Efficacy and safety of prophylactic intracameral moxifloxacin ...

ARTICLE

Efficacy and safety of prophylactic intracameral moxifloxacin injection in Japan Kazuki Matsuura, MD, Teruyuki Miyoshi, MD, Chikako Suto, MD, Junsuke Akura, MD, Yoshitsugu Inoue, MD

PURPOSE: To report endophthalmitis rates after cataract surgery and the incidence of complications 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 after the introduction of intracameral moxifloxacin was evaluated. The survey was performed by mail or interview in February 2013. RESULTS: All institutions used total-replacement administration rather than small-volume injection. At 3 institutions, 50 to 100 mg/mL moxifloxacin; at 9 institutions, 100 to 300 mg/mL moxifloxacin; and at 7 institutions, 500 mg/mL moxifloxacin was administered. The highest concentration (500 mg/mL) was administered in 14 124 cases. Endophthalmitis cases occurred 1 month or sooner postoperatively in 8 of 15 958 cases (ie, 1 in 1955) without intracameral moxifloxacin administration and in 3 of 18 794 cases (ie, 1 in 6265) with intracameral moxifloxacin administration. CONCLUSIONS: Intracameral moxifloxacin (50 to 500 mg/mL) administration decreased the risk for endophthalmitis by 3-fold. In more than 18 000 cases, moxifloxacin administration of 500 mg/mL or less did not result in severe complications, such as toxic anterior segment syndrome or corneal endothelial cell loss. Financial Disclosure: No author has a financial or proprietary interest in any material or method mentioned. J Cataract Refract Surg 2013; 39:1702–1706 Q 2013 ASCRS and ESCRS

Although endophthalmitis is rare, it is a concern for surgeons because the results can be devastating. According to Ciulla et al.,1 only the use of povidone– iodine before surgery is effective in preventing endophthalmitis. Furthermore, little evidence regarding the efficacy of prophylactic antibiotic administration, Submitted: March 19, 2013. Final revision submitted: May 9, 2013. Accepted: May 11, 2013. From Nojima Hospital (Matsuura) and Tottori University (Inoue), Tottori, the Miyoshi Eye Center (Miyoshi), Hiroshima, the Tokyo Women’s Medical University (Suto), Tokyo, and the Kushimoto Rehabilitation Center (Akura), Wakayama, Japan. Corresponding author: Kazuki Matsuura, MD, Nojima Hospital, 2714-1, Sesaki-machi, Kurayoshi-city, Tottori 682-0863, Japan. E-mail: [email protected], [email protected].

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Q 2013 ASCRS and ESCRS Published by Elsevier Inc.

such as preoperative eyedrops, subconjunctival injections, or intraocular irrigation, is available. However, intracameral antibiotic administration at the final stage of a surgical procedure has recently been reported to be effective in many cases. Intracameral cefuroxime administration has generally been accepted, particularly in Europe.2,3 The number of reports regarding the safety of intracameral administration of moxifloxacin has increased.4–9 In addition, moxifloxacin has advantages as an antibiotic for intracameral injection. Commercial moxifloxacin eyedrops can be used for intracameral administration (diluted, if necessary) because they do not contain preservatives. Enterococcus faecalis is sensitive to moxifloxacin, whereas cefuroxime is ineffective against this bacterium. Although acute endophthalmitis caused by E faecalis is uncommon in Europe and the United States, E faecalis accounts for 0886-3350/$ - see front matter http://dx.doi.org/10.1016/j.jcrs.2013.05.036

EFFICACY AND SAFETY OF INTRACAMERAL MOXIFLOXACIN

approximately 20% of acute endophthalmitis cases in Japan. Endophthalmitis caused by E faecalis has a poor prognosis. Furthermore, because medication turnover after intracameral administration is rapid, moxifloxacin, which is concentration dependent, may be more effective than cefuroxime, which is time dependent. However, few studies have evaluated the efficacy and safety of intracameral moxifloxacin in a large group of patients. Therefore, we assessed the incidence of endophthalmitis and the complications before and after the introduction of intracameral moxifloxacin administration in Japan. MATERIALS AND METHODS A retrospective survey was performed at 19 institutions in west central Japan at which intracameral moxifloxacin injection was administered. Evaluated were the number of surgeries before and after the introduction of intracameral moxifloxacin administration and the number of endophthalmitis cases occurring 1 month or sooner after surgery at these institutions over 4 years (2009 through 2012). Other assessments included the methods of solution preparation and administration, concentration of the solution administered, and incidence of complications associated with such administration. Medical charts of the endophthalmitis cases were carefully reviewed. The presence of identified bacteria had to be confirmed for the diagnosis of endophthalmitis. The diagnosis of suspected endophthalmitis was determined on the basis of the overall symptoms and course of the illness. Patients scheduled to have routine phacoemulsification cataract surgery were included; however, those having combined surgeries or those with severe preoperative corneal damage were excluded. The survey was performed by mail or interview in February 2013. Before and after the introduction of intracameral moxifloxacin administration, corneal endothelial cell loss was assessed in cases at institution 5 and institution 7. The 1-tailed chi-square test was used for statistical analysis.

