DOSING REGIMEN ANALYSIS AND ENDOPHTHALMITIS

In cataract surgery, topical antibiotic drops are included in prophylaxis regimens at “preoperative†or “postoperative†times. Results of the ESCRS Endophthalmitis Study Group1 on prophylaxis of endophthalmitis compared drop regimens with intracameral injection in previously undescribed ways. Some critiques suggest the intensive drop dosing regimen used in the study may not be fully understood.

No studies have compared clinical outcomes after prophylactic drop regimens in a controlled setting. Yet topical antibiotics are added to preoperative antisepsis with povidone-iodine and may be added after surgery to protect against contamination for an extended period of time.

Critics suggest that the ESCRS Study failed to adequately test the value of topical antibiotic drops because postoperative drops were “withheld for one day†after surgery. However, details of the regimen used may be misunderstood.

Group C in the ESCRS study received an intensive drop regimen in two phases: two preoperative drops (one at 30 and 60 minutes before surgery); then, three additional, pulsed drops at the close of surgery (each five minutes apart). The latter were immediate “postoperative†drops, given at comparable times to the intracameral injection, making “apples to apples†analysis possible and imposing a stiffer statistical challenge to the intracameral injection.

To mitigate against suggestions that study drops were withheld for one day postoperatively, or that drop dosing regimens made a difference, three time frames may be analysed. First, data show that preoperative dosing more intense than the two drops given in ESCRS study groups would unlikely add significant effects over the povidone-iodine used in all study groups. Studies show prolonging or increasing preoperative antibiotic drops had little impact over prudent use of povidone-iodine alone.2,3 Therefore it is unlikely that drop differences in this time frame could dismantle ESCRS study outcomes.

Focusing on the immediate postoperative period, the notion that drops were delayed for one day after surgery is inaccurate. The three pulsed drops used in ESCRS study Group C (and Group D) are comparable to the administration of antibiotic drops immediately after surgery or in the postoperative holding area (although such practices vary widely or may be omitted altogether). A study by Sundelin and associates4 duplicated the drop regimen of Group C, measuring aqueous humour (AH) antibiotic levels before and after surgery to anticipate what levels had likely been achieved in ESCRS study groups. Mean AH levels were higher than any previously reported for topical fluoroquinolones, no matter what regimen had been used, achieving peaks of 4.4 ug/ml levofloxacin at one hour after the last postoperative drop and remaining at 3.1 ug /ml at 90 minutes afterwards, still higher than previously reported levels (Figure 1). These AH levels imply that corneal sequestration also occurred, with antibiotic remaining on ocular surface layers and conjunctiva for a period of time after surgery.

During the extended postoperative period, all study groups received QID antibiotic drops beginning the day after surgery x six days. Is it reasonable, then, to surmise that any other immediate “postoperative†dosing regimen, during a few hours time, in Group C (or D), would nullify the statistically significant differences seen between controls and Group C, or between Group C and the intracameral injection in Group B (Table 1)?

Table 2 shows statistical results for the value of the two different interventions in approximately 4,000 patients per group. Aside from these clear data, discussion in an upcoming issue will focus on why further comparisons in larger numbers of patients between regimens in Groups A vs. C, or Groups B vs. C are likely futile.

Intracameral cefuroxime

Approaches to managing risks for postoperative infection are unclear and vary widely among settings. Dr Günther Grabner of the Salzburg University Eye Clinic, who entered the most patients in the ESCRS study, has encountered no case of endophthalmitis since initiation of the study and instillation of cefuroxime at the end of surgery (with 2800-3500 surgeries/year and increasing). At the end of surgery, a drop of ofloxacin is given, continued the next day TID for approximately one week, then reduced weekly at the discretion of the referring ophthalmologist.

Dr Luis Cordoves of Spain describes use of immediate postoperative drops after intracameral cefuroxime (eg: chloramphenicol, ofloxacin, moxifloxacin), which patients continue hourly until bedtime, and reduce afterwards to 4x daily for 5-7 days until wound healing is complete. An eye shield at night for these first few days is also incorporated into the regimen.

Crucial to interpretation of the ESCRS study results is an understanding that early postoperative drops were initiated in two study groups in the form of the three pulsed doses given over 15 minutes immediately postoperatively. These are anticipated to have produced higher aqueous humour fluoroquinolone levels than previously reported. Even this, however, did not compare statistically with the overwhelming effect of the intracameral cefuroxime injection.

References

1. Endophthalmitis Study Group, European Society of Cataract & Refractive Surgeons. Prophylaxis of postoperative endophthalmitis following cataract surgery: results of the ESCRS multicenter study and identification of risk factors. J Cat Refract Surg 2007; 33: 978-88.

2. He L, et al. Prospective randomized comparison of 1-day and 3-day application of topical 0.5% moxifloxacin in eliminating preoperative conjunctival bacteria. J Ocular Pharmacol Ther 2009; 25:373-8.

3. Moss JM, Sanisio SR, Ta CN. A prospective randomized evaluation of topical gatifloxacin on conjunctival flora in patients undergoing intravitreal injections. Ophthalmology 2009; 116:1498-501.

4. Sundelin K, Seal D, Gardner S, et al. Increased anterior chamber penetration of topical levofloxacin 0.5% after pulsed dosing in cataract patients. Acta Ophthalmol. 2009;87:160-165.

* Susanne Gardner, Pharm. D, is a specialist in ocular antiinfectives and ocular pharmacokinetics, with a background in academics, research and publishing.