Endophthalmitis is a rare but potentially devastating complication of intraocular surgery. Its incidence after cataract surgery, as reported in two large survey articles, was 0.072%1 and 0.082%,2 respectively. The majority of cases appear to result from intraocular contamination by patients' own normal, external bacterial flora.3 Gram-positive bacteria are the most common isolates found in cataract surgery infections.4 In one study, researchers isolated Staphylococcus epidermidis and Staphylococcus aureus from 59% of postoperative pseudophakic endophthalmitis cases. Of these, 57% of the isolates associated with filtering blebs were of the Streptococcus species.5
Ophthalmologists have employed numerous treatment strategies to try to ensure an aseptic ocular environment at the time of surgery and thereby minimize the incidence of postoperative ocular infections.6-8 The use of preoperative topical antibiotics, especially fluoroquinolones, is now routine. Selecting which topical antibiotic to use prophylactically and determining the optimal dosing regimen are the frequent subjects of debate.ANTIBIOTIC SELECTION
An important consideration in postoperative prophylaxis is whether the preoperative administration of a topical antibiotic produces drug concentrations in the aqueous humor that are greater than the minimum inhibitory concentration (MIC) for potential bacterial pathogens. The medication chosen should (1) have a broad spectrum of antimicrobial activity, particularly against gram-positive organisms, (2) cause minimal corneal toxicity, and (3) have excellent solubility (bioavailability) so that it can readily penetrate the ocular tissues.
Third-generation fluoroquinolones such as ciprofloxacin and ofloxacin were effective prophylactic agents throughout the 1990s, but, by 2001, widespread resistance to these agents was well documented.9 The newer, fourth-generation fluoroquinolones, gatifloxacin and moxifloxacin, exhibit greater bacteriocidal activity by selectively inhibiting two essential bacterial enzymes, DNA gyrase and topoisomerase IV.10 The chemical structure and subsequent activity of these newer fluoroquinolones is enhanced by the presence of an 8-methoxy group. Both gatifloxacin and moxifloxacin appear to be highly effective against gram-positive isolates and have demonstrated similar MIC90 values when tested in vitro.11
When trying to choose between gatifloxacin and moxifloxacin, the clinician should consider the issues of bioavailability and toxicity. Moxifloxacin is a 0.5% nonpreserved formulation, whereas gatifloxacin is a 0.3% formulation preserved with 0.005% benzalkonium chloride. Penetration studies have shown that moxifloxacin achieves higher aqueous levels with topical use relative to its higher concentration. At least four studies,12-15 however, have suggested that moxifloxacin may have significant toxicity issues related to its higher concentration or other unknown factors. This research demonstrated delayed epithelialization and a decreased expression of type IV collagen, which can be very important in corneal wound healing.A REAL-WORLD COMPARISON
As already stated, the higher concentration of Vigamox (moxifloxacin 0.5%; Alcon Laboratories, Inc.; Fort Worth, TX) versus Zymar (0.3% gatifloxacin; Allergan, Inc., Irvine, CA) results in a higher degree of aqueous penetration. Nonetheless, no evidence suggests that aqueous levels much higher than the MIC values are beneficial. My colleagues and I performed an in vivo comparison of gatifloxacin and moxifloxacin using two different treatment regimens prior to cataract surgery.16,17 We compared preoperative regimens of Zymar and Vigamox on eyelid and conjunctival cultures before surgery and aqueous cultures immediately after phacoemulsification. Two dosing regimens were used.
Group 1 consisted of 100 patients randomized to receive Zymar (n = 50) or Vigamox (n = 50) q.i.d. for 2 days preoperatively as well as one drop in the morning before surgery (nine drops total). Group 2 included 120 patients randomized to receive Zymar (n = 60) or Vigamox (n = 60) just as administered in group 1, but with an additional four drops given once every 10 minutes during the hour prior to surgery (12 total drops). We obtained conjunctival and eyelid cultures in a masked fashion prior to applying povidone-iodine 7.5% immediately before surgery. We also collected aqueous specimens (0.15mL) at the completion of surgery using a 30-gauge needle on a TB syringe. We took samples through the peripheral clear corneal incisions and deposited these immediately in blood culture media.
