Efficacy and safety of prophylactic intracameral moxifloxacin injection in japan

Efficacy and safety of prophylactic intracameral Kazuki Matsuura, MD, Teruyuki Miyoshi, MD, Chikako Suto, MD, Junsuke Akura, MD, PURPOSE: To report endophthalmitis rates after cataract surgery and the incidence of complica-tions after intracameral moxifloxacin injection.
SETTING: Nineteen clinics in Japanese institutions.
DESIGN: Retrospective survey cohort study.
METHODS: The number of surgeries and endophthalmitis cases in the past 4 years before and afterthe introduction of intracameral moxifloxacin was evaluated. The survey was performed by mail orinterview in February 2013.
RESULTS: All institutions used total-replacement administration rather than small-volumeinjection. At 3 institutions, 50 to 100 mg/mL moxifloxacin; at 9 institutions, 100 to 300 mg/mLmoxifloxacin; and at 7 institutions, 500 mg/mL moxifloxacin was administered. The highestconcentration (500 mg/mL) was administered in 14 124 cases. Endophthalmitis cases occurred1 month or sooner postoperatively in 8 of 15 958 cases (ie, 1 in 1955) without intracameralmoxifloxacin administration and in 3 of 18 794 cases (ie, 1 in 6265) with intracameralmoxifloxacin administration.
CONCLUSIONS: Intracameral moxifloxacin (50 to 500 mg/mL) administration decreased the riskfor endophthalmitis by 3-fold. In more than 18 000 cases, moxifloxacin administration of500 mg/mL or less did not result in severe complications, such as toxic anterior segmentsyndrome or corneal endothelial cell loss.
Financial Disclosure: No author has a financial or proprietary interest in any material or methodmentioned.
J Cataract Refract Surg 2013; 39:1702–1706 Q 2013 ASCRS and ESCRS Although endophthalmitis is rare, it is a concern for such as preoperative eyedrops, subconjunctival injec- surgeons because the results can be devastating.
tions, or intraocular irrigation, is available. However, According to Ciulla et al.,only the use of povidone– intracameral antibiotic administration at the final iodine before surgery is effective in preventing en- stage of a surgical procedure has recently been dophthalmitis. Furthermore, little evidence regarding reported to be effective in many cases. Intracameral the efficacy of prophylactic antibiotic administration, The number of reports regarding the safety of intracameral administration of moxifloxacin has Final revision submitted: May 9, 2013.
incIn addition, moxifloxacin has advantages as an antibiotic for intracameral injection. Commercial From Nojima Hospital (Matsuura) and Tottori University (Inoue), moxifloxacin eyedrops can be used for intracameral Tottori, the Miyoshi Eye Center (Miyoshi), Hiroshima, the Tokyo administration (diluted, if necessary) because they Women’s Medical University (Suto), Tokyo, and the Kushimoto do not contain preservatives. Enterococcus faecalis is Rehabilitation Center (Akura), Wakayama, Japan.
sensitive to moxifloxacin, whereas cefuroxime is inef- Corresponding author: Kazuki Matsuura, MD, Nojima Hospital, fective against this bacterium. Although acute en- 2714-1, Sesaki-machi, Kurayoshi-city, Tottori 682-0863, Japan.
