomycin solution was on the lower end of the suitable range for intracameral injection. Based on our findings, intracameral vancomycin seems to be a safe alternative to cefuroxime in terms of corneal endothelial toxicity. No significant differences in the overall percentage of endothelial cell loss, CoV, or hexagonality between vancomycin and
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cefuroxime were observed. No signs of persistent anterior segment toxicity were registered, and no significant differences were noted in IOP or pachymetry changes between the 2 groups 1 week, 1 month, and 3 months after surgery. These results, along with those in previous studies of animal models, support the safety profile of intracameral injections of vancomycin at a dose of 1 mg in 0.1 mL. We decided to analyze the data 3 months after surgery because similar studies evaluating the safety profile of intracameral antibiotics had a follow-up period of 1 to 3 months.20,21 In summary, our findings support the safety of intracameral vancomycin in terms of corneal endothelial damage and anterior chamber inflammation. Although further studies are needed to confirm our observations and determine its retinal safety, vancomycin appears to be a safe alternative to cefuroxime as a prophylaxis method for postoperative endophthalmitis.
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WHAT WAS KNOWN The use of intracameral vancomycin after cataract surgery is effective in preventing postoperative endophthalmitis. Based on in vitro observations and studies in animal models, intracameral injections of vancomycin seem to be safe in terms of corneal endothelial toxicity.
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WHAT THIS PAPER ADDS
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Based on specular microscopy analysis, intracameral vancomycin after cataract surgery appears to be as safe as intracameral cefuroxime in terms of corneal endothelial toxicity and anterior segment inflammation in humans.
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First author: Jose L. Perez-Canales, MD Department of Ophthalmology, Hospital Virgen de los Lirios, Alcoy, Spain
