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Comparative corneal endothelial cell toxicity of differing intracameral moxifloxacin doses after phacoemulsification

Chang, David F. MD; Prajna, N. Venkatesh FRCO; Szczotka-Flynn, Loretta B. OD, PhD; Benetz, Beth Ann CRA, FOPS; Lass, Jonathan H. MD; O'Brien, Robert C. PhD; Menegay, Harry J. PhD; Gardner, Susanne PharmD; Shekar, Madhu MS; Rajendrababu, Sharmila DNB; Rhee, Douglas J. MD

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Journal of Cataract and Refractive Surgery: March 2020 - Volume 46 - Issue 3 - p 355-359
doi: 10.1097/j.jcrs.0000000000000064
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Routine intracameral antibiotic prophylaxis (ICAP) for cataract surgery remains a controversial practice, particularly in those settings in which an approved drug formulation is not commercially available.1–4 Nonetheless, ICAP continues to increase in popularity with proponents citing the growing body of published evidence supporting its efficacy.5–8 Vancomycin has historically been a popular choice for ICAP, particularly in the United States.6 However, elucidation of its rare but devastating association with hemorrhagic occlusive retinal vasculitis has prompted a shift to alternative antibiotics, such as moxifloxacin.3,9

Moxifloxacin has the advantage of being broad spectrum, bactericidal, and commercially available as an unpreserved, topical formulation that has been used off-label for ICAP in North America.4,10 At the Aravind Eye Care System (AECS) in southern India, a commercially approved 5 mg/mL moxifloxacin formulation (Auromox) has been used routinely in more than 1 million consecutive cases.11,12 A recent AECS retrospective study of more than 2 million eyes found that a 0.1 mL intracameral injection containing 500 μg of moxifloxacin reduced the rate of postoperative endophthalmitis (POE) from 0.07% to 0.02% (P < 0.001).12

Several early clinical studies reported no adverse effects from intracameral moxifloxacin prophylaxis (ICMP) using a variety of doses (50 to 500 μg, 100 μg, 250 μg, and 500 μg) after cataract surgery.13–17 A recent meta-analysis of studies using 100 to 500 μg doses reached this same conclusion.18 The large AECS clinical study likewise reported no increased incidence of postoperative corneal decompensation or prolonged corneal edema with ICMP.12 Haruki et al. reported greater corneal endothelial cell toxicity in vitro with increasing doses of moxifloxacin.19 However, there are no clinical studies that have compared the 250 μg and 500 μg intracameral moxifloxacin doses for potential corneal endothelial cell toxicity.

Although the 250 μg dose might theoretically pose less risk for corneal endothelial cell toxicity, fluoroquinolones are known to be concentration dependent. In vitro data suggest that the lower 250 μg dose of moxifloxacin may be less effective against certain bacteria.20 This observation may relate in part to a shorter period of time for the bactericidal effect after a single injection intracamerally. Given the potential for corneal endothelial cell toxicity from moxifloxacin, the ideal ICMP dose that optimally balances safety with efficacy has not been definitively established. A randomized, prospective, masked, paired-eye clinical study was performed to compare the central corneal endothelial cell loss (ECL) 3 months postoperatively for a 250 μg vs 500 μg intracameral dose of moxifloxacin after phacoemulsification.

METHODS

The protocol was jointly executed between investigators at the AECS, Madurai, Tamil Nadu, India, and the University Hospitals Eye Institute (UHEI), Cleveland, Ohio, USA. All clinical care and clinical study execution was performed within the AECS and was locally approved by the Institutional Ethics Committee of the Aravind Medical Research Foundation. The UHEI Vision Research Coordinating Center monitored the study for adherence and regulatory activities, accepted deidentified study data, and maintained the study database, whereas the UHEI Cornea Image Analysis Reading Center (CIARC) accepted the clinical images of endothelial cells for the analysis of endothelial cell density (ECD). The subsequent deidentified databases were transmitted to the Jaeb Center for Health Research in Tampa, Florida, for statistical analysis. The trial was registered at http://ctri.nic.in with a registration number (CTRI/2017/12/010759). All patients provided written informed consent. The trial was conducted in compliance with the tenets of the Declaration of Helsinki.

This design was a bilateral, paired-eye, prospective, single-site, masked, randomized clinical trial. The primary objective was to demonstrate noninferiority of central ECL between eyes receiving 500 μg/0.1 mL vs 250 μg/0.1 mL intracameral moxifloxacin after phacoemulsification. Adult patients between 45 years and 85 years of age undergoing phacoemulsification for both eyes and in good general health were eligible. Patients were excluded if they had uncontrolled glaucoma, blunt or penetrating trauma, pseudoexfoliation syndrome, previous angle-closure glaucoma, uveitis, Fuchs endothelial corneal dystrophy, hard poly(methyl methacrylate) contact lens wear, bilateral nuclear density of NO4/NC4 on Lens Opacities Classification System III, or any contraindication to moxifloxacin.21 Patients who had refractive surgery, laser trabeculoplasty, other laser surgery within the past 3 months, or other ocular surgery (eg, filtration surgery) within the past 12 months were also excluded. Central ECD was required to be more than 2000 cells/mm2 in each eye at baseline with a difference between eyes of less than 200 cells as assessed by the CIARC.