dophthalmitis caused by E faecalis is uncommon in Europe and the United States, E faecalis accounts for EFFICACY AND SAFETY OF INTRACAMERAL MOXIFLOXACIN approximately 20% of acute endophthalmitis cases in Complications such as toxic anterior segment syn- Japan. Endophthalmitis caused by E faecalis has a drome (TASS) or severe corneal damage were not re- poor prognosis. Furthermore, because medication ported. Moreover, no institution confirmed drug turnover after intracameral administration is rapid, administration errors. At institutions 5 and 7, no differ- moxifloxacin, which is concentration dependent, ence was observed in corneal endothelial cell loss be- may be more effective than cefuroxime, which is tween the group with intracameral moxifloxacin time dependent. However, few studies have evaluated administration (555 of 18 794 cases [3.1%]) and the the efficacy and safety of intracameral moxifloxacin in group without intracameral moxifloxacin administra- a large group of patients. Therefore, we assessed the incidence of endophthalmitis and the complicationsbefore and after the introduction of intracameral mox- A multicenter clinical trial performed by the Endoph-thalmitis Study Group of the European Society of Cata- ract & Refractive Surgeons (ESCRS) in 20reported a5-fold decrease in the infection rate after intracameral A retrospective survey was performed at 19 institutions inwest central Japan at which intracameral moxifloxacin cefuroxime administration into the anterior chamber. In- injection was administered. Evaluated were the number of tracameral administration is popular in Europe; 59.0% of surgeries before and after the introduction of intracameral ESCRS members performed intracameral administra- moxifloxacin administration and the number of endophthal- tion according to a 2012 ESCRS report.However, the mitis cases occurring 1 month or sooner after surgery at these practice is not as popular in North America. In a 2011 sur- institutions over 4 years (2009 through 2012). Other assess-ments included the methods of solution preparation and vey, only 18.0% of members of the American Society of administration, concentration of the solution administered, Cataract and Refractive Surgery reported performing and incidence of complications associated with such admin- intracameral antibiotic administration.In Sweden, istration. Medical charts of the endophthalmitis cases were reports state that 99.4% of surgeons have performed carefully reviewed. The presence of identified bacteria had intracameral administratioNevertheless, intracam- to be confirmed for the diagnosis of endophthalmitis. Thediagnosis of suspected endophthalmitis was determined on eral administration is uncommon in Japan. In our 2012 the basis of the overall symptoms and course of the illness.
surveyonly 1.0% of surgeons performed intracameral Patients scheduled to have routine phacoemulsification cata- administration. However, its use is gaining popularity in ract surgery were included; however, those having com- recent years in certain areas of the country.
bined surgeries or those with severe preoperative corneal As mentioned, moxifloxacin is active against E faeca- The survey was performed by mail or interview in lis and is used in Japan. Commercial moxifloxacin February 2013. Before and after the introduction of intracam- (Vigamox) is preservative free and can be diluted eral moxifloxacin administration, corneal endothelial cell and used for intracameral administration. Several loss was assessed in cases at institution 5 and institution 7.
studies of moxifloxacin safety are available; however, The 1-tailed chi-square test was used for statistical analysis.
few had a large number of cases. Shorstein et found that the rate of endophthalmitis after intracam- eral administration decreased to 1 in 13. However, The number of cases ranged from 50 to 3000 each year.
cefuroxime was mainly used in that study, with moxi- Of these, 1 institution used intracameral moxifloxacin floxacin used in few cases, such as in allergic patients.
administration in only high-risk cases (, institu- tion 11). At all institutions, moxifloxacin was diluted to multisite data, mainly from North America, and found a predefined concentration and administered using a 1 case of endophthalmitis among approximately 5 mL syringe to completely replace the aqueous humor 35 000 patients who received intracameral moxifloxa- at the final stage of surgery; in addition, a moxifloxacin cin. However, detailed descriptions of the administra- irrigating solution was administered at 1 institution.
tion methods, the incidence of complications at each The administered concentration was 50 to 100 mg/mL institution, and the details of the endophthalmitis at 3 institutions, 100 to 300 mg/mL at 9 institutions, case were not provided. Although our study was and 500 mg/mL at 7 institutions. The highest concen- limited because of its retrospective nature, to our tration (500 mg/mL) was administered in 14 124 cases knowledge, it is the first multicenter study that evalu- (Endophthalmitis occurred 1 month or sooner ated infection rates and the incidence of complications after surgery in 8 of 15 958 cases (ie, 1 in 1955 [0.051%]) after intracameral moxifloxacin administration.
before the introduction of intracameral moxifloxacin The concentration range in our study was primarily administration and decreased significantly to 3 of 100 to 500 mg/mL. Although the incidence of posterior 18 794 cases (ie, 1 in 6265 [0.015%]) after the introduc- capsule rupture was not assessed, the outcome was tion of intracameral moxifloxacin (PZ.037).
favorable in the group receiving intracameral J CATARACT REFRACT SURG - VOL 39, NOVEMBER 2013 EFFICACY AND SAFETY OF INTRACAMERAL MOXIFLOXACIN Table 1. Incidence of postoperative endophthalmitis before and after moxifloxacin administration.
