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Review/Update

Perspectives on antibiotics for postoperative endophthalmitis prophylaxis: Potential role of moxifloxacin

O'Brien, Terrence P. MD; Arshinoff, Steve A. MD, FRCSC; Mah, Francis S. MD

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Journal of Cataract & Refractive Surgery: October 2007 - Volume 33 - Issue 10 - p 1790-1800
doi: 10.1016/j.jcrs.2007.06.026
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Abstract

Postoperative endophthalmitis remains one of the most devastating complications of cataract surgery. Studies in the United States and other countries show that, fortunately, postoperative endophthalmitis is a rare clinical occurrence, with reported rates ranging between 0.06% and 0.25%.1–10 However, postoperative endophthalmitis poses a significant public health issue considering the millions of people who have cataract surgery each year.11–13 Evidence that the incidence of endophthalmitis after cataract surgery is increasing,1,9,14 together with the anticipated rise in cataract surgery case volume accompanying growth of the older population, raises concern about its future burden and underscores the importance of identifying effective prophylaxis methods for improving surgical safety.

Several techniques aimed at prophylaxis are used by cataract surgeons preoperatively, perioperatively, and postoperatively to reduce the risk for postoperative endophthalmitis. Preoperative povidone–iodine antisepsis combined with preoperative and postoperative topical antibiotic therapy is considered the standard of care,15,16 although there is significant variation among surgeons with respect to their antibiotic choice and administration regimen. Intracameral antibiotics as an adjunct to postoperative topical antibiotic dosing are used less often and appears to be more popular among European cataract surgeons than among surgeons in the United States. In a recent survey of members of the American Society of Cataract and Refractive Surgery (ASCRS) and the European Society of Cataract & Refractive Surgeons (ESCRS), almost one third of European respondents, compared with only 12% of U.S. respondents, indicated they were injecting an antibiotic intracamerally (D.V. Leaming MD, “Practice Styles and Preferences of U.S. ASCRS Members—2005 Survey,” poster presented at the ASCRS Symposium on Cataract, IOL and Refractive Surgery, San Francisco, California, USA, March 2006). Approximately 30% of respondents in both groups were using an antibiotic in the irrigating solution.

The diversity of prophylactic techniques used in clinical practice reflects the paucity of good evidence-based literature to support or refute any of the various methods of infection prophylaxis.15 Recognizing the importance of this issue and the need to investigate it in a systematic fashion, ESCRS performed a prospective investigator-masked placebo-controlled multicenter clinical trial to explore the hypothesis that when surgery incorporates best practice for surgical hygiene, preoperative povidone–iodine antisepsis, and postoperative levofloxacin 0.5% ophthalmic solution for 1 week, the addition of intracameral cefuroxime at the end of surgery, preoperative levofloxacin, or intracameral cefuroxime plus preoperative levofloxacin would have a significant effect on the incidence of postoperative endophthalmitis.17–19

Therefore, all ESCRS trial participants were operated on with best practice for surgical hygiene, received preoperative povidone–iodine antisepsis and postoperative levofloxacin 0.5% (Oftaquix) 4 times daily for 6 days starting the day after surgery, and were randomized into 4 groups for additional treatment with (1) preoperative placebo eyedrops and no intracameral cefuroxime injection; (2) preoperative placebo eyedrops and intracameral cefuroxime injection 1 mg/0.1 mL; (3) preoperative levofloxacin eyedrops (1 drop 1 hour before surgery, a second drop half an hour before surgery, and 3 more drops at 5-minute intervals immediately after surgery) and no intracameral cefuroxime; (4) preoperative levofloxacin eyedrops (1 drop 1 hour before surgery, a second drop half an hour before surgery, and 3 more drops at 5-minute intervals immediately after surgery) and intracameral cefuroxime 1 mg/0.1 mL

That ESCRS study was launched in September 2003 and planned to randomize 32 000 patients. The study was halted early in January 2006 after analysis of the available data from 16 211 patients showed the incidence of endophthalmitis in treatment groups not receiving intracameral cefuroxime was significantly higher than those in which intracameral cefuroxime was used.18,19 The risk for presumed infectious postoperative endophthalmitis was increased nearly 5-fold in patients not receiving intracameral cefuroxime (24/8103; 0.30%) compared with those receiving that intervention (5/8108; 0.06%) (odds ratio [OR], 4.92; 95% confidence interval [CI], 1.87-12.9; P = .001). The difference in risk exceeded 5-fold in the analysis of cases of proven infectious endophthalmitis (OR, 5.86; 95% CI, 1.72-20.0; P = .005). The incidence of endophthalmitis in patients receiving perioperative levofloxacin alone (10/4049; 0.25%) was not significantly different from the rate in patients who received no additional perioperative treatment (14/4054; 0.35%). The chairman of the ESCRS study concluded that these data should convince surgeons to adopt the use of intracameral cefuroxime as a standard part of the procedure of modern phacoemulsification cataract surgery. However, he acknowledged that although the ESCRS study proved the efficacy of cefuroxime, speculation remains as to whether another antibiotic might be better (P. Barry, FRCS, “ESCRS Endophthalmitis Study; the Ridley Medal Lecture,” presented at the XXIV Congress of the European Society of Cataract & Refractive Surgeons, London, United Kingdom, September 2006).

We suggest that the optimum antibiotic regimen and route of delivery for cataract surgery require further study. Although the preliminary data in the ESCRS endophthalmitis study show that antibiotic prophylaxis, including intracameral cefuroxime, has a statistically significant benefit relative to the comparator arms not receiving the cephalosporin injection, it did not unequivocally establish such a regimen as best practice. The purpose of this paper is to aid the cataract surgeon's understanding of the ESCRS study and to place its results in perspective after taking into account more recent advances in ophthalmic antibiotics. Specifically, it addresses the limitations of the ESCRS study design and of cefuroxime for intracameral use and provides evidence to support the suggestions that (1) a fourth-generation fluoroquinolone agent, such as moxifloxacin hydrochloride ophthalmic solution 0.5% (Vigamox), currently offers the best available option for topical antibiotic prophylaxis and (2) moxifloxacin is a better alternative to cefuroxime if intracameral injection is used.

