• 45 chapter Antibiotics

vancomycin and ceftazadime. Topical vancomycin, amikacin, and cycloplegics were administered in all patients as well.1

Patients were randomized to the following groups: (1) three-port pars plana vitrectomy with IV antibiotics (ceftazadime and amikacin);

(2) three-port pars plana vitrectomy without IV antibiotics; (3) vitreous tap with IV antibiotics; and (4) vitreous tap without IV antibiotics.1

The EVS found no difference in outcomes between immediate threeport pars plana vitrectomy versus vitreous tap/biopsy for patients with hand motion or better vision. For patients with a presenting visual acuity of only light perception, much better visual results occurred in the immediate three-port pars plana vitrectomy group versus the vitreous tap/biopsy group. These patients were three times more likely to achieve greater than 20/40 vision (33% versus 11%), twice as likely to achieve greater than 20/100 vision (56% versus 30%), and less likely to incur vision less than 5/200 (20% versus 47%). No difference in final visual acuity or media clarity was experienced whether or not systemic antibiotics were employed.1

Confirmed bacterial growth isolates were more likely to be positive in the vitreous compared to aqueous specimens. Figure 45.1 demonstrates that 94.2% of confirmed growth isolates were Gram-positive organisms (the vast majority due to one organism alone: Staphylococcus

70%

Gram-positve coagulase-negative organisms

(Staphylococcus

epidermidis)

Figure 45.1  Endophthalmitis Vitrectomy Study-confirmed growth isolates. Reproduced from Endophthalmitis Vitrectomy Study Group. Results of the Endophthalmitis Vitrectomy Study: a randomized trial of immediate vitrectomy and of intravenous antibiotics for the treatment of postoperative bacterial endophthalmitis. Arch Ophthalmol 1995; 113:1479–1496, with permission.

HN

Gatifloxacin

Figure 45.2  Structures of gatifloxacin and moxifloxacin.

epidermidis, 70%). Gram-negative organisms only comprised 5.9% of confirmed growth isolates. At the time of the EVS, all Grampositive organisms were sensitive to vancomycin. However, 2 of 19 Gram-negative organisms were resistant to both amikacin and ceftazadime.5–8

A subset analysis of diabetic patients included in the EVS resulted in two interesting findings. First, diabetes was associated with a higher yield of S. epidermidis. Secondly, only 39% of diabetic patients had a final visual outcome of greater than 20/40 versus 55% of nondiabetic patients. As a group, diabetic patients fared worse and attained a less desirable visual outcome compared to nondiabetic patients.1

The EVS answered some of the most controversial issues surrounding endophthalmitis management at the time. It was a very welldesigned study that utilized antibiotics that were the best available in the early 1990s. Additionally, the EVS has taught us valuable information regarding the spectrum of infecting organisms in postoperative endophthalmitis. The EVS clearly was a landmark study which provided ophthalmologists with evidence-based outcomes and strategies to manage postoperative endophthalmitis.

POTENTIAL NEW TREATMENT REGIMENS

TOPICAL FLUOROQUINOLONES

While topical antibiotics were not specifically studied in the EVS, they may soon play an increasingly important role in the management and prophylaxis of ocular infection. In the early 1990s, topical ciprofloxacin was released as the first ophthalmic fluoroquinolone – this agent was embraced by corneal, cataract, and refractive surgeons as a powerful weapon against ocular infection. Other topical fluoroquinolones were subsequently released; however, some of our most powerful weapons have lost a portion of their effect due to increasing levels of resistant organisms each year, especially against the Gram-positive organisms. A serious clinical problem could arise if current trends of resistance to older-generation fluoroquinolones continue. The rise in resistant organisms has challenged empiric monotherapy, creating the need for newer topical antibiotics with a broader spectrum of coverage and less risk for resistance.