RESULTS The number of cases ranged from 50 to 3000 each year. Of these, 1 institution used intracameral moxifloxacin administration in only high-risk cases (Table 1, institution 11). At all institutions, moxifloxacin was diluted to a predefined concentration and administered using a 5 mL syringe to completely replace the aqueous humor at the final stage of surgery; in addition, a moxifloxacin irrigating solution was administered at 1 institution. The administered concentration was 50 to 100 mg/mL at 3 institutions, 100 to 300 mg/mL at 9 institutions, and 500 mg/mL at 7 institutions. The highest concentration (500 mg/mL) was administered in 14 124 cases (Table 1). Endophthalmitis occurred 1 month or sooner after surgery in 8 of 15 958 cases (ie, 1 in 1955 [0.051%]) before the introduction of intracameral moxifloxacin administration and decreased significantly to 3 of 18 794 cases (ie, 1 in 6265 [0.015%]) after the introduction of intracameral moxifloxacin (PZ.037).

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Complications such as toxic anterior segment syndrome (TASS) or severe corneal damage were not reported. Moreover, no institution confirmed drug administration errors. At institutions 5 and 7, no difference was observed in corneal endothelial cell loss between the group with intracameral moxifloxacin administration (555 of 18 794 cases [3.1%]) and the group without intracameral moxifloxacin administration (222 of 15 958 cases [3.6%]). DISCUSSION A multicenter clinical trial performed by the Endophthalmitis Study Group of the European Society of Cataract & Refractive Surgeons (ESCRS) in 20062 reported a 5-fold decrease in the infection rate after intracameral cefuroxime administration into the anterior chamber. Intracameral administration is popular in Europe; 59.0% of ESCRS members performed intracameral administration according to a 2012 ESCRS report.A However, the practice is not as popular in North America. In a 2011 survey, only 18.0% of members of the American Society of Cataract and Refractive Surgery reported performing intracameral antibiotic administration.B In Sweden, reports state that 99.4% of surgeons have performed intracameral administration.3 Nevertheless, intracameral administration is uncommon in Japan. In our 2012 survey,10 only 1.0% of surgeons performed intracameral administration. However, its use is gaining popularity in recent years in certain areas of the country. As mentioned, moxifloxacin is active against E faecalis and is used in Japan. Commercial moxifloxacin (Vigamox) is preservative free and can be diluted and used for intracameral administration. Several studies of moxifloxacin safety are available; however, few had a large number of cases. Shorstein et al.11 found that the rate of endophthalmitis after intracameral administration decreased to 1 in 13. However, cefuroxime was mainly used in that study, with moxifloxacin used in few cases, such as in allergic patients. In addition, Arshinoff and Bastianelli12 analyzed multisite data, mainly from North America, and found 1 case of endophthalmitis among approximately 35 000 patients who received intracameral moxifloxacin. However, detailed descriptions of the administration methods, the incidence of complications at each institution, and the details of the endophthalmitis case were not provided. Although our study was limited because of its retrospective nature, to our knowledge, it is the first multicenter study that evaluated infection rates and the incidence of complications after intracameral moxifloxacin administration. The concentration range in our study was primarily 100 to 500 mg/mL. Although the incidence of posterior capsule rupture was not assessed, the outcome was favorable in the group receiving intracameral

J CATARACT REFRACT SURG - VOL 39, NOVEMBER 2013

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Table 1. Incidence of postoperative endophthalmitis before and after moxifloxacin administration.