There were no statistically significant differences in the number of colony-forming units between Zymar and Vigamox with either the conjunctival or eyelid-study regimens (Figure 1). Table 1 shows the results of the positive cultures obtained from the aqueous humor of patients from the two treatment groups with both fourth-generation fluoroquinolones. The overall rate of positive aqueous cultures in the 220 patients from groups 1 and 2 combined was less than 1% (2/220 = 0.9%). My co-investigators and I observed one positive culture in an eye that had received gatifloxacin preoperatively as well as one positive aqueous culture in an eye that received moxifloxacin preoperatively. Each positive specimen contained a single species of Staphylococcus.
The results of our study revealed that preoperative Zymar and Vigamox maintained aqueous humor sterility with very low rates of contamination. The data also supported the efficacy of the two preoperative dosing regimens for the topical anti-infectives used. These postoperative results for the aqueous humor are consistent with the preoperative results in cultures taken from the conjunctiva and eyelids of the same patients. There were no differences in colony-forming units in either group.
The positive aqueous culture rate (0.9%) in the entire patient population of our study is substantially lower than what has been reported in the literature. Oguz et al18 reported 8.1%, and Tervo et al19 reported 9.7% culture rates. Our reduced positive aqueous culture rate is likely the result of the improved antimicrobial efficacy of the fourth-generation fluoroquinolones as well as our specimen collection technique, which avoids collecting aqueous samples through a paracentesis site. The higher concentration of fluoroquinolone in Vigamox did not appear to result in lower yields of organisms from the aqueous humor.DOSING CHOICES PRIOR TO
The goals of prophylactic antibiotic treatment prior to cataract surgery include (1) reducing the bacterial population on the conjunctiva and eyelids and (2) maximizing corneal and aqueous humor tissue concentrations at the time of surgery. Ta et al20 demonstrated that 3 days of topical ofloxacin administration combined with one dose in the hour prior to surgery eliminated more bacteria from the conjunctiva compared with administering the 1-hour preoperative dose alone. Other studies, however, suggest that ocular penetration is also important for preventing endophthalmitis. Jensen and Fiscella21 showed that the rate of endophthalmitis in a large series of patients undergoing cataract surgery was significantly higher for those receiving ciprofloxacin compared with those receiving ofloxacin. Because ofloxacin has been shown to be more readily absorbed than ciprofloxacin,22,23 this finding strongly suggests that the ocular penetration of fluoroquinolones is important for preventing endophthalmitis. Selecting dosing regimens that generate aqueous levels that exceed the published MIC90 values for most bacteria causing endophthalmitis is critical.
Which dosing strategies achieve the highest aqueous penetration? The three most common prophylactic treatment regimens prior to cataract surgery include (1) q.i.d. for several days preoperatively, (2) four-dose pulsing every 10 minutes in the hour prior to surgery, and (3) a combination of these two regimens. Although a detailed comparison of these techniques between gatifloxacin and moxifloxacin has not yet been completed, prior studies with other fluoroquinolones provide valuable information. In a comparison of 2-day, q.i.d. preoperative dosing versus five-dose pulsing every 10 minutes in the hour prior to surgery, the pulsed group had a threefold greater aqueous concentration for ciprofloxacin and ofloxacin22 (Figure 2) and a fourfold greater aqueous concentration for levofloxacin24 (Figure 3).
Most interesting was the observation that a combination of a “days prior” regimen with an immediate preoperative “pulsing” regimen achieved an almost sixfold greater aqueous concentration than the “days prior” alone group and a 50% greater concentration than the “pulsing” alone group.24 Combination dosing (“days prior” with “pulsing”) offers the distinct advantage of maximizing the exposure of the fluoroquinolone to the bacteria of the eyelids and conjunctiva while simultaneously achieving optimal aqueous penetration.IS A COMBINED APPROACH ADVISABLE?