During the spring of 2003, topical gatifloxacin 0.3% (Zymar, Allergan Pharmaceuticals) and topical moxifloxacin 0.5% (Vigamox, Alcon Laboratories) were released for clinical use (Figure 45.2). These fourthgeneration fluoroquinolones have been engineered to be effective against a number of currently resistant organisms; thus, theoretically they should be able to delay the development of new resistant strains more effectively than their older-generation predecessors. Concerns, however, have recently been raised regarding the development of resistant strains of staphylococcal endophthalmitis isolates to topical fourthgeneration fluoroquinolones, specifically in the last 5 years.8

O

H

HN N

N

OCH3

H

Moxifloxacin

The structure of gatifloxacin and moxifloxacin gives these drugs the capacity to delay resistance through a two-pronged approach that inhibits both the prokaryotic DNA gyrase and topoisomerase IV. The structure increases hydrophobicity, which decreases resistance due to efflux pumps. Overall, the fourth-generation fluoroquinolones have enhanced Gram-positive and atypical coverage while retaining Gram-negative coverage essentially identical to the older-generation flurorquinolones.9,10

Topical fourth-generation fluoroquinolones are poised to be a powerful weapon for the corneal, cataract, and refractive surgeon for various anterior-segment indications. Unfortunately, there are limited data regarding the intraocular penetration of these new-generation agents in humans. Several prior studies of earlier-generation agents have demonstrated that topically administered agents do not achieve adequate intraocular concentrations to be effective against the pathogens most commonly responsible for bacterial endophthalmitis.11

We completed two investigations to determine the intraocular penetration of moxifloxacin 0.5% in humans to see if therapeutic concentrations of drug could be achieved in the aqueous and vitreous after topical or collagen shield route administration.12,13 In these studies we obtained aqueous and vitreous samples in noninflamed eyes after topical or collagen shield administration of moxifloxacin 0.5%.

In the topical study, moxifloxacin was administered either every 2 hours (Q2H) or every 6 hours (Q6H), for 3 days prior to surgery. We found that mean moxifloxacin concentrations in the Q2H group for aqueous (n = 9) and vitreous (n = 10) were 2.28 ± 1.23 and 0.11 ± 0.05 g/ ml, respectively. Mean moxifloxacin concentrations in the Q6H group for aqueous (n = 10) and vitreous (n = 9) were 0.88 ± 0.88 and 0.06 ± 0.06 g/ml, respectively (Figure 45.3). MIC90 levels were far exceeded in the aqueous for a wide spectrum of key pathogens. Concentration of moxifloxacin in the vitreous did exceed the MIC90 for several organisms; however, the MIC50 (minimum inhibitory concentration of antibiotic required to kill 50% of isolates) was exceeded in the Q2H group for Staphylococcus epidermidis, S. aureus, Streptococcus pneumoniae, Haemophilus influenzae, Bacillus cereus, and other Gram-negatives.

In the second study, delivery of moxifloxacin via a collagen shield revealed a mean aqueous concentration of 0.30 ± 0.17 g/ml 4 hours after placement (n = 5). Vitreous levels at 4 hours and aqueous and vitreous levels at 24 hours were negligible using this route of administration. Peak aqueous moxifloxacin levels occurred soon after shield placement. Theoretically this is when high concentrations of moxifloxacin are most needed to clear the aqueous of bacteria. The MIC90 levels were exceeded for organisms commonly responsible for endophthalmitis in the 4-hour aqueous group; however, negligible concentrations of moxifloxacin were detected at 24 hours. Although aqueous moxifloxacin levels achieved through the use of a collagen shield delivery device are lower than via topical drops, there are several advantages to this route of delivery that make it appealing in the immediate postoperative period.

Figure 45.3  Intraocular concentrations of moxifloxacin after topical administration. Q2H, one drop every 2 hours for 3 days; Q6H, one drop every 6 hours for 3 days. Reproduced from 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, with permission.

Further studies will determine the precise role of topical and collagen shield administration of moxifloxacin 0.5% in the management and/or prophylaxis of intraocular infections. These data may be of significance when considering antibiotic prophylaxis against the development of infection in settings such as after ocular surgery and after intravitreal injections.