Institution 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 Total

Cases without ICI

Endophthalmitis without ICI

Cases with ICI

Endophthalmitis with ICI

Antibiotic Concentration (mg/mL)

d 100 1500 619 900 900 1800 50 350 1500 2100 2000 140 1000 177 240 1000 646 936 15958

d 0 0 0 1 0 3 0 0 2 0 2 0 0 0 0 0 0 0 8

112 300 500 507 900 130 1000 150 10 4500 10 9000 70 300 90 80 200 624 311 18797

0 0 0 0 0 0 1 0 0 0 0 1 0 0 0 0 0 1 0 3

500 500 500 500 200 120 200 200 200 500 200 500 120 50 50 80 200 500 200 d

ICI Z intracameral injection

moxifloxacin, in which the incidence of endophthalmitis was 1 in 6265 cases. The incidence in the group that did not receive intracameral moxifloxacin (1 in 1955 cases) is similar to findings by Oshika et al.13 (1 in 1933 cases). Our data indicate a 3-fold decrease in the incidence of endophthalmitis after intracameral moxifloxacin administration, appearing to have a smaller impact than that in the ESCRS study, in which the data indicate a 5-fold decrease after intracameral cefuroxime administration. We speculate that this occurred because of a difference in infection rates in the control group. In the present study, the infection rate in the group that did not receive intracameral moxifloxacin was much lower (1 in 1955 cases) than in the control group in the ESCRS study (1 in 307 cases). Arshinoff and Bastianelli12 found an endophthalmitis incidence of 1 in 35 000 cases; however, this study mostly described the results of proponents of immediately sequential bilateral cataract surgery, who tend to be expert surgeons. Moreover, high-risk patients may have been excluded. Reported infection rates after intracameral antibiotic administration (mostly cefuroxime) were 1 in 3756 cases (Sweden)3 and 1 in 3152 cases (California).14 The data from California were from a single-center study. Our study contained data from expert surgeons as well as less experienced surgeons who operate on fewer than 100 patients each year. Therefore, our data are supposed to represent results for a surgeon with an average experience level.

In Europe and the U.S., it is common to use a relatively small volume (0.05 to 0.2 mL) of highly concentrated moxifloxacin solution, undiluted or diluted at 5-fold to 10-fold. In Japan, the standard method involves total replacement of the aqueous humor with 2 to 3 mL of solution. A cannula through which the antibiotic solution flowed was inserted through a side port, and the anterior chamber was flushed for 10 to 20 seconds. Once the anterior chamber was flushed, the needle was removed while the solution flow was maintained. The advantage of this method is that compared with a small-volume injection, the concentration is stable. In addition, 90% or more of the aqueous humor can be diluted and flushed at the final stage of the surgery9; therefore, there is no risk for recontamination after self-sealing of the surgical wound. In 13 of 19 institutions, surgeons intentionally irrigated the area behind the intraocular lens (IOL) so that this area was flushed with diluted antibiotics (bag and chamber flushing9). In practice, we have observed that flushing behind the IOL allows ophthalmic viscosurgical devices and debris, which are not completely removed by irrigation/aspiration, to float inside the anterior chamber. We believe this method is effective in washing the inside of the bag. Eleven institutions placed the drug in a hydrodissection syringe. A 40 mg/mL solution was prepared by adding 1 drop (200 mg/mL in 0.04 mL) of moxifloxacin to a 5 mL syringe. Similarly, to prepare a 200 mg/mL


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Table 2. Cases of postoperative endophthalmitis. Case 1 2 3 4 5 6 7 8 1 2 3

Intracameral Injection

Onset

PCR

Culture

Treatment

Final CDVA

Institution

d d d d d d d d MFLX MFLX MFLX

1 week 2 weeks 10 days 2 weeks 1 week 10 days 5 days 2 weeks 10 days 1 week 2 weeks

d d d d d d d d d d d

MRSA d d d MRSA d d d d d d

Vitrectomy, IOL removal Vitrectomy, IOL removal Ant irr Vitrectomy, IOL removal Vitrectomy, IOL removal Vit injection Vit injection Vit injection Vit injection Vitrectomy, IOL removal Vit injection