One day before surgery, participants used topical ofloxacin 0.3% 6 times daily in the study eye. On the day of surgery, topical ofloxacin 0.3%, tropicamide 0.8%, and phenylephrine hydrochloride 5% were administered preoperatively. Cataract surgery was performed in both eyes by 2 experienced staff surgeons (M.S., S.R.), with a minimum of 14 days between surgeries. The same surgeon did not necessarily perform both cataract surgeries on the same patient but remained masked as to which treatment group the eye was randomized. The Centurion phacoemulsification machine (Alcon Laboratories, Inc.) was used for all study surgeries along with the same irrigating fluid (balanced salt solution) and ophthalmic viscosurgical device (hydroxypropyl methylcellulose 2%). All study eyes received the same model of the hydrophobic acrylic intraocular lens (Aurovue, Aurolab). Aspects of the surgical technique and procedure were tracked, but not standardized, including phacoemulsification time, cumulative dissipated energy, and significant surgical complications.

At the conclusion of the first eye cataract surgery, the patient was randomized to receive intracameral moxifloxacin ophthalmic solution containing either 500 μg/0.1 mL or 250 μg/0.1 mL. The second eye received the alternate dosage. At Aravind Eye Hospital, intracameral moxifloxacin is available as a 0.5% solution containing 5.0 mg in 1 mL vial. The surgical nurse prepared the proper intracameral injection following the randomization code and handed it to the surgeon in a masked manner. For the 500 μg/0.1 mL dose, a tuberculin syringe containing 0.1 mL was drawn directly from the vial. For the 250 μg/0.1 mL dose, 1 mL of balanced salt solution was first injected into the moxifloxacin vial to achieve the proper dilution; 0.1 mL was then drawn from the vial and injected intracamerally. Postoperatively, all patients were prescribed topical prednisolone acetate 1% 6 times per day tapered over 6 weeks, ofloxacin 0.3% 4 times per day for 2 weeks, and nepafenac 0.1% starting 1 month postoperatively, 3 times per day for 1 month. Prednisolone phosphate 1% was substituted for prednisolone acetate after the sixth patient was enrolled because of emergent drug availability in India as per standard of care. Slitlamp biomicroscopy, in particular assessing the evidence of corneal edema and inflammation, anterior chamber inflammation, and intraocular pressure, was performed preoperatively and postoperatively at 1 day, 1 week, 1 month, and 3 months for each eye.

A noncontact specular microscope (Konan Medical, Inc.) was used to capture 3 images of the central corneal endothelium preoperatively and at 1 month and 3 months on both eyes of each patient and transmitted to the CIARC for the determination of the ECD, coefficient of variation, and percentage of hexagonal cells in a masked manner to the treatment arm. The majority (45/50 eyes) had baseline images acquired 1 day preoperatively, with the remaining 5 eyes ranging from 3 to 27 days postoperatively. In addition, a calibration image was submitted for the microscope, and certification images for assessment of image quality were submitted to the CIARC before the initiation of the study. The CIARC conducted dual grading of images by certified readers to determine the ECD by the Konan center method with adjudication if the difference was greater than 5% between readers.22,23 The coefficient of variation and percentage of hexagonal cells were also determined by the Konan center method, and an adjudication was performed if the 2 readers differed by greater than 15%.

Statistical Analyses

Nineteen patients were required for the primary analysis of ECL at 3 months postoperatively, assuming 1:1 treatment dose allocation to both patient eyes, normal distribution for the difference in ECL between the 2 treatment doses, a 0.9 correlation of ECL between both patient eyes, 90% power, a 2-sided alpha level of 0.05, a noninferiority margin of 5%, and no expected difference in % ECL between the 2 treatment doses of moxifloxacin.24 Twenty-five patients were enrolled to account for incomplete data or follow-up as specified in the protocol.