moxifloxacin, in which the incidence of endophthalmi- In Europe and the U.S., it is common to use a rela- tis was 1 in 6265 cases. The incidence in the group that tively small volume (0.05 to 0.2 mL) of highly concen- did not receive intracameral moxifloxacin (1 in 1955 trated moxifloxacin solution, undiluted or diluted at cases) is similar to findings by Oshika et al.(1 in 5-fold to 10-fold. In Japan, the standard method in- 1933 cases). Our data indicate a 3-fold decrease in the volves total replacement of the aqueous humor with incidence of endophthalmitis after intracameral moxi- 2 to 3 mL of solution. A cannula through which the anti- floxacin administration, appearing to have a smaller biotic solution flowed was inserted through a side port, impact than that in the ESCRS study, in which the and the anterior chamber was flushed for 10 to 20 sec- data indicate a 5-fold decrease after intracameral cefur- onds. Once the anterior chamber was flushed, the oxime administration. We speculate that this occurred needle was removed while the solution flow was because of a difference in infection rates in the control maintained. The advantage of this method is that group. In the present study, the infection rate in the compared with a small-volume injection, the concen- group that did not receive intracameral moxifloxacin tration is stable. In addition, 90% or more of the was much lower (1 in 1955 cases) than in the control aqueous humor can be diluted and flushed at the final group in the ESCRS study (1 in 307 cases).
stage of the surgery; therefore, there is no risk for re- Arshinoff and Bastifound an endophthalmi- contamination after self-sealing of the surgical wound.
tis incidence of 1 in 35 000 cases; however, this study In 13 of 19 institutions, surgeons intentionally irrigated mostly described the results of proponents of immedi- the area behind the intraocular lens (IOL) so that this ately sequential bilateral cataract surgery, who tend to area was flushed with diluted antibiotics (bag and be expert surgeons. Moreover, high-risk patients may chamber flusIn practice, we have observed have been excluded. Reported infection rates after in- that flushing behind the IOL allows ophthalmic visco- tracameral antibiotic administration (mostly cefurox- surgical devices and debris, which are not completely ime) were 1 in 3756 cases (Swand 1 in 3152 removed by irrigation/aspiration, to float inside the cases (California).The data from California were anterior chamber. We believe this method is effective from a single-center study. Our study contained data from expert surgeons as well as less experienced sur- Eleven institutions placed the drug in a hydrodissec- geons who operate on fewer than 100 patients each tion syringe. A 40 mg/mL solution was prepared by year. Therefore, our data are supposed to represent re- adding 1 drop (200 mg/mL in 0.04 mL) of moxifloxacin sults for a surgeon with an average experience level.
to a 5 mL syringe. Similarly, to prepare a 200 mg/mL J CATARACT REFRACT SURG - VOL 39, NOVEMBER 2013 EFFICACY AND SAFETY OF INTRACAMERAL MOXIFLOXACIN Table 2. Cases of postoperative endophthalmitis.
Ant irr Z anterior chamber irrigation; CDVA Z corrected distance visual acuity; IOL Z intraocular lens; MFLX Z moxifloxacin; MRSA Z Methicillin-resistantStaphylococcus aureus; PCR Z posterior capsule rupture; Vit injection Z Intravitreal antibiotic injection solution, 5 drops were added to a 5 mL syringe.
moIn the present study, as many as 14 124 cases were given a 500 mg/mL solution with no adverse directly dropped into the 5 mL syringe prepared for effects. Surgeons justified not using intracameral hydrodissection. At 1 institution, 5 mL of moxifloxacin administration for reasons such as dilution errors, solution (5000 mg/mL) was mixed in a 500 mL bottle contamination, drug toxicity, and the risk for TASS of a balanced salt solution. This was subsequently However, we did not encounter any of these problems.
transferred into a 5 mL syringe (100-fold dilution, Some concentrations used at certain centers may have 50 mg/mL); moreover, at 7 institutions, a 10-fold dilu- been inadequate. Arshinoffcited the Montan et tion was prepared by mixing moxifloxacin. Subse- report that the half-life of cefuroxime is 30 minutes quently, 3 mL to 5 mL of moxifloxacin was taken and recommend the use of 300 mg/0.2 mL for simple in- from a commercially available bottle using a 5 mL jection. However, this results in a concentration as high syringe with a sterilized 21-gauge needle and injected as 1000 mg/mL immediately after injection. Asena into a 30 to 50 mL syringe. Balanced salt solution was et al.recently estimated that the half-life of moxiflox- acin was 2.2 hours. Arshinoff and Bastianreport 1 obtained, and this was transferred into 5 mL syringes.