LIMITATIONS OF THE ESCRS STUDY

When drafting the protocol in 2002, the ESCRS study planning committee aimed to investigate “the most promising means of prophylaxis.” Cefuroxime was chosen as the antibiotic for intracameral use based on a Swedish retrospective study that showed it was safe and reduced the rate of postoperative endophthalmitis from 0.26% to 0.06% during consecutive 5-year periods.10,17–20 Levofloxacin 0.5% ophthalmic solution was selected for topical antibiotic prophylaxis because it was considered to offer the best combination of antimicrobial coverage and pharmacokinetic and pharmacodynamic properties of all other options available in Europe in 2002. In addition, Santen GmbH provided product and partial funding for the ESCRS study.

However, in the few years since the ESCRS study was planned and launched, the antibiotic regimens it investigated have potentially become outdated outside of Europe because of new developments in ophthalmic antibiotics. In 2003, the fourth-generation fluoroquinolones moxifloxacin 0.5% ophthalmic solution and gatifloxacin 0.3% ophthalmic solution (Zymar) were launched in the United States. Moxifloxacin 0.5% is currently in the approval process in the European Union. As outlined below, we suggest there is solid evidence supporting the theory that moxifloxacin 0.5% is a better choice than levofloxacin 0.5% for topical antibiotic prophylaxis. The corollary to that concept is that the results of the ESCRS study might be different if the trial were repeated substituting moxifloxacin for levofloxacin in order to demonstrate a statistical advantage of intracameral use compared with topical antibiotic alone. However, if intracameral use is considered, we suggest available data indicate moxifloxacin has multiple potential advantages over cefuroxime.

LIMITATIONS OF CEFUROXIME

Results in the ESCRS postoperative endophthalmitis study, the Endophthalmitis Vitrectomy Study (EVS), and other studies characterizing endophthalmitis isolates demonstrate that gram-positive organisms account for 90% or more of pathogens isolated in culture-positive cases of postcataract surgery endophthalmitis, with coagulase-negative staphylococci (ie, Staphylococcus epidermidis) and Staphylococcus aureus representing the leading causes.19,21–23 Even though gram-negative bacteria were not recovered in the ESCRS postoperative endophthalmitis study, there were 9 cases of endophthalmitis for which the causative organisms were not identified; however, the EVS study reported that approximately 6% of endophthalmitis cases were caused by gram-negative bacteria.21 Therefore, the role of gram-negative organisms should not be overlooked and the ideal antibiotic for postoperative endophthalmitis prophylaxis should provide potent, broad-spectrum activity. In that regard, results in in vitro susceptibility tests and a Swedish retrospective study of intracameral cefuroxime demonstrate that cefuroxime has important gaps in antimicrobial coverage that include gram-negative pathogens, Enterococci, and methicillin-resistant S aureus (MRSA).10,24,25 Furthermore, although Montan et al.10 considered cefuroxime a reasonable choice for intracameral postoperative endophthalmitis prophylaxis because rates of colonization with MRSA and methicillin-resistant coagulase-negative staphylococci were low to negligible in their outpatient setting; community-acquired MRSA infection has recently emerged as a new concern. In vitro testing of clinical isolates from cases of community-acquired MRSA infections show those organisms are resistant to β-lactams and macrolides but susceptible to most other antibiotics, including fluoroquinolones.26

Kill-kinetic studies may be more useful than minimum inhibitory concentration (MIC) data in predicting in vivo efficacy.27 In kinetics of kill testing with ocular isolates of S aureus and S epidermidis that were susceptible to cefuroxime and other β-lactams, cefuroxime showed a slow to negligible rate of kill (5% to 90%) at 2 concentrations, 100 μg/mL and 1000 μg/mL (Figures 1 and 2). Neither concentration of cefuroxime had bactericidal activity against staphylococcal isolates resistant to cephems, even when measured for 3 hours (data not shown). In comparison, moxifloxacin at 50 μg/mL studied against these same ocular staphylococcal isolates demonstrated significant killing (>99.5%) in 60 minutes (Figures 1 and 2).

Figure 1
Figure 1:
Kinetics of kill of S aureus by cefuroxime and moxifloxacin.
Figure 2
Figure 2:
Kinetics of kill of S epidermidis by cefuroxime and moxifloxacin

The time-dependent killing profile of cefuroxime may also result in less than optimum activity when the drug is administered as a single bolus injection because β-lactam antibiotics are time-dependent (versus fluoroquinolones, which are concentration-dependent). Results in a pharmacokinetics study of intracameral cefuroxime20 found its aqueous humor concentration decreased by 4-fold within 60 minutes, and it is unknown whether sufficient cefuroxime concentrations persist in the aqueous humor for a sufficient duration to optimize eradication of contaminants that gain entry into the eye during or after surgery.

Although the higher antibiotic concentration achieved with intracameral administration offers the opportunity to optimize efficacy, it raises additional concerns about the short-term and long-term safety of increased amounts in the eye. However, few studies have investigated the potential ocular toxicity of intracameral cefuroxime.20,28,29 In addition, widespread use of intracameral cefuroxime for cataract surgery endophthalmitis prophylaxis poses a potential safety concern with respect to the risk for systemic β-lactam hypersensitivity reactions. Various studies20,30 estimate that the prevalence of penicillin allergy ranges between 1% and 10%. Although there is some disagreement in the literature regarding cross-allergenicity between penicillin and cephalosporins,30–32 severe anaphylactic reactions to intraocular and subconjunctival injections of cephalosporins have been reported in patients with a known and unknown allergy to penicillin.33,34 Furthermore, from a mechanistic perspective, because cataract surgery causes a breakdown in the blood–aqueous barrier, even a small intracameral dose of cefuroxime could be postulated to lead to a serious hypersensitivity reaction in a susceptible patient.