7/10 20/20 25/20 20/20 8/10 4/10 20/20 20/20 20/20 7/10 20/20

10 10 12 12 7 7 7 5 7 12 18

Ant irr Z anterior chamber irrigation; CDVA Z corrected distance visual acuity; IOL Z intraocular lens; MFLX Z moxifloxacin; MRSA Z Methicillin-resistant Staphylococcus aureus; PCR Z posterior capsule rupture; Vit injection Z Intravitreal antibiotic injection

solution, 5 drops were added to a 5 mL syringe. Preservative-free commercial moxifloxacin was directly dropped into the 5 mL syringe prepared for hydrodissection. At 1 institution, 5 mL of moxifloxacin solution (5000 mg/mL) was mixed in a 500 mL bottle of a balanced salt solution. This was subsequently transferred into a 5 mL syringe (100-fold dilution, 50 mg/mL); moreover, at 7 institutions, a 10-fold dilution was prepared by mixing moxifloxacin. Subsequently, 3 mL to 5 mL of moxifloxacin was taken from a commercially available bottle using a 5 mL syringe with a sterilized 21-gauge needle and injected into a 30 to 50 mL syringe. Balanced salt solution was added until the scheduled concentration was obtained, and this was transferred into 5 mL syringes. None of the institutions ordered the hospital pharmacy to dilute the drug. At all institutions, a physician or a nurse who specialized in ophthalmology performed the dilution in an operating room. Because moxifloxacin can be diluted and used directly, complicated preparation procedures are not necessary. Also, as long as specialists perform the dilution, it is unlikely that errors in dilution or contamination will occur. Unlike cephems or imipenem, moxifloxacin is not time dependent; however, it is concentration dependent and requires approximately 2 hours to be effective.7 Assuming that the half-life of moxifloxacin in the anterior chamber is 1 hour,15 an immediate after-administration concentration of approximately 150 mg/mL would be required to attain the minimum inhibitory concentration of 90% pathogen for the highly resistant methicillin-resistant Staphylococcus epidermidis (32 mg/mL)16 for 2 hours. There have been reports of irreversible changes to cells at concentrations of more than 250 mg/mL in vitro17; however, this was because of action of the drug solution on cells for 24 hours. There have been several reports of the safety of moxifloxacin at concentrations of 500 mg/mL or

more.4–8 In the present study, as many as 14 124 cases were given a 500 mg/mL solution with no adverse effects. Surgeons justified not using intracameral administration for reasons such as dilution errors, contamination, drug toxicity, and the risk for TASS.18 However, we did not encounter any of these problems. Some concentrations used at certain centers may have been inadequate. ArshinoffC cited the Montan et al.19 report that the half-life of cefuroxime is 30 minutes and recommend the use of 300 mg/0.2 mL for simple injection. However, this results in a concentration as high as 1000 mg/mL immediately after injection. Asena et al.20 recently estimated that the half-life of moxifloxacin was 2.2 hours. Arshinoff and Bastianelli12 report 1 case of endophthalmitis in 35 000 cases. Although details were not mentioned, the concentration in their study was estimated to be 100 to 500 mg/mL. Therefore, we believe that a moxifloxacin concentration range of 150 to 500 mg/mL is safe and effective. The endophthalmitis case in the moxifloxacin administration group in our study occurred after uneventful surgery; anterior chamber fibrin developed 10 days later. Although the causal bacterium was not identified, irrigation of the anterior chamber and single intravitreal injection of vancomycin and ceftazidime resulted in a favorable outcome (Table 2). Even in the moxifloxacin administration group, the risk for endophthalmitis resulting from highly resistant bacteria and postoperative infection was not totally eliminated. Because intracameral administration has become more appreciated, more people are advocating that treatment in the form of eyedrops is unnecessary.3,11 Eyedrops are not considered a reliable method of treatment because they are often self-administered by elderly patients and if used inappropriately, can cause various complications. However, when used appropriately, eyedrops can be effective in preventing endophthalmitis caused by postoperative infection, which cannot be prevented


