ESCRS ENDOPHTHALMITIS STUDY MISCONCEPTIONS

In a previous article (EuroTimes, Volume 17, Issue 3, March 2012) we clarified misconceptions that early “postoperative†antibiotic drops were excluded in the ESCRS Endophthalmitis Study.1 Discussion here further addresses critiques that larger patient numbers would have produced statistically significant results for topical drops vs. controls, and minimised differences between drops and intracameral injection. A quick review of basic pharmacokinetic and pharmacodynamic (PK/PD) principles that underlie antibacterial actions may quell further confusion on this issue.

To address whether greater patient numbers would have changed study results, we can analyse two scenarios basic to this argument from a pharmacodynamic point of view. Because the literature confirms that increasing the preoperative antibiotic drop frequency, when povidone-iodine is also used, offers no advantages, only two scenarios or time-frames remain for debate: the three immediate postoperative drops in study Group C vs. controls, and again, the three postoperative drops vs. intracameral injection (Group B).

Scenario 1:

While study Group C showed a trend, differences over controls did not reach statistical significance.1 This implies that the immediate postoperative drop intervention did not significantly impact postoperative endophthalmitis rates.

Because intraoperative bacterial contamination is linked to the patient’s own ocular surface flora, and sterilisation of conjunctiva is rarely achieved preoperatively, a risk does remain that bacteria may enter the eye during cataract surgery. Frequent topical drops given immediately after surgery (eg, Group C) deliver only low antibiotic levels to the aqueous humour (AH), as abundantly shown in previous clinical studies that measured AH levels after intensive drop regimens. Furthermore, because of high interpatient variability after drops, clinicians cannot be certain what levels are actually achieved in any given patient.

Nevertheless, one can interpret even the relatively “high†AH levels anticipated in ESCRS study Group C,2 through PK/PD parameters associated with bacterial eradication. The table above compares peak AH levels and calculated AUCs after topical drops and intracameral injection.

Target values for peak/MIC ratios for fluoroquinolones (FQ) fall near 10, and desired AUC values near 50-100.3 The table shows initial AH antibiotic levels after drops are low, although initial peak/MIC ratios may exceed 10 for some microorganisms. However, due to AH turnover, the concentrations over time (AUC) are inadequate, being well below target values of 50-100. Any increase in patient study numbers would not override such pharmacodynamic fundamentals.

Scenario 2:

To diminish study differences between intracameral injection and frequent topical drops, again, analysis of AH peaks, and calculated AUCs would be fundamental. The table shows that intracameral injection delivers approximately 1,000 times higher AH antibiotic levels than do topical drops. This translates into much higher calculated AUCs (and related parameters such as AUIC, T>MIC) bringing the estimated AUC after a cefuroxime 1mg intracameral injection into the range of 4,000 mg•hr/L, about a thousand-fold higher than AUC after the FQ drops.

While target AUC values for fluoroquinolones are well described, the action of cephalosporins and other antibiotics are also tied to the AUC. For beta-lactams, including cephalosporins, the key pharmacodynamic parameter is exposure time above the MIC, (AUIC – area under the inhibitory curve, and T>MIC)). Therefore, it is an oversight to focus only on achieved antibiotic peaks (Cmax) as a predictor of antibiotic effect. In vitro studies show that even extremely high concentrations of FQ required substantial amounts of time to achieve bacterial kill.4

Intracameral injections deliver high, immediate antibiotic levels to the AH, without interpatient variability. Because of these high initial levels, concentrations remain above bacterial MICs for longer periods of time, which translates into the higher AUCs and AUICs necessary to eradicate bacteria.

Patient study numbers are not tied to these recognised PK/PD fundamentals and dismissing their role in fighting bacterial infection likely results only in futile argument.

Antibiotic prophylaxis is aimed primarily at eliminating bacteria that enter the eye during cataract surgery. There should be little confusion over which regimen – intracameral injection or topical drops – delivers the highest antibiotic levels directly to the anterior chamber.

Other factors such as inoculum size and bacterial virulence also impact the risk for serious infection. Poor wound healing or surgical complications may permit surface contaminants to enter the eye postoperatively during wound healing; under these conditions, ongoing surface antisepsis is a separate matter.

Nevertheless, to eradicate bacteria entering the eye during cataract surgery, there can be little doubt that the intracameral injection delivers higher antibiotic levels over time, levels that are impossible to achieve with clinical topical drop regimens. Fundamental principles of PK/PD support clinical findings of the ESCRS study. Increasing patient numbers in study groups would not alter the basic principles of bacterial eradication already well established within the scientific community, all wishful thinking aside.

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. 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.

3. Odenholt I, Cars O. Pharmacodynamics of moxifloxacin and levofloxacin against Streptococcus pneumoniae, Staphylococcus aureus, Klebsiella pneumoniae and Escherichia coli: simulation of human plasma concentrations after intravenous dosage in an in vitro kinetic model. J Antimicrob Chemother. 2006;58:960-965.

4. Callegan MC, Novosad BD, Ramadan RT, et al. Rate of bacterial eradication by ophthalmic solutions of fourth-generation fluoroquinolones. Adv Ther 2009;26:447-54.

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