With the risk of allergic reactions in mind, Montan et al.10,20 screened for immunoglobulin E–mediated cefuroxime hypersensitivity in cataract surgery patients. Patients who reported a history of probable systemic anaphylaxis to the use of penicillins or cephalosporins had cefuroxime skin-prick testing, and patients testing positive were reported to have safely had surgery incorporating intracameral cefuroxime after receiving pretreatment with an oral antihistamine. Their strategy appears to offer an effective method for mitigating the risk for anaphylaxis but adds a significant burden to the preoperative evaluation of cataract surgery patients.

In addition, practical limitations that relate to dose preparation accompany the use of intracameral cefuroxime. In the ESCRS study, the off-label use of cefuroxime required a special exemption, which ended when the study was terminated, and a specific preparation that is not commercially available was created for the study (P. Barry, FRCS, “ESCRS Endophthalmitis Study; the Ridley Medal Lecture,” presented at the XXIV Congress of the European Society of Cataract & Refractive Surgeons, London, United Kingdom, September 2006). When used in clinical practice, cefuroxime for intracameral administration is usually prepared at a remote pharmacy by reconstituting a product intended for intravenous administration. It is then administered at room temperature or refrigerated for later use. In addition to its inconvenience, extemporaneous preparation of cefuroxime solution for intracameral injection also carries risks for dilution and dosage errors, including an increased potential for causing toxic anterior segment syndrome (TASS). In the ESCRS study, the authors said they believed that TASS was not a cause of endophthalmitis in the 9 unproven cases.19 Stability, particularly of the β-lactam ring in aqueous solution, must be taken into account as well. Reconstituted cefuroxime is stable for 24 hours at room temperature and for 7 days if frozen.35

EVIDENCE FOR TOPICAL MOXIFLOXACIN

When the ESCRS postoperative endophthalmitis study was designed in 2002, levofloxacin was selected as the antibiotic for use in the topical preoperative prophylaxis arm and for prevention of postoperative infection based on data demonstrating it achieved anterior chamber penetration and offered broader spectrum coverage than the earlier generation fluoroquinolones (ciprofloxacin and ofloxacin) that were available for ophthalmic use at that time (D.V. Leaming, MD, “Practice Styles and Preferences of U.S. ASCRS Members—2005 Survey,” poster presented at the ASCRS Symposium on Cataract, IOL and Refractive Surgery, San Francisco, California, USA, March 2006).

However, the fourth-generation fluoroquinolones offer several advantages over levofloxacin that would theoretically favor their use in endophthalmitis prophylaxis.36 The benefits include a broader spectrum of antibacterial activity and greater potency against gram-positive pathogens, superior ocular penetration characteristics for moxifloxacin, and reduced susceptibility to resistance development. Between the 2 fourth-generation fluoroquinolones, moxifloxacin may be regarded as a superior choice based on differences in potency and penetration, which are the 2 major determinants of antibiotic efficacy. In addition, unlike gatifloxacin, moxifloxacin does not contain the preservative benzalkonium chloride.

In Vitro Potency

Outcomes data from comparative clinical trials represent the ideal method for evaluating the relative efficacy of different antibiotics. In vitro susceptibility by itself is an inadequate parameter for determining antibiotic activity in vivo. However, in the absence of clinical study results, pharmacodynamic evaluations that integrate laboratory susceptibility data with pharmacokinetic information about antibiotic concentrations achieved in target tissues and fluids represent the principal method of assessing the potential in vivo activity of antibiotics and appropriate dosing.37 Results in in vitro antimicrobial susceptibility tests show that moxifloxacin has potent activity against the key pathogens causing postoperative endophthalmitis and greater potency against S aureus and S epidermidis than other ophthalmic fluoroquinolones, including gatifloxacin and levofloxacin38–41 (Stroman DW, et al. IOVS 2006; 47:ARVO E-Abstract 1881).

Table 1 summarizes the results of in vitro susceptibility testing of 110 bacterial endophthalmitis isolates against 5 fluoroquinolones: ciprofloxacin, ofloxacin, levofloxacin, gatifloxacin, and moxifloxacin. Statistical comparisons of antibacterial activity based on MIC values showed moxifloxacin had the greatest potency against fluoroquinolone-susceptible and fluoroquinolone-resistant S aureus, fluoroquinolone-susceptible coagulase-negative staphylococci, Streptococcus pneumoniae, and Streptococcus viridans. In addition, moxifloxacin was significantly more potent than levofloxacin and the second-generation fluoroquinolones against fluoroquinolone-resistant coagulase-negative staphylococci.

Table 1
Table 1:
Median MICs of gram-positive bacterial keratitis clinical isolates to 5 fluoroquinolones.38

As shown in Table 2, similar results favoring moxifloxacin were reported in a study testing the in vitro susceptibility of 77 bacterial endophthalmitis isolates to the ophthalmic fluoroquinolones.40 In that study, moxifloxacin had the greatest potency of all antibiotics against fluoroquinolone-susceptible and fluoroquinolone-resistant S aureus and coagulase-negative staphylococci, S pneumoniae, S viridans, β-hemolytic streptococci, and Enterococcus species, and it was also more active than levofloxacin against fluoroquinolone-resistant coagulase-negative staphylococci and Bacillus species.

Table 2
Table 2:
Median MICs of gram-positive bacterial endophthalmitis clinical isolates to 5 fluoroquinolones.40

Pharmacodynamics

Kill-curve studies show that moxifloxacin has rapid bactericidal activity against important endophthalmitis pathogens. In tests using a fluoroquinolone-susceptible strain of S aureus, moxifloxacin 50 mcg/mL (1:100 dilution of the commercial ophthalmic solution) produced a greater than 3 log unit reduction in bacterial count (>99.9%) in fewer than 2 hours; the same concentration of moxifloxacin resulted in a greater than 3 log unit reduction in colony counts of a fluoroquinolone-resistant S aureus strain in fewer than 3 hours (Stroman DW, et al. IOVS 2006; 47:ARVO E-Abstract 1881) (Figure 1). These results are in marked contrast to the results observed in testing the bactericidal activity of cefuroxime 100 mcg/mL and 1000 mcg/ml against the same S aureus strains (Figure 1). Figure 2 shows the kinetics of kill for moxifloxacin and cefuroxime against S epidermidis. Rapid bactericidal activity is an important attribute for limiting the development of resistance and preserving the clinical utility of any antibiotic and has special relevance for the fourth-generation fluoroquinolones because resistance to these agents requires a 2-step mutation process. By rapidly diminishing the pool of bacteria carrying a single mutation, moxifloxacin limits the possibility for stepwise acquisition of a second mutation.42–44 Rapid bactericidal activity is also a desirable feature of an antibiotic intended to be used topically to eradicate surface flora in a preoperative prophylaxis regimen.