The effect of moxifloxacin dose on 3-month % ECL adjusted for preoperative ECD and various clinical variables (ie, nuclear grade, cumulative dissipated energy, phacoemulsification time, and prednisolone phosphate vs prednisolone acetate) was evaluated in a linear mixed-effects model. The model included a random intercept for the surgeon to accommodate the correlation in 3-month % ECL among surgeries performed by the same surgeon (surgeon effect), and the correlation between eyes of the same patient was modeled using an unstructured covariance matrix.25 None of the clinical variables were retained in the model because they did not appear to be significantly related to the outcome (P > .40 for all clinical variables). The same model was used in evaluating the effect of dose on the secondary outcomes 1-month % ECL and 1-month and 3-month ECD. All reported P values are 2-sided. The data were analyzed using SAS version 9.4 (SAS Institute) and R version 3.5.1.

RESULTS

The mean age of the 25 patients with complete follow-up was 55 years (range 48 to 69 years). Fifteen (60%) of the 25 patients were women, and 4 (16%) were diabetic. Preoperative, surgical, and postoperative eye-level data stratified by treatment groups are provided in Table 1. There were no serious adverse events. Nonsignificant potentially related adverse events included early capsular phimosis between 4 weeks and 59 days postoperatively in 3 study eyes (2 eyes of one patient from both treatment groups, and 1 eye in the 500 μg group), mild epithelial edema at 1 week in 1 eye (500 μg dose), and mild iritis at 1 week (1 eye) and 4 weeks (1 eye) both in the 250 μg dose. The mean ECD in the 250 μg moxifloxacin group dropped by 225 cells/mm2 from 2721 to 2496 cells/mm2, whereas in the 500 μg group the ECD dropped by 313 cells/mm2 from 2700 to 2387 cells/mm2. The mean % ECL at 3 months was 8.2% in the 250 μg dose arm and 11.5% in the 500 μg dose arm.

Table 1
Table 1:
Eye-level data summarized by doses (N = 50 paired study eyes).

The point estimate and 95% CI for the mean difference in % ECL between the 500 μg and 250 μg doses was 0.8% (−5.8%, 7.4%) (Table 2). Because the upper limit of the 95% CI was greater than or equal to 5% (ie, 7.4% ≥ 5%), we were not able to conclude that the 500 μg dose was noninferior (within 5%) to the 250 μg dose with all 50 study eyes. The greater mean % ECL in the 500 μg dose arm was attributable to 2 eyes of 2 different patients each receiving the 500 μg dose that were statistical outliers as shown in Figure 1. These 2 outliers were identified by the % ECL for these eyes being greater than the 75th percentile of the data (Q3) plus 1.5 times the interquartile range (IQR) (Q3 = 21.5%, IQR = 20.6% at 1 month and Q3 = 15.3%, IQR = 13.7% at 3 months). Their % ECL showed early advanced ECL with high polymegethism (Supplemental Figure, see Supplementary Digital Content, http://links.lww.com/JRS/A17) at 1 month postoperatively at 58.4% and 53.1%, with comparable 3-month % ECL of 51.5% and 40.2%, respectively. Upon identifying and removing these 2 outliers, the point estimate and 95% CI for the mean difference was calculated as −2.2% (−6.5%, 2.1%) (Table 2). With the 2 outliers removed, the 500 μg dose was deemed noninferior to the 250 μg dose because in that case the upper limit of the 95% CI was strictly less than the noninferiority margin of 5% (ie, 2.1% < 5%).

Table 2
Table 2:
Model-based mean differences in ECD and % ECL by study visits (N = 50 paired study eyes).
Figure 1
Figure 1:
Scatterplot of endothelial cell density at baseline and 3 months after phacoemulsification using 250 μg and 500 μg of moxifloxacin intracamerally (outliers circled in red).

DISCUSSION

Because only one ICAP injection is given at the conclusion of cataract surgery, the agent and dose must be optimized for efficacy against the broad spectrum of potential POE pathogens. Libre and Mathews used an in vitro model to test the efficacy of moxifloxacin, cefuroxime, and vancomycin against 18 different endophthalmitis isolates.20 Antibiotic efficacy was concentration dependent, and lower concentrations were ineffective against staphylococci and Pseudomonas spp. in particular. The only single antibiotic eliminating all colony-forming units per milliliter against all isolates, except the methicillin-resistant Staphylococcus aureus and methicillin-resistant Staphylococcus epidermidis, was the 500 μg dose of moxifloxacin. These in vitro data on therapeutic efficacy must be balanced against another in vitro study, suggesting potential corneal endothelial cell toxicity from moxifloxacin concentrations higher than 500 μg/mL.19

For this reason, a clinical comparison of 2 intracameral moxifloxacin doses (250 μg and 500 μg) was undertaken to evaluate potential differences in corneal endothelial cell toxicity and ECL. Because there is no U.S. Food and Drug Administration–approved commercial intracameral antibiotic for endophthalmitis prophylaxis available in the United States, this bilateral eye study was conducted in India where the 5 mg/mL solution of moxifloxacin is commercially available and approved for intraocular use. Diluting the 500 μg commercially available concentration to the 250 μg concentration ensured that the same source of moxifloxacin was used throughout the study.