case of endophthalmitis in 35 000 cases. Although de- None of the institutions ordered the hospital phar- tails were not mentioned, the concentration in their macy to dilute the drug. At all institutions, a physician study was estimated to be 100 to 500 mg/mL. There- or a nurse who specialized in ophthalmology per- fore, we believe that a moxifloxacin concentration formed the dilution in an operating room. Because range of 150 to 500 mg/mL is safe and effective.
moxifloxacin can be diluted and used directly, compli- The endophthalmitis case in the moxifloxacin admin- cated preparation procedures are not necessary. Also, istration group in our study occurred after uneventful as long as specialists perform the dilution, it is unlikely surgery; anterior chamber fibrin developed 10 days that errors in dilution or contamination will occur.
later. Although the causal bacterium was not identified, Unlike cephems or imipenem, moxifloxacin is not irrigation of the anterior chamber and single intravitreal time dependent; however, it is concentration depen- injection of vancomycin and ceftazidime resulted in a dent and requires approximately 2 hours to be effec- favorable outcome (). Even in the moxifloxacin tive.Assuming that the half-life of moxifloxacin administration group, the risk for endophthalmitis re- in the anterior chamber is 1 hour,an immediate sulting from highly resistant bacteria and postoperative after-administration concentration of approximately infection was not totally eliminated. Because intracam- 150 mg/mL would be required to attain the minimum eral administration has become more appreciated, inhibitory concentration of 90% pathogen for the more people are advocating that treatment in the highly resistant methicillin-resistant Staphylococcus form of eyedrops is unnecessary.Eyedrops are not epidermidis (32 mg/mL)for 2 hours. There have been considered a reliable method of treatment because reports of irreversible changes to cells at concentrations they are often self-administered by elderly patients of more than 250 mg/mL in vitr; however, this was and if used inappropriately, can cause various compli- because of action of the drug solution on cells for 24 cations. However, when used appropriately, eyedrops hours. There have been several reports of the safety can be effective in preventing endophthalmitis caused of moxifloxacin at concentrations of 500 mg/mL or by postoperative infection, which cannot be prevented J CATARACT REFRACT SURG - VOL 39, NOVEMBER 2013 EFFICACY AND SAFETY OF INTRACAMERAL MOXIFLOXACIN by intracameral administration. In the future, esta- blishing the safety and efficacy of intracameral admini- stration may lead to changes in the methods of preventing intraoperative and postoperative infections, including the use of eyedrops and disinfection.
13. Oshika T, Hatano H, Kuwayama Y, Ogura Y, Ohashi Y, Oki K, Uno T, Usui N, Yoshitomi F. Incidence of endophthalmitis after  Intracameral injection has been widely used in Europe, cataract surgery in Japan. Acta Ophthalmol Scand 2007; whereas few clinicians have adopted this method in Japan.
85:848–851. Available at: Accessed May 29, 2013  The efficacy of moxifloxacin as an intracameral antibiotic may be similar to that of cefuroxime; however, few studies have assessed the clinical outcomes of intracameral mox- 16. Miller D, Flynn PM, Scott IU, Alfonso EC, Flynn HW Jr. In vitro  Intracameral moxifloxacin (50 to 500 mg/mL) admini- fluoroquinolone resistance in staphylococcal endophthalmitis stration resulted in a 3-fold decrease in the risk for isolates. Arch Ophthalmol 2006; 124:479–483. Available at:  Intracameral moxifloxacin at 500 mg/mL or less did not result in severe complications such as TASS or corneal endothelial cell loss in approximately 19 000 cases.
A. Barry P, “ESCRS Endophthalmitis Study: Uptake of Intracameral Cefuroxime Since 2006,” presented at the XXX Congress of the European Society of Cataract & Refractive Surgeons, Milan, Italy, September 2012. Reported by O’hEineachain R. Endophthalmitis; Intracameral antibiotics becoming standard practice among European cataract surgeons. EuroTimes December/January B. Leaming DV. 2011 Survey of US ASCRS members. Available at: C. Arshinoff SA, “Dose and Administration of Intracameral Moxiflox- acin,” presented at the ASCRS Symposium on Cataract, IOL and Refractive Surgery, San Francisco, California, USA, March 2011 J CATARACT REFRACT SURG - VOL 39, NOVEMBER 2013

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