Penetration

A topical antibiotic used for postoperative endophthalmitis prophylaxis must achieve concentrations in ocular fluids and tissues that exceed MIC values for target pathogens. However, attainment of levels far in excess of the MIC is desirable because it can reduce the risk for resistance emergence and optimize eradication of less susceptible organisms.45 Results in animal and human studies evaluating penetration into the tear film, aqueous humor, cornea, iris–ciliary body, and conjunctiva after topical antibiotic administration show that compared with other ophthalmic fluoroquinolones, moxifloxacin offers superior ocular bioavailability.46–54 This benefit of moxifloxacin can be partly attributed to its 0.5% concentration, which is higher than the concentrations of gatifloxacin, ciprofloxacin, and ofloxacin in their commercially available formulations. Moxifloxacin also has a unique molecular structure that confers it with the desirable combination of high lipophilicity, which enhances corneal penetration, as well as high aqueous solubility, which drives corneal penetration by increasing the concentration gradient at the tear film–corneal epithelial interface. Compared with other fluoroquinolones, moxifloxacin offers higher aqueous solubility and greater lipophilicity.51

Among the many penetration studies of moxifloxacin, clinical trials investigating concentrations achieved in the aqueous humor and cornea after topical administration are of particular relevance in a discussion of topical antibiotics for cataract surgery prophylaxis46–49,51–53 (Holland EJ, et al. IOVS 2006; 47:ARVO E-Abstract 3557) (Table 3, Figure 3). Those trials investigated a variety of dosing regimens, and several had a randomized double-masked design and compared moxifloxacin penetration with that of other fluoroquinolones (gatifloxacin and ciprofloxacin). Collectively, their results show that moxifloxacin rapidly penetrates the cornea and aqueous humor to achieve concentrations that far exceed the MIC and mutant prevention concentration (defined as the MIC of the least-susceptible mutant subpopulation of a microbial culture54) values for the most important endophthalmitis pathogens. In addition, the ocular concentrations of moxifloxacin achieved were consistently at least 2-fold higher than those occurring with topically instilled gatifloxacin, 9-fold higher than those achieved with ciprofloxacin, and based on historical controls, up to 27-fold higher than those achieved in clinical studies of aqueous humor penetration of topical ofloxacin 0.3% or levofloxacin 0.5% ophthalmic solutions55–57 (Holland EJ, et al. IOVS 2006; 47:ARVO E-Abstract 3557).

Table 3
Table 3:
Moxifloxacin clinical trial results of aqueous humor penetration.
Figure 3
Figure 3:
Mean (±SD) concentrations (μg/g) of moxifloxacin and gatifloxacin in the human corneal stroma in samples collected 0.25, 0.50, 1.00, and 2.00 hours after instillation of 2 doses (1 drop each) given 5 minutes apart (Holland EJ, et al. IOVS 2006; 47:ARVO E-Abstract 3557).

A study by Kim et al.53 found that after the preoperative administration of just 4 doses 1 hour before surgery, moxifloxacin 0.5% achieved a mean aqueous humor concentration 4-fold higher than that of gatifloxacin 0.3% (mean 1.80 ± 1.21 mcg/mL versus 0.48 ± 0.34 mcg/mL) (P = .00003). The mean levels achieved with both fluoroquinolones exceeded the respective minimum bactericidal concentration for 90% of tested strains (MBC90) value for fluoroquinolone-susceptible S aureus, but only moxifloxacin achieved a concentration exceeding the MBC90 for S epidermidis, S pneumoniae, Propionibacterium acnes, and Serratia marcescens. To account for protein binding and other host factors that could affect antimicrobial activity in vivo, Kim et al. also used broth dilution assay methodology to assess the relative biological activity of the 2 fluoroquinolones against S epidermidis. Aqueous humor concentrations estimated by multiplying the minimal inhibitory dilution by the MIC of the reference S epidermidis yielded similar results and showed moxifloxacin achieved an almost 5-fold higher concentration than gatifloxacin (mean 2.1 ± 1.7 mcg/mL versus 0.4 ± 0.4 mcg/mL).

Relevant to the ESCRS study, no published studies directly compare aqueous humor penetration of topical moxifloxacin and topical levofloxacin. However, penetration of those fluoroquinolones into conjunctival tissue was assessed in a trial of healthy volunteers.50 Twenty minutes after administration of a single drop, the mean concentration achieved with moxifloxacin was significantly higher than that achieved after administration of levofloxacin 0.5% (18.00 versus 2.34 mcg/g) (P<.001). Significant differences favoring moxifloxacin were also noted when comparing its achieved conjunctival concentration with that measured after treatment with ciprofloxacin 0.3% (2.65 mcg/g), gatifloxacin 0.3% (2.54 mcg/g), and ofloxacin 0.3% (1.26 mcg/g) (P<.001 for all comparisons with moxifloxacin). There were no significant differences between any other fluoroquinolones in the achieved conjunctival concentrations (P = .35).