Because so many different factors affect ECL during phacoemulsification, the study was designed to minimize the number of confounding variables. The 2 moxifloxacin doses were prospectively randomized to bilateral eyes of the same patient, the surgeons and postoperative examiners were masked to dose, and all surgeries were performed with the same instrumentation, ophthalmic viscosurgical device, irrigating solution, phacoemulsification instrumentation, phacoemulsification technique, and intraocular lenses. Patients with similar grades of nuclear density in each eye were selected, and those with dense brunescent nuclei were excluded. Postoperative medication dosing was also standardized, and the corneal endothelial cell photographs were analyzed remotely by masked graders.

Despite these attempts at standardization, there were 2 eyes that received the 500 μg dose that experienced marked ECL (40.2% and 51.5%) (Figure 1). Because these 2 outlier eyes had much higher ECL than all the other study eyes, we performed a secondary statistical analysis because of the high risk and likelihood that surgical trauma, rather than drug toxicity, was the etiology. Typical ECL at 3 months with modern phacoemulsification is in the range of 10% but can exceed 35%.22,26 Earlier studies report even higher ranges of ECL.27,28 Such wide variability is attributable to differing degrees of surgical trauma, which we believe is responsible for the very high ECL in the 2 outliers. If drug toxicity was the cause, we would have expected many more eyes to have been affected.

The relatively small size of our study population increased the chance that a few cases of excessive but unrelated ECL could artificially skew the averages being statistically analyzed. A larger study that would be less affected by a few outliers might provide stronger support for our conclusions. Scientifically, the best comparison study would have been to analyze corneal endothelial cell toxicity after intracameral injections of different moxifloxacin doses without concomitant surgery. Unfortunately, our study could only be ethically performed after cataract surgery, which clearly introduced many variable causes of surgical ECL unrelated to the drug. After eliminating the 2 outlier eyes, we found no statistical difference in ECL between the 250 μg and 500 μg doses.

Another limitation of the study, as with any specular microscopy study following a surgical procedure, is sampling error.23 Given the difficulty of imaging the exact same area of corneal endothelial cells centrally within a field of 240 × 400 µm for the Konan instrument used preoperatively and again at 1 month and 3 months postoperatively, it is understandable why gains in the ECD (Table 1) were noted by the reading center after dual grading of the submitted images. This is particularly an issue when there are dynamic changes in the endothelial mosaic during the immediate postoperative period. However, this sampling issue affected both groups contributing to the variability of ECL noted.

Given the major confounding effect of concomitant cataract surgery on ECL, a better clinical safety study comparing different moxifloxacin doses is difficult to design. However, we believe that the results of our study are reassuring with respect to the higher 500 μg dose, when combined with the extensive clinical experience gained with routine ICMP use at the AECS's 10 hospitals over the past 4½ years. These authors have recently completed a review of 1 million cases across 10 AECS centers, which transitioned to uniform use of ICMP in 2015.12 Considering AECS's enormous annual surgical volume, the complete transition to routine ICMP occurred rapidly within a period of only 1 year. The AECS-standardized electronic health record serves as a system-wide registry designed to monitor and detect clinical trends, such as an increase in postoperative corneal complications. That no such trend was detected provides indirect but additional independent support for the safety of the 500 μg/0.1 mL ICMP dosing. Therefore, our data along with this large clinical experience support that clinical and corneal endothelial cell safety are acceptable for 500 μg intracameral moxifloxacin.12 In this study, both doses were well tolerated, supporting the use of the higher concentration for improved antimicrobial coverage for the prevention of POE.

WHAT WAS KNOWN

  • Both retrospective and randomized prospective studies support the efficacy of intracameral moxifloxacin prophylaxis in reducing the endophthalmitis rate after cataract surgery. However, fluoroquinolones are concentration dependent, and in vitro data suggest that lower concentrations of moxifloxacin are less effective against methicillin-resistant staphylococci.
  • An in vitro study raised a theoretical concern that higher intracameral moxifloxacin concentrations could cause corneal endothelial cell toxicity.

WHAT THIS PAPER ADDS

  • After removal of 2 outliers, there was no difference in central corneal endothelial cell loss between a 250 μg and 500 μg dose of moxifloxacin given as an intracameral bolus after phacoemulsification.
  • This study adds additional new evidence that the higher 500 μg dose is clinically safe.

Coordination support for endothelial image acquisition was provided by Tanisha Rankins-Coker at the Cornea Image Analysis Reading Center, Cleveland, Ohio, USA. Coordination of surgeries and patient follow-up was provided by S.N. Kamatchi and Manisha Shah, MD, at Aravind Eye Hospital, Madurai, India.

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