ORAL AND INTRAVENOUS ANTIBIOTICS

While intravitreal antibiotic injections are clearly the most effective way to achieve therapeutic antibiotic levels in the vitreous, using certain orally administered antibiotics can be a potential alternative/adjunct as they have been shown to achieve vitreous concentrations exceeding the MIC90 level for the organisms most commonly involved in bacterial endophthalmitis. Hence, use of oral antibiotics has important implications for the ophthalmologist, particularly in the prophylaxis and/or management of postoperative, posttraumatic, or bleb-associated bacterial endophthalmitis.

As previously noted, the EVS investigated the use of IV amikacin and ceftazidime in conjunction with intravitreal antibiotic injection for managing acute postoperative endophthalmitis and found no improved outcomes with the use of systemic antibiotics.1 According to later published studies, amikacin and ceftazidime were found to have very limited intravitreal penetration.2,3 Therefore, the only conclusion which can be inferred from the EVS data regarding systemic antibiotic use is that IV amikacin and ceftazidime specifically have no apparent role in managing postoperative endophthalmitis. Therefore, do EVS data still apply, given the recent advancements in the development of antimicrobials? The answer is: most likely not.

Over the past 10 years there has been mounting evidence in the literature that agents in the fluoroquinolone class of antibiotics are able to achieve effective concentrations in the vitreous after oral administration (Table 45.1).14–19 Our group has reported that orally administered gatifloxacin (Tequin, Bristol-Myers Squibb) can achieve therapeutic aqueous and vitreous levels in the noninflamed human eye and the activity spectrum appears to encompass appropriately the most frequently encountered bacterial species involved in the various causes of endophthalmitis.14,15 The fourth-generation fluoroquinolones, gatifloxacin and moxifloxacin, have high oral bioavailability of greater than 90% and reach peak plasma concentrations 1–2 hours after oral dosing. Both are well tolerated with minimal side-effects.

We designed a prospective, nonrandomized clinical study of 24 patients scheduled for elective pars plana vitrectomy surgery to investigate the aqueous and vitreous concentration of gatifloxacin achieved after oral administration of two 400 mg tablets taken 12 hours apart before surgery. The percentages of plasma gatifloxacin concentration achieved in the vitreous and aqueous were 26.17% and 21.02%, respectively. Mean inhibitory vitreous and aqueous MIC90 levels were achieved against a wide spectrum of bacteria (e.g., the vitreous concentration of gatifloxacin achieved with this dosing regimen exceeded the MIC90 for Staphylococcus epidermidis by over fivefold).

Garcia-Saenz and colleagues reported that orally administered moxifloxacin (Avelox, Bayer) can achieve therapeutic levels in the human aqueous; however, vitreous concentration data were not obtained in this study.17 To address this, we designed a second prospective, nonrandomized clinical study of 15 patients scheduled for elective pars plana vitrectomy surgery to investigate the aqueous and vitreous concentration of moxifloxacin achieved after oral administration of two 400 mg tablets taken 12 hours apart before surgery. The percentages of plasma moxifloxacin concentration achieved in the vitreous and aqueous were 37.6% and 44.3%, respectively. Mean inhibitory vitreous and aqueous MIC90 levels were achieved against a wide spectrum of bacteria.18

Moxifloxacin has an inherent advantage over gatifloxacin for Grampositive organisms. Table 45.1 reviews the mean vitreous penetration of several fluoroquinolones along with their respective MIC90 levels for the organisms we are most concerned about in endophthalmitis. Upon reviewing this table, it is readily apparent that moxifloxacin has roughly 50% lower MIC90 levels compared to gatifloxacin for Gram-positives. Although our studies have shown similar vitreous

Diseases Retinal in Mechanisms and Drugs • 4 section

• 45 chapter Antibiotics

Diseases Retinal in Mechanisms and Drugs • 4 section

• 45 chapter Antibiotics