Penetration of moxifloxacin into the vitreous after topical administration was investigated in a study of 20 patients having pars plana vitrectomy.52 Treatment was initiated 3 days before surgery, and the mean moxifloxacin vitreous concentration was 0.11 ± 0.05 mcg/mL in patients using a dosing schedule of every 2 hours and 0.06 ± 0.06 mcg/mL after administration every 6 hours. The authors note the mean vitreous concentration achieved in the 2-hour group exceeded the MIC50 for S epidermidis, S aureus, S pneumoniae, Bacillus cereus, Haemophilus influenzae, and other gram-negative pathogens and approached the MIC90 for S epidermidis, suggesting this may be adequate for treatment intended for infection prophylaxis. In addition, they point out that vitreous penetration of topical moxifloxacin might be enhanced in the inflamed postoperative eye.

Safety

Extensive testing in in vitro and animal models, combined with the results of clinical trials and postmarketing clinical experience, attests to the safety of topically administered moxifloxacin. Studies in animal models using exaggerated dosing regimens demonstrate an absence of corneal toxicity and suggest moxifloxacin may have a better corneal safety profile than other topical fluoroquinolones, a benefit that may be related to its benzalkonium chloride–free formulation.51,55–58 Confocal analyses were conducted to examine the effects of moxifloxacin on the normal human cornea. Studies of patients having cataract and refractive surgery also demonstrate that moxifloxacin has no adverse effects on corneal or conjunctival healing.46,59–62

In Vivo Efficacy

Based on its favorable potency, penetration, and safety profiles, moxifloxacin appears to be an excellent topical antibiotic choice for postoperative endophthalmitis prophylaxis. Although confirmation of its role would require a very large prospective randomized clinical trial to achieve proper statistical power, results in a landmark animal study63 provide valuable proof that topical moxifloxacin might be effective in preventing bacterial endophthalmitis after cataract surgery. In that controlled trial, animals received anterior chamber inoculations with S aureus 5 × 104 colony-forming units (CFU) and were treated with 1 of 3 regimens of moxifloxacin 0.5% or saline: (1) full prophylaxis; that is, preprophylaxis with 5 drops every 15 minutes beginning 1 hour before bacterial exposure plus postprophylaxis with 5 more doses over the next 24 hours, (2) preprophylaxis only, or (3) postprophylaxis only. At the end of the treatment period, the animals were examined by slitlamp and samples were taken for microbial culture from the anterior and posterior chambers. Among the moxifloxacin-treated eyes, all anterior and posterior chamber cultures were negative and there was no clinical evidence of infection in eyes receiving the full prophylaxis regimen. Culture-positive rates for the 3 saline-treated groups ranged from 30% to 60% for the anterior chamber and 10% to 30% for the posterior chamber, and there were significant differences in median scores for clinical signs of endophthalmitis comparing each group with the corresponding moxifloxacin-treated group.

ROLE FOR INTRACAMERAL MOXIFLOXACIN

Moxifloxacin represents the only option for intracameral use of a fourth-generation fluoroquinolone. Although use of gatifloxacin for intravenous injection (Tequin) has been reported, that product was withdrawn from the market and is no longer available in much of the U.S. (Holland EJ, et al. IOVS 2006; 47:ARVO E-Abstract 3557; E.D. Donnenfeld, MD, “Safety of Prophylactic Intracameral Gatifloxacin in Cataract Surgery,” presented at the annual meeting of the Ocular Microbiology and Immunology Group, Anaheim, California, USA, November 2003; http://www.medpagetoday.com/ProductAlert/Prescriptions/tb/3212). Formulation with benzalkonium chloride precludes intracameral administration of gatifloxacin ophthalmic solution.

Compared with cefuroxime, moxifloxacin offers broader spectrum and more potent activity against key postoperative endophthalmitis pathogens. In addition, because moxifloxacin is commercially available as a self-preserved ophthalmic formulation that surgeons can dilute themselves in the operating room or administer directly into the eye with no further preparation, it eliminates concerns regarding the stability and inconvenience of using an extemporaneously compounded preparation. The concentration-dependent killing profile of moxifloxacin may also make it more effective than cefuroxime in achieving rapid eradication of intraocular contaminants after a single bolus injection.

All these features make moxifloxacin an attractive alternative for intracameral administration. Although the efficacy and safety of intracameral moxifloxacin require further investigation, findings in several preclinical studies of the injection of moxifloxacin 0.5% directly into the aqueous humor or vitreous as well as anecdotal clinical experience with intracameral moxifloxacin during cataract surgery provide encouraging data. In experiments using New Zealand White rabbits, Kowalski et al.64 investigated the efficacy and safety of intracameral moxifloxacin for the prevention of bacterial endophthalmitis. Toxicity evaluations were performed in animals that received intravitreal inoculation with S aureus 5 × 103 CFU followed by a single anterior or posterior chamber injection of vancomycin 1 mg, saline, or moxifloxacin 50, 125, 250, or 500 mcg as well as in animals that received 2 intravitreal doses of saline, vancomycin 1 mg, or moxifloxacin 250 or 500 mcg without bacterial challenge. Clinical grading from comprehensive examinations of the exterior eye, cornea, anterior chamber, vitreous, and retina showed no significant differences between the moxifloxacin-treated animals and the vancomycin and saline groups.

Other studies of rabbits, mice, and nonhuman primates evaluated the potential toxicity of intravitreal moxifloxacin in doses up to 300 mcg with assessments performed up to 10 weeks postinjection65 (Griffin JM, et al. IOVS 2006; 47:ARVO E-Abstract 3578; Dembinska O, et al. IOVS 2006; 47:ARVO E-abstract 4681; S.A. Arshinoff, MD, “Intracameral Moxifloxacin for Antibacterial Prophylaxis in Cataract Surgery,” presented at the XXIV Congress of the European Society of Cataract & Refractive Surgeons, London, United Kingdom, September 2006). The assessments in those trials included electroretinography, histology, measurement of intraocular pressure, corneal thickness, endothelial cell area and density, and indirect ophthalmoscopic examination of the optic nerve, retina, choroid, and vitreous. There was no evidence of treatment-related adverse effects in any study.

