Untitled

PEER REVIEW
Prophylactic Intracameral
Antibiotics in Cataract Surgery
Editor: Ming Wang, MD, PhD, Clinical
Reviewer: Baseer U. Khan, MD, FRCS(C), fellow of
glaucoma and anterior segment at the University of Director of the Wang Vision Institute inNashville, Tennessee Panel Members: Y. Ralph Chu, MD; Nina Goyal, MD;
Wei Jiang, MD; Baseer Khan, MD; Patty Lin, MD, MBA;
Co-Editor: Tracy Swartz, OD, MS,
Gregory J. McCormick, MD; Lav Panchal, MD; Jay S. Pepose, MD, PhD; Paul Sanghera, MD; Vision Institute in Nashville, Tennessee Postoperative infectious endophthalmitis is a feared and devastating complication of cataract surgery. Although advances in surgical techniques and instrumentation during the last 20 years have reduced its incidence, postopera- tive infectious endophthalmitis following phacoemulsification continues to occur at a frequency of 0.1% or less.1,2 Because this pathologic condition is rare, its relative infrequency has made it virtually impossible to design and con- duct randomized, controlled trials that will produce uniform guidelines for cataract surgeons to abide by in order to further minimize the complication. In the absence of evidence-based guidelines, surgeons derive treatment algorithms and practices from empirical observations and theoretical analysis to reduce the risk of the infection in patients.
Interestingly, although the role of prophylactic antibiotics in “clean cases” continues to be debated in other surgical specialties, there is virtual unanimity among cataract surgeons in advocating antibiotic prophylaxis following uncom- plicated cataract surgery.3 More accurately, the debate in the ophthalmic community has focused on the timing and delivery of prophylaxis—pre-, intra- and/or postoperatively, via drops or intracameral instillation. The last can be deliv- ered either through the irrigating solution or injected as a bolus at the conclusion of the case. This article will attempt to review some recent findings in the literature highlighting arguments for and against the use of prophylactic intra- cameral antibiotics while focusing specifically on vancomycin and cefuroxime. The following articles were reviewed: 1. Gimbel HV, Sun R, DeBroff BM. Prophylactic intracameral antibiotics during cataract surgery: the incidence of endoph- thalmitis and corneal endothelial loss. Eur J Implant Refract Surg. 1994;6:280-285. 2. Montan PG, Wejde G, Koranyi G, Rylander M. Prophylactic intracameral cefuroxime. Efficacy in preventing endophthalmi- tis after cataract surgery. J Cataract Refract Surg. 2002;28:977-981. 3. Liesegang TJ. Use of antimicrobials to prevent postoperative infection in patients with cataracts. Curr Opin Ophthalmol.
4. Han DP, Wisniewski SR, Wilson LA, et al. Spectrum and susceptibilities of microbiologic isolates in the Endophthalmitis Vitrectomy Study. Am J Ophthalmol. 1996;122:1-17. 5. Wejde G, Montan P, Lundstrom M, et al. Endophthalmitis following cataract surgery in Sweden: national prospective sur- vey 1999-2001. Acta Ophthalmol Scand. 2005;83:7-10. 6. Gordon YJ. Vancomycin prophylaxis and emerging resistance: are ophthalmologists the villains? The heroes? Am J NOVEMBER/DECEMBER 2005 I CATARACT & REFRACTIVE SURGERY TODAY I 31
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7. Libre PE, Della-Latta P, Chin NX. Intracameral antibiotic agents for endophthalmitis prophylaxis: a pharmacokinetic model. J Cataract Refract Surg. 2003;29:1791-1794. 8. Axer-Siegel R, Stiebel-Kalish H, Rosenblatt I, et al. Cystoid macular edema after cataract surgery with intraocular van- comycin. Ophthalmology. 1999;106:1660-1664. 9. 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. 10. Gupta MS, McKee HD, Saldana M, Stewart OG. Macular thickness after cataract surgery with intracameral cefuroxime. J Cataract Refract Surg. 2005;31:1163-1166. 11. Mendivil Soto A, Mendivil MP. The effect of topical povidone-iodine, intraocular vancomycin, or both on aqueous humor cultures at the time of cataract surgery. Am J Ophthalmol. 2001;131:293-300. 12. Dickey JB, Thompson KD, Jay WM. Intraocular gentamicin sulfate and postcataract anterior chamber aspirate cultures. J Cataract Refract Surg. 1994;20:373-377. C AUSAT IVE PAT H OG ENS