My colleagues and I compared the efficacy of lid scrubs to a preoperative fluoroquinolone (levofloxacin 0.5%) for decreasing the bacterial load of the eyelids and conjunctiva prior to cataract surgery.25 The results were both interesting and surprising (Figure 4). We randomized 74 patients to four groups: (1) control, with no levofloxacin and no lid scrubs; (2) levofloxacin q.i.d. for 2 days preoperatively; (3) lid scrubs for 2 days preoperatively; and (4) levofloxacin and lid scrubs for 2 days preoperatively.
Surprisingly, the lid-scrub group yielded more colony-forming units than the control group. The levofloxacin group showed 36% fewer (P=.049) colony-forming units compared with the control. The combination group, which received the fluoroquinolone and lid scrubs, yielded the lowest amount of colony-forming units—84% less than the control group and 89% less than the lid-scrub group. Performing eyelid scrubs preoperatively in the absence of a concomitant broad-spectrum antibiotic may shift bacteria toward the eye, thus increasing the risk of ocular infection rather than decreasing it as one intends. By contrast, lid scrubs used in combination with a fluoroquinolone dramatically reduced ocular surface bacteria when compared with either technique alone.FINAL RECOMMENDATIONS
My current suggestions to surgeons regarding surgical prophylaxis are as follows.
1. Although studies of the new levofloxacin 1.5% formulation, Iquix (Santen Inc., Napa, CA), may yield interesting findings, I currently recommend selecting a fourth-generation fluoroquinolone as a prophylactic antibiotic.
2. Surgeons should combine a “days prior” regimen with an immediate preoperative “pulsing” regimen. Patients should use the anti-infective topical medication 2 to 3 days preoperatively (q.i.d.) and at least four times every 10 minutes during the hour prior to surgery.
3. Preoperative lid-scrub and fluoroquinolone regimens should be combined.
4. Povidone-iodine should be applied to the lids and ocular surface prior to surgery.
5. The draping technique should sequester the lids and lashes during the surgery.
6. Patients should receive a fourth-generation fluoroquinolone immediately postoperatively, while still on the table, and four to six times per day for 5 to 7 days. It is important to avoid extended, low-frequency dosing of postoperative fluoroquinolones, because this practice facilitates the development of resistant organisms. n
Frank A. Bucci, Jr, MD, is Medical Director of Bucci Laser Vision Institute in Wilkes Barre, Pennsylvania. He states that he holds no financial interest in any product or company mentioned herein. Dr. Bucci may be reached at (570) 825-5949; email@example.com. Kattan HM., Flynn HW Jr., Pfugfelder SC, et al. Nosocomial endophthalmitis survey: current incidence of infection after intraocular surgery. Ophthalmology. 1991;98:227-238.
2. Aaberg TM Jr, Flynn HW Jr, Schiffman J, Newton J. Nosocomial acute-onset postoperative endophthalmitis survey: a 10-year review of incidence and outcomes. Ophthalmology. 1998;105:1004-1010.
3. Speaker MG, Milch FA, Shaf MK, et al. Role of external bacterial flora in the pathogenesis of acute postoperative endophthalmitis. Ophthalmology. 1991;98:639-649.
4. Mezer E, Gelfand YA, Lotan R, Tamir A, Miller B. Bacteriological profile of ophthalmic infections in an Israeli hospital. Eur J Ophthalmol. 1999;9:120-124.
5. Isenberg SJ, Apt L, Yoshimori R, Khwarg S. Chemical preparation of the eye in ophthalmic surgery, IV. Comparison of povidone-iodine on the conjunctiva with a prophylactic antibiotic. Arch Ophthalmol. 1985;103:1340-1342.
6. Schlegel L, Chaumeil C, Quesnot S, et al. Retrospective study of the prevalence and sensitivity to antibiotics of bacteria isolated from ocular samplings. J Fr Ophthalmol. 1995;18:250-258.
7. Apt L, Isenberg SJ, Yoshimori R, et al. The effect of povidone-iodine solution applied at the conclusion of ophthalmic surgery. Am J Ophthalmol. 1995;119:701-705.