Recently, several studies of intracameral moxifloxacin in human patients have been conducted. Arshinoff reported his clinical experience with intracameral administration of moxifloxacin during cataract surgery (S.A. Arshinoff, MD, “Advantages and Use of Intracameral Moxifloxacin for Bacterial Prophylaxis in Cataract Surgery,” poster presented at the ASCRS Symposium on Cataract, IOL and Refractive Surgery, San Diego, California, USA, April 2007). His postoperative endophthalmitis prophylaxis protocol included administration of 4 doses of topical moxifloxacin at 10-minute intervals before surgery, povidone–iodine antisepsis, and moxifloxacin diluted in a balanced salt solution (50 or 100 mcg/0.1 cc) injected intracamerally under the capsulorhexis margin intracapsularly at the end of the case. All patients also receive topical moxifloxacin 1 drop 6 times a day for 3 days followed by 4 times a day for 5 days. To date, in the 1500 cases performed with that regimen, Arshinoff encountered no cases of endophthalmitis and noted no adverse ocular effects that could be attributed to the intracameral antibiotic. In a study designed specifically to evaluate the safety of intracameral moxifloxacin, Espiritu et al.66 found no adverse effects on visual acuity, anterior chamber reaction, pachymetry, or corneal endothelial cell density in 65 eyes receiving moxifloxacin 0.5 mg/0.1 mL injected into the capsule at the end of cataract surgery. In a study of 200 patients, Arbisser compared patients who received intracameral moxifloxacin with those who did not (Arbisser L. IOVS 2007; 48:ARVO E-Abstract 776). One day postoperatively, 4 treated eyes (2.0%) had aqueous cell counts of 3+ or higher compared with 11 eyes (11.0%) in the control group (P = .0007, Pearson chi-square test). No postoperative epithelial defect or stromal edema was observed in the treated group; however, 1 patient in the control group had a defect. In summary, Arbisser, Arshinoff, and Espiritu et al. have not observed deleterious effects of intracameral moxifloxacin injections after cataract surgery.

FUTURE DIRECTIONS

Compared with topical administration, intracameral antibiotic injection has the advantage of providing a much higher intraocular concentration. However, there is interest in exploring other methods of antibiotic delivery that could enhance and prolong the duration of maintenance of effective intraocular antimicrobial concentrations after cataract surgery. In testing in an animal model, Kleinmann et al.67 found application of collagen shields presoaked in oversaturated solutions of gatifloxacin or moxifloxacin resulted in aqueous humor antibiotic concentrations exceeding those reported with conventional topical administration. Relatively high anterior chamber concentrations of both fluoroquinolones were maintained for up to 6 hours and were achieved without clinical or histologic evidence of toxicity.

CONCLUSION

Topical antibiotic therapy remains the standard of care in postoperative endophthalmitis prophylaxis among cataract surgeons. Earlier retrospective studies and case series suggest adjunctive intracameral antibiotics may further reduce the incidence of postoperative endophthalmitis in patients having cataract surgery. Results of the randomized controlled ESCRS postoperative endophthalmitis prophylaxis study are consistent with that concept. However, that trial does not provide the final answer to what the optimal antibiotic regimen for preventing postoperative endophthalmitis is.

The ideal agent should offer potent activity against the common pathogens, favorable pharmacokinetics, minimum potential to promote resistance, excellent safety, and ease of use. When judged against these criteria, intracameral cefuroxime and topical levofloxacin have several shortcomings. The fourth-generation fluoroquinolone moxifloxacin has many advantages over levofloxacin that would favor its use for topical prophylaxis. In addition, moxifloxacin appears to offer benefits relative to cefuroxime for intracameral use. Further studies of efficacy and safety are needed before recommendations can be made regarding the role of topical or intracameral moxifloxacin for postoperative endophthalmitis prophylaxis. However, no study will provide the final answer regarding optimum antibiotic prophylaxis. The potential for changes in bacterial sensitivity patterns, emergence of new pathogens, and advances in antimicrobial therapy and modes of delivery make this a dynamic area and highlight the need for continued investigation and periodic guideline reviews to keep pace with new developments to optimize patient care.