against all gram-positive bacteria, but it is ineffective In order to select an appropriate antimicrobial agent, it against gram-negatives. Vancomycin has been adminis- is imperative to identify which organisms should be tar- tered via either infusion (concentrations of 10 to geted. Pathogens causing postoperative infectious en- 50µg/mL)6-8 or in the capsular bag (up to 1mg/mL).1 dophthalmitis are thought to originate mostly from the More recently, cefuroxime has been proposed and used endogenous lid and conjunctival flora, but they may also as an intracameral prophylactic antibiotic. Cefuroxime is a arise from airborne contaminants, tainted intraocular second-generation cephalosporin that works by bacterioci- solutions, infected lenses or surgical instruments, and OR dal, beta-lactam action—inhibiting penicillin-binding pro- personnel.3 The Endophthalmitis Vitrectomy Study4 re- teins, which prevent cross-linking of peptidoglycan strands ported the growth of different organisms cultured from normally needed for the cell wall’s integrity and leads to 291 culture-positive intraocular specimens, the vast osmotic lysis of the bacterium. Cefuroxime provides less majority of which were found to be gram-positive, coagu- gram-positive coverage than vancomycin, while providing lase-negative micrococci (Tables 1 and 2). Of note, all some gram-negative coverage, notably against Haemophilus gram-positive cultures were found to be sensitive to van- influenzae, Escherichia coli, Klebsiella, and Proteus. It has only comycin. Although occurring much less frequently, gram- been described for intracameral injection (1mg).2,5,9 negative organisms have been found to be more virulentand to result in poorer visual outcomes.5 REVIEW OF EVIDENCE
Safety
CH OICE OF INTR AC A MER AL DRUGS
Because vancomycin and cefuroxime are not labeled for If the purpose of antibiotic prophylaxis is to clear an intracameral use, the burden of demonstrating their safe- inoculation of organisms introduced during surgery, ty rests with the treating surgeons.9 A review of the litera- then the antibiotic should be in the anterior chamber at ture finds no formal studies that have evaluated the safety the time of introduction or shortly thereafter.3 The of intracameral vancomycin in humans. There are empiri- intracameral administration of antibiotics provides the cal reports1 of doses greater than 2000µg/mL being used greatest intraocular bioavailability. Given the findings of safely in thousands of patients, which is much higher dose the Endophthalmitis Vitrectomy Study, the relative fre- than what is found in other studies. A retrospective analy- quency of gram-positive organisms, and their 100% sus- sis by Gimbal et al1 demonstrated that the average ceptibility to vancomycin, the drug is an attractive and endothelial cell count loss in these patients was equiva- viable option for intracameral antibiotic prophylaxis.
lent to that in patients not receiving intracameral antibi- Vancomycin is a bacteriocidal agent that works by bind- otics reported in other studies. One clinical trial demon- ing to the target of a peptidogylan precursor and blocks strated an almost threefold increase in the rate of cystoid both transglycolation and tranpeptidation. This action macular edema in eyes infused with 10µg/mL compared prevents polymerization of peptidoglycans, causes the with the control group; however, the results of this study loss of cell wall integrity, and finally results in autolysis were confounded by posterior capsular rupture, diabetes, of the bacterium.6 Vancomycin is highly effective 32 I CATARACT & REFRACTIVE SURGERY TODAY I NOVEMBER/DECEMBER 2005
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In contrast to vancomycin, the safety profile of cefuroxime that simulated decreasing vancomycin levels during an has been studied formally in an observer-masked, controlled 8-hour period, approximately four half-lives; demon- trial. Montan et al9 found that the intracameral instillation of strating a 1,000-fold reduction in the amount of methi- 1mg of cefuroxime at the completion of surgery did not sig- cillin-resistant Staphylococcus aureus colony-forming nificantly affect visual acuity, endothelial cell counts, flare, or units as compared with controls. In a retrospective the postoperative rates of cystoid macular edema. The last study, Gimbel et al1 reported on almost 12,000 surgeries has also been confirmed by optical coherence tomography without a single case of postoperative infectious en- of the macula in a separate study.10 Furthermore, Montan et dophthalmitis while utilizing a gentamycin infusion and al9 concluded that IgE hypersensitivity to cefuroxime was not a contraindication for its use intracamerally if patients were Despite the apparent reduction in culture-positive pretreated with oral antihistamines.