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by intracameral administration. In the future, establishing the safety and efficacy of intracameral administration may lead to changes in the methods of preventing intraoperative and postoperative infections, including the use of eyedrops and disinfection. WHAT WAS KNOWN Intracameral injection has been widely used in Europe, whereas few clinicians have adopted this method in Japan. 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 moxifloxacin administration. WHAT THIS PAPER ADDS Intracameral moxifloxacin (50 to 500 mg/mL) administration resulted in a 3-fold decrease in the risk for endophthalmitis. 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. REFERENCES 1. Ciulla TA, Starr MB, Masket S. Bacterial endophthalmitis prophylaxis for cataract surgery; an evidence-based update. Ophthalmology 2001; 109:13–24 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 €m M, Stenevi U, Montan P. Six-year incidence 3. Friling E, Lundstro of endophthalmitis after cataract surgery: Swedish national study. J Cataract Refract Surg 2013; 39:15–21 4. 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 5. Kim S-Y, Park Y-H, Lee Y-C. Comparison of the effect of intracameral moxifloxacin, levofloxacin and cefazolin on rabbit corneal endothelial cells. Clin Exp Ophthalmol 2008; 36:367–370 6. 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 7. O’Brien TP, Arshinoff SA, Mah FS. Perspectives on antibiotics for postoperative endophthalmitis prophylaxis: potential role of moxifloxacin. J Cataract Refract Surg 2007; 33:1790–1800 8. Arbisser LB. Safety of intracameral moxifloxacin for prophylaxis of endophthalmitis after cataract surgery. J Cataract Refract Surg 2008; 34:1114–1120 9. Matsuura K, Suto C, Akura J, Inoue Y. Bag and chamber flushing: a new method of using intracameral moxifloxacin to irrigate the anterior chamber and the area behind the intraocular lens. Graefes Arch Clin Exp Ophthalmol 2013; 251:81–87 10. Matsuura K, Suto C, Inoue Y, Saeki Y, Miyamoto T, Moti T, Ohkubo S, Tanito M. A Japanese survey of perioperative antibiotic prophylaxis in cataract surgery. Asia-Pacific J Ophthalmol 2012; 1:283–286

11. Shorstein NH, Winthrop KL, Herrinton LJ. Decreased postoperative endophthalmitis rate after institution of intracameral antibiotics in a northern California eye department. J Cataract Refract Surg 2013; 39:8–14 12. Arshinoff SA, Bastianelli PA. Incidence of postoperative endophthalmitis after immediate sequential bilateral cataract surgery. J Cataract Refract Surg 2011; 37:2105–2114 13. Oshika T, Hatano H, Kuwayama Y, Ogura Y, Ohashi Y, Oki K, Uno T, Usui N, Yoshitomi F. Incidence of endophthalmitis after cataract surgery in Japan. Acta Ophthalmol Scand 2007; 85:848–851. Available at: http://onlinelibrary.wiley.com/doi/10. 1111/j.1600-0420.2007.00932.x/pdf. Accessed May 29, 2013 14. Shorsrein N, Winthrop K, Herrinton L. reply to letter by V Galvis and A Tello.Intracameral antibiotics and endophthalmitis incidence. J Cataract Refract Surg 2013; 39:313 15. Matsuura K, Suto C, Akura J, Inoue Y. Comparison between intracameral moxifloxacin administration methods by assessing intraocular concentrations and drug kinetics. Graefes Arch Clin Exp Ophthalmol 2013 Apr 2 [Epub ahead of print] 16. Miller D, Flynn PM, Scott IU, Alfonso EC, Flynn HW Jr. In vitro fluoroquinolone resistance in staphylococcal endophthalmitis isolates. Arch Ophthalmol 2006; 124:479–483. Available at: http://archopht.jamanetwork.com/data/Journals/OPHTH/9954/ ECS50028.pdf. Accessed May 29, 2013 17. Kernt M, Neubauer AS, Liegl RG, Lackerbauer CA, Eibl KH, Alge CS, Ulbig MW, Kampik A. Intracameral moxifloxacin: in vitro safety on human ocular cells. Cornea 2009; 28:553–561 18. 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. Pro19. Montan PG, Wejde G, Setterquist H, Rylander M, Zettersto phylactic intracameral cefuroxime; evaluation of safety and kinetics in cataract surgery. J Cataract Refract Surg 2002; 28:982–987 € Karabay G, 20. Asena L, Akova YA, Goktas‚ MT, Bozkurt A, Yas‚ar U, Dermiralay E. Ocular pharmacokinetics, safety and efficacy of intracameral moxifloxacin 0.5% solution in a rabbit model. Curr Eye Res 2013; 38:472–479

OTHER CITED MATERIAL 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 2013, page 5. Available at: http://escrs.org/publications/eurotimes/ 12Dec-Jan/ENDOPHTHALMITIS.pdf. Accessed May 29, 2013 B. Leaming DV. 2011 Survey of US ASCRS members. Available at: http://www.analeyz.com/AnaleyzASCRS2011.htm. Accessed May 29, 2013 C. Arshinoff SA, “Dose and Administration of Intracameral Moxifloxacin,” presented at the ASCRS Symposium on Cataract, IOL and Refractive Surgery, San Francisco, California, USA, March 2011


First author: Kazuki Matsuura, MD Nojima Hospital, Tottori, Japan