8. Adenis JP, Robert PY. Local antimicrobial prophylaxis in cataract surgery: recent controversies and clinical guidelines. Ophthalmologica. 1997;211(Suppl 1):77-80.
9. Kowalski RP, Karenchak LM, Romanowski EG. Infectious disease: changing antibiotic susceptibility. Ophthalmol Clin North Am. 2003;16:1-9.
10. Drlica K. Mechanism of fluoroquinolone action. Curr Opin Microbiol. 1999;2:504-508.
11. Fouraker B. Callegan M, Desjardins M, et al. In vitro susceptibility and minimal inhibitory concentration data for ocular pathogens for gatifloxacin in comparison with 4 other fluoroquinolones. Paper presented at: The 2003 OMIG Meeting; November 15, 2003; Anaheim, CA.
12. Nguyen QH, Friedlaender MH, Sharf L, Breshears D. Objective and subjective measurement of drug toxicity. Paper presented at: The ARVO Annual Meeting; April 29, 2004; Fort Lauderdale, FL.
13. Farley WJ, Luo L, Chen LZ, et al. Effects of commercial fourth-generation fluoroquinolones on corneal epithelial barrier function in experimental murine dry eye. Invest Ophthalmol Vis Sci. 2004;45:E-Abstract 4904.
14. Gao J, Siemasko KF, Vu C, et al. Effect of the fourth-generation fluoroquinolone on rabbit cornea. Invest Ophthalmol Vis Sci. 2004;45:E-Abstract 4889.
15. Schmidt L, Beuerman R. Comparison of gatifloxacin and moxifloxacin in healing of a linear incision in the rabbit cornea. Paper presented at: The ARVO Annual Meeting; April 26, 2004; Fort Lauderdale, FL.
16. Bucci FA. A comparison of conjunctival and eyelid cultures in phaco patients using gatifloxacin and moxifloxacin preoperatively. Paper presented at: The ARVO Annual Meeting; April 28, 2004; Fort Lauderdale, FL.
17. Evans RE, Bucci FA. A comparison of immediate postop aqueous cultures in phaco patients receiving gatifloxacin and moxifloxacin preoperatively. Paper presented at: The ARVO Annual Meeting; April 28, 2004; Fort Lauderdale, FL.
18. Oguz H, Satici A, Guzey M, et al. Microbiologic analysis of aqueous humor in phacoemulsification. Jpn J Ophthalmol. 1999;43:162-165.
19. Tervo T, Ljungberg P, Kautiainen T, et al. Prospective evaluation of external ocular microbial growth and aqueous humor contamination during cataract surgery. J Cataract Refract Surg. 1999;25:65-71.
20. Ta CN, Egbert PR, Singh K, et al. Prospective randomized comparison of 3-day versus 1-hour preoperative ofloxacin prophylaxis for cataract surgery. Ophthalmology. 2002;109:2036-2040.
21. Jensen MK, Fiscella RG. Comparison of endophthalmitis rates over four years associated with topical ofloxacin versus ciprofloxacin. Invest Ophthalmol Vis Sci. 2002;43:B398.
22. Bucci FA, O'Brien TP, Evans RE, Myers PJ. A prospective comparison of four methods of pre-phacoemulsification antibiotic treatment with ofloxacin and ciprofloxacin [Abstract]. Invest Ophthalmol Vis Sci. 2000;41:S768.
23. Cekic O, Batman C, Totan Y, et al. Aqueous humor levels of topically applied ciprofloxacin and ofloxacin in the same subjects. Eye. 1999;13:656-659.
24. Bucci FA. An in vivo study comparing the ocular absorption of levofloxacin and ciprofloxacin prior to phacoemulsification. Am J Ophthalmol. 2004;137:308-312.
25. Bucci, FA, Amico LM, Guerino A, Evans R. The effect of preop lid scrubs and levofloxacin on eyelid and conjunctival cultures prior to cataract surgery. Paper presented at: The ARVO Annual Meeting; May 5, 2003; Fort Lauderdale, FL.