isolates, the fact that vancomycin-sensitive organismswere still present in the Mendivil and Mendivil11 study is Efficacy
indicative of vancomycin’s inability to achieve a com- The most convincing data to support the use of vanco- plete bacteriocidal effect, and yet there were no cases of mycin infusion come from Mendivil and Mendivil,11 who postoperative infectious endophthalmitis. This strongly reported a reduction in the culture-positive intraocular suggests that the pathogenicity of postoperative infec- aspirates from 13% to 5%, 2 hours after cataract surgery.
tious endophthalmitis is far more complicated than this All bacteria cultured were sensitive to vancomycin.
single variable.6 In fact, Dickey et al12 reported that 43% Furthermore, the investigators determined that 47% of of postoperative anterior chamber aspirates were cul- the initial concentration of vancomycin remained in the ture-positive, yet there was not a single case of postop- anterior chamber, significantly greater than the approxi- erative infectious endophthalmitis in the study; these mate 0.5- to 2.0-µg/mL minimum inhibitory concentra- results are indicative of eyes’ inherent ability to defend tion of most bacteria that are responsible for endoph- themselves against bacterial infections. Furthermore, thalmitis. The pharmacokinetics derived from this study the sole use of vancomycin leaves a small but significant were used to generate an in vitro model by Libre et al7 gap in its lack of coverage of gram-negative organisms.
TABLE 1. ENDOPHTHALMITIS VITRECTOMY STUDY SUMMARY OF PATHOGENS CAUSING POSTOPERATIVE
INFECTIOUS ENDOPHTHALMITIS BASED ON GRAM STAIN
Culture Type
Number of Cases (Percentage of Total)
Sensitivity to Vancomycin
*The total number of cases is less than the sum of each group due to polymicrobial cases. TABLE 2. ENDOPHTHALMITIS VITRECTOMY STUDY SUMMARY OF PATHOGENS CAUSING POSTOPERATIVE
INFECTIOUS ENDOPHTHALMITIS: BREAKDOWN OF GRAM-POSITIVE PATHOGENS
Type of Bacteria
Number of Cases (Percentage of Total) Sensitivity to Vancomycin
*The total number of cases is less than the sum of each group due to polymicrobial cases. NOVEMBER/DECEMBER 2005 I CATARACT & REFRACTIVE SURGERY TODAY I 33
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tively (P<0.001). In both the Montan et al9 study and TABLE 3. SWEDISH NATIONAL CATARACT
the Swedish survey,5 the proportion of enterococcus re- REGISTER SUMMARY OF PATHOGENS
sponsible for postoperative infectious endophthalmitis CAUSING POSTOPERATIVE INFECTIOUS
in culture-proven cases was significantly higher (38.0% ENDOPHTHALMITIS BASED ON GRAM STAIN
and 29.9%, respectively [Tables 3 and 4]) than thatfound in the Endophthalmitis Vitrectomy Study.4 These Type of Pathogen
Number of Cases
findings constitute a serious gap in the coverage of (Percentage of Total)
cefuroxime against gram-positive bacteria.
Resistance
The greatest opposition to the prophylactic use of intracameral vancomycin stems from concerns regard- ing increasing drug resistance. Vancomycin is typicallyused in bacterial infections that are life threatening orrecalcitrant to other antimicrobial therapies. In the TABLE 4. SWEDISH NATIONAL CATARACT
wake of increasing vancomycin resistance, the Centers REGISTER SUMMARY OF PATHOGENS CAUSING
for Disease Control and Prevention and the AAO jointly POSTOPERATIVE INFECTIOUS ENDOPHTHALMITIS:
issued a statement in 1999 discouraging the use of van- BREAKDOWN OF GRAM-POSITIVE PATHOGENS
comycin for surgical prophylaxis in cataract surgery.