REFERENCES

1. Taban M, Behrens A, Newcomb RL, et al. Acute endophthalmitis following cataract surgery; a systematic review of the literature. Arch Ophthalmol. 2005;123:613-620.
2. West ES, Behrens A, McDonnell PJ, et al. The incidence of endophthalmitis after cataract surgery among the U.S. Medicare population increased between 1994 and 2001. Ophthalmology. 2005;112:1388-1394.
3. Javitt JC, Vitale S, Canner JK, et al. National outcomes of cataract extraction: endophthalmitis following inpatient surgery. Arch Ophthalmol. 1991;109:1085-1089.
4. Javitt JC, Street DA, Tielsch JM, et al. National Outcomes of cataract extraction, retinal detachment and endophthalmitis after outpatient cataract surgery; the Cataract Patient Outcomes Research Team. Ophthalmology. 1994;101:100-105. discussion by PP Lee, 106.
5. Powe NR, Schein OD, Gieser SC, et al. Synthesis of the literature on visual acuity and complications following cataract extraction with intraocular lens implantation; the Cataract Patient Outcome Research Team. Arch Ophthalmol. 1994;112:239-252. erratum, 889.
6. Aaberg TM JR, Flynn HW Jr, Schiffman J, Newton J. Nosocomial acute-onset postoperative endophthalmitis survey: a ten-year review of incidence and outcomes. Ophthalmology 1998; 105:1004–1010
7. Schmitz S, Dick HB, Krummenauer F, Pfeiffer N. Endophthalmitis in cataract surgery; results of a German survey. Ophthalmology. 1999;106:1869-1877.
8. Khan RI, Kennedy S, Barry P. Incidence of presumed postoperative endophthalmitis in Dublin for a 5-year period (1997–2001). J Cataract Refract Surg. 2005;31:1575-1581.
9. Nagaki Y, Hayasaka S, Kadoi C, et al. Bacterial endophthalmitis after small-incision cataract surgery; effect of incision placement and intraocular lens type. J Cataract Refract Surg. 2003;29:20-26.
10. Montan PG, Wejde G, Koranyi G, Rylander M. Prophylactic intracameral cefuroxime; efficacy in preventing endophthalmitis after cataract surgery. J Cataract Refract Surg. 2002;28:977-981.
11. Javitt JC, Kendix M, Tielsch JM, et al. Geographic variation in utilization of cataract surgery. Med Care. 1995;33:90-105.
12. Leaming DV. Practice styles and preferences of ASCRS members—2002 survey. J Cataract Refract Surg. 2003;29:1412-1420.
13. Foster A., 2001. Cataract and “Vision 2020—the right to sight” initiative [editorial], Br J Ophthalmol, 85, 635-637.
14. Colleaux KM, Hamilton WK. Effect of prophylactic antibiotics and incision type on the incidence of endophthalmitis after cataract surgery. Can J Ophthalmol. 2000;35:373-378. discussion by RA Morgan, 378.
15. Ciulla TA, Starr MB, Masket S. Bacterial endophthalmitis prophylaxis for cataract surgery; an evidence-based update. Ophthalmology. 2002;109:13-24. questions for review and CME credit request, 25–26.
16. Bratzler DW, Houck PM. Antimicrobial prophylaxis for surgery: an advisory statement from the National Surgical Infection Prevention Project; the Surgical Infection Prevention Guidelines Writers Workgroup. Clin Infect Dis. 2004;38:1706-1715. erratum 2004; 39:441.
17. Seal DV, Barry P, Gettinby G, et al. ESCRS study of prophylaxis of postoperative endophthalmitis after cataract surgery; case for a European multicenter study; the ESCRS Endophthalmitis Study Group. J Cataract Refract Surg. 2006;32:396-406.
18. Barry P, Seal DV, Gettinby G, et al. ESCRS study of prophylaxis of postoperative endophthalmitis after cataract surgery; preliminary report of principal results from a European multicenter study; the ESCRS Endophthalmitis Study Group. J Cataract Refract Surg. 2006;32:407-410.
19. 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.
20. Montan PG, Wejde G, Setterquist H, et al. Prophylactic intracameral cefuroxime; evaluation of safety and kinetics in cataract surgery. J Cataract Refract Surg. 2002;28:982-987.
21. Han DP, Wisniewski SR, Wilson LA, et al. Spectrum and susceptibilities of microbiologic isolates in the Endophthalmitis Vitrectomy Study; the Endophthalmitis Vitrectomy Study Group. Am J Ophthalmol. 1996;122:1-17. correction, 920.
22. Benz MS, Scott IU, Flynn HW Jr, et al. Endophthalmitis isolates and antibiotic sensitivities: a 6-year review of culture-proven cases. Am J Ophthalmol. 2004;137:38-42.
23. Recchia FM, Busbee BG, Pearlman RB, et al. Changing trends in the microbiologic aspects of postcataract endophthalmitis. Arch Ophthalmol. 2005;123:341-346.
24. von Eiff C, Friedrich AW, Becker K, Peters G. Comparative in vitro activity of ceftobiprole against staphylococci displaying normal and small-colony variant phenotypes. Antimicrob Agents Chemother. 2005;49:4372-4374.
25. Noviello S, Ianniello F, Leone S, Esposito S. Comparative activity of garenoxacin and other agents by susceptibility and time-kill testing against Staphylococcus aureus, Streptococcus pyogenes and respiratory pathogens. J Antimicrob Chemother. 2003;52:869-872.
26. Kazakova SV, Hageman JC, Matava M, et al. A clone of methicillin-resistant Staphylococcus aureus among professional football players. N Engl J Med. 2005;352:468-475.
27. Stratton CW, Liu C, Weeks LS. Activity of LY146032 compared with that of methicillin, cefazolin, cefamandole, cefuroxime, ciprofloxacin, and vancomycin against staphylococci as determined by kill-kinetic studies. Antimicrob Agents Chemother. 1987;31:1210-1215.
28. Gupta MS, McKee HDR, Saldaña M, Stewart OG. Macular thickness after cataract surgery with intracameral cefuroxime. J Cataract Refract Surg. 2005;31:1163-1166.
29. Koul S, Philipson A, Philipson B, et al. Intraocular levels of cefuroxime in uninflamed rabbit eyes. Acta Ophthalmol (Copenh). 1990;68:455-465.
30. Lin RY. A perspective on penicillin allergy. Arch Intern Med. 1992;152:930-937.
31. Anne S, Reisman RE. Risk of administering cephalosporin antibiotics to patients with histories of penicillin allergy. Ann Allergy Asthma Immunol. 1995;74:167-170.
32. Pumphrey RSH, Davis S. Under-reporting of antibiotic anaphylaxis may put patients at risk. Lancet. 1999;353:1157-1158.
33. Berrocal AM, Schuman JS. Subconjunctival cephalosporin anaphylaxis. Ophthalmic Surg Lasers. 2001;32:79-80.
34. Villada JR, Vicente U, Javaloy J, Alió JL. Severe anaphylactic reaction after intracameral antibiotic administration during cataract surgery. J Cataract Refract Surg. 2005;31:620-621.
35. Trissel LA. 2001. Handbook on Injectable Drugs, 11th ed. American Society of Health-System Pharmacists, Bethesda, MD.
36. Mah FS. Fourth-generation fluoroquinolones: new topical agents in the war on ocular bacterial infections. Curr Opin Ophthalmol. 2004;15:316-320.
37. Wright DH, Brown GH, Peterson ML, Rotschafer JC. Application of fluoroquinolone pharmacodynamics. J Antimicrob Chemother. 2000;46:669-683.
38. Kowalski RP, Dhaliwal DK, Karenchak LM, et al. Gatifloxacin and moxifloxacin: an in vitro susceptibility comparison to levofloxacin, ciprofloxacin, and ofloxacin using bacterial keratitis isolates. Am J Ophthalmol. 2003;136:500-505.
39. Bauernfeind A. Comparison of the antibacterial activities of the quinolones Bay 12-8039, gatifloxacin (AM 1155), trovafloxacin, clinafloxacin, levofloxacin and ciprofloxacin. J Antimicrob Chemother. 1997;40:639-651.
40. Mather R, Karenchak LM, Romanowski EG, Kowalski RP. Fourth generation fluoroquinolones: new weapons in the arsenal of ophthalmic antibiotics. Am J Ophthalmol. 2002;133:463-466.
41. Yang S-C, Hsueh P-R, Lai H-C, et al. High prevalence of antimicrobial resistance in rapidly growing mycobacteria in Taiwan. Antimicrob Agents Chemother. 2003;47:1958-1962.
42. Doern GV. Antimicrobial use and the emergence of antimicrobial resistance with Streptococcus pneumoniae in the United States. Clin Infect Dis. 2001;33(suppl 3):S187-S192.
43. Hwang DG. Fluoroquinolone resistance in ophthalmology and the potential role for newer ophthalmic fluoroquinolones. Surv Ophthalmol. 2004;49(suppl 2):S79-S83.
44. Mah FS. New antibiotics for bacterial infections. Ophthalmol Clin North Am. 2003;16(1):11-27.
45. Schentag JJ, Gilliland KK, Paladino JA. What have we learned from pharmacokinetic and pharmacodynamic theories? Clin Infect Dis. 2001;32(suppl 1):S39-S46.
46. Katz HR, Masket S, Lane SS, et al. Absorption of topical moxifloxacin ophthalmic solution into human aqueous humor. Cornea. 2005;24:955-958.
47. Levine JM, Noecker RJ, Lane LC, et al. Comparative penetration of moxifloxacin and gatifloxacin in rabbit aqueous humor after topical dosing. J Cataract Refract Surg. 2004;30:2177-2182.
48. Solomon R, Donnenfeld ED, Perry HD, et al. Penetration of topically applied gatifloxacin 0.3%, moxifloxacin 0.5%, and ciprofloxacin 0.3% into the aqueous humor. Ophthalmology. 2005;112:466-469.
49. McCulley JP, Caudle D, Aronowicz JD, Shine WE. Fourth-generation fluoroquinolone penetration into the aqueous humor in humans. Ophthalmology. 2006;113:955-959.
50. Wagner RS, Abelson MB, Shapiro A, Torkildsen G., 2005. Evaluation of moxifloxacin, ciprofloxacin, gatifloxacin, ofloxacin, and levofloxacin concentrations in human conjunctival tissue [letter], Arch Ophthalmol, 123, 1282-1283.
51. Robertson SM, Curtis MA, Schlech BA, et al. Ocular pharmacokinetics of moxifloxacin after topical treatment of animals and humans. Surv Ophthalmol. 2005;50(suppl 1):S32-S45.
52. Hariprasad SM, Blinder KJ, Shah GK, et al. Penetration pharmacokinetics of topically administered 0.5% moxifloxacin ophthalmic solution in human aqueous and vitreous. Arch Ophthalmol. 2005;123:39-44.
53. Kim DH, Stark WJ, O'Brien TP, Dick JD. Aqueous penetration and biological activity of moxifloxacin 0.5% ophthalmic solution and gatifloxacin 0.3% solution in cataract surgery patients. Ophthalmology. 2005;112:1992-1996.
54. Mather R, Stewart JM, Prabriputaloong T, et al. The effect of cataract surgery on ocular levels of topical moxifloxacin. Am J Ophthalmol. 2004;138:554-559.
55. Dong Y, Zhao X, Domagala J, Drlica K. Effect of fluoroquinolone concentration on selection of resistant mutants of Mycobacterium bovis BCG and Staphylococcus aureus. Antimicrob Agents Chemother. 1999;43:1756-1758.
56. Price FW Jr, Dobbins K, Zeh W. Penetration of topically administered ofloxacin and trimethoprim into aqueous humor. J Ocular Pharmacol Ther. 2002;18:445-453.
57. Bucci FA Jr. An in vivo study comparing the ocular absorption of levofloxacin and ciprofloxacin prior to phacoemulsification. Am J Ophthalmol. 2004;137:308-312.
58. McGee DH, Holt WF, Kastner PR, Rice RL. Safety of moxifloxacin as shown in animal and in vitro studies. Surv Ophthalmol. 2005;50(suppl 1):S46-S54.
59. Donaldson KE, Marangon FB, Schatz L, et al. The effect of moxifloxacin on the normal human cornea. Curr Med Res Opin. 2006;22:2073-2080.
60. Kovoor TA, Kim AS, McCulley JP, et al. Evaluation of the corneal effects of topical ophthalmic fluoroquinolones using in vivo confocal microscopy. Eye Contact Lens. 2004;30:90-94.
61. Durrie DS, Trattler W. A comparison of therapeutic regimens containing moxifloxacin 0.5% ophthalmic solution and gatifloxacin 0.3% ophthalmic solution for surgical prophylaxis in patients undergoing LASIK or LASEK. J Ocul Pharmacol Ther. 2005;21:236-241.
62. Burka JM, Bower KS, Vanroekel C, et al. The effect of fourth-generation fluoroquinolones gatifloxacin and moxifloxacin on epithelial healing following photorefractive keratectomy. Am J Ophthalmol. 2005;140:83-87.
63. Kowalski RP, Romanowski EG, Mah FS, et al. Topical prophylaxis with moxifloxacin prevents endophthalmitis in a rabbit model. Am J Ophthalmol. 2004;138:33-37.
64. Kowalski RP, Romanowski EG, Mah FS, et al. Intracameral Vigamox® (moxifloxacin 0.5%) is non-toxic and effective in preventing endophthalmitis in a rabbit model. Am J Ophthalmol. 2005;140:497-504.
65. Gao H, Pennesi ME, Qiao X, et al. Intravitreal moxifloxacin: retinal safety study with electroretinographic and histopathology in animal models. Invest Ophthalmol Vis Sci. 2006;47:1606-1611.
66. 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.
67. Kleinmann G, Larson S, Neuhann IM, et al. Intraocular concentrations of gatifloxacin and moxifloxacin in the anterior chamber via diffusion through the cornea using collagen shields. Cornea. 2006;25:209-213.
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