Critics have pointed out that an intraocular dose of Type of Bacteria
Number of Cases
1mg, distributed over 40L of body water, is equivalent (Percentage of Total)
to a systemic dosage of 0.025µg/mL, which is much too low to affect an exposed organism’s survival and repro-duction. Thus, a 1-mg dose of vancomycin creates no pressure on an organism to develop resistance.7 Gordon6 surmised that, of the 12,000kg of vancomycinused in the US in 2000, only approximately 7.5kg were used for prophylaxis in cataract surgery, representing 0.07% of the total amount. He therefore concluded thatophthalmic usage would constitute an insignificant selection pressure for promoting vancomycin-resistant Evaluating cefuroxime, Montan et al9 reported bacteria. No commentary regarding cefuroxime resist- cefuroxime levels that exceeded the minimum inhibito- ry concentration for several relevant species for up to 5 hours after surgery, while acknowledging that it could BOT TOM LINE
not be automatically concluded that this presence was Given the relative infrequency of postoperative infectious sufficient to eradicate all the target contaminants. How- endophthalmitis, it is unlikely that a proper, evidence-based ever, clinically, Montan et al9 reported a drop in postop- algorithm will ever be developed to end the debate about erative infectious endophthalmitis from 0.26% to 0.06% antibiotic prophylaxis in cataract surgery. With respect to (P<.001) in 34,100 and 32,180 consecutive cases, respec- vancomycin, the evidence that is available is conflicting and tively, after introducing intracameral cefuroxime injec- inconclusive. The most notable opinion in this debate tions. When only phacoemulsification was evaluated, comes from the joint statement from the Centers for the difference was even more impressive; the rate of Disease Control and Prevention and the AAO, which dis- postoperative infectious endophthalmitis dropped from couraged the use of vancomycin for prophylaxis. Unlike vancomycin, cefuroxime has considerably more evidence to These findings were consistent with a national pro- support its usage as a prophylactic agent, in the form of a spective study conducted in Sweden, in which 95% of prospective survey from Sweden that included more than the total number of cataracts in Sweden were tracked 180,000 cases during a 3-year period. Whether or not these by the Swedish National Cataract Register, which found findings could be duplicated in North America is undeter- rates of postoperative infectious endophthalmitis to be mined. Until then, cataract surgeons will have to continue 0.22% and 0.053% in patients not receiving and receiv- to generate their own practice patterns based on their own ing intracameral antibiotics (98.5% cefuroxime), respec- experiences and extrapolations of the available literature. ■ 34 I CATARACT & REFRACTIVE SURGERY TODAY I NOVEMBER/DECEMBER 2005
Zyoptix® XP Microkeratome vs.
IntraLase: equivalent outcomes Reviewer
Baseer Khan, MD, states that he holds no financial interest in
demonstrate precision & predictability any product mentioned herein. Dr. Khan may be reached at(415) 258-8211; [email protected]. Panel Members
Y. Ralph Chu, MD, is Medical Director, Chu Vision Institute
in Edina, Minnesota. He states that he holds no financial interest in any product mentioned herein. Dr. Chu may be reached at (952) 835-1235; [email protected]. Nina Goyal, MD, is a resident in ophthalmology at the Rush University Medical Center in Chicago. She states that she holds no financial interest in any product mentioned herein. Dr. Goyal may be reached at (312) 942-5315; Wei Jiang, MD, is a resident in ophthalmology at the Jules Stein Eye Institute in Los Angeles. She states that she holds no financial interest in any product mentioned herein. Dr. Jiangmay be reached at (310) 825-5000; [email protected]. Patty Lin, MD, MBA, is a resident in ophthalmology at the Jules Stein Eye Institute in Los Angeles. She states that she holds no financial interest in any product mentioned herein. Dr. Lin may be reached at (310) 825-5000; [email protected]. flap creation, so I was particularly pleased to learn about Gregory J. McCormick, MD, is a cornea and refractive fellow the exceptional level of precision and predictability in flap at the University of Rochester Eye Institute in New York. He thickness of Bausch & Lomb’s new Zyoptix® XP states that he holds no financial interest in any product men- Microkeratome, at this year’s American Academy of tioned herein. Dr. McCormick may be reached at (585) 256- Ophthalmology. In the first controlled contralateral study 2569; [email protected]. involving 100 eyes at TTS Hospital in Singapore comparing Lav Panchal, MD, is a fellow at the Wang Vision Institute in the Zyoptix XP Microkeratome and the IntraLase® Nashville, Tennessee. He states that he holds no financial interest Femtosecond Device; the XP Microkeratome actually in any product mentioned herein. Dr. Panchal may be reached showed statistically significant improvement in accuracy at (917) 751-8651; [email protected]. in intended flap thickness, with an average flap thickness of Jay S. Pepose, MD, PhD, is Professor of Clinical Ophthal- 116um (120um head) versus 152um with the IntraLase set mology & Visual Sciences, Washington University School at 120um as measured by Ultrasound Pachymetry.2 The of Medicine, St. Louis. He states that he holds no financial standard deviation for both systems was essentially the interest in any product mentioned herein. Dr. Pepose may same with 16.1um for the XP Microkeratome and 16.2um be reached at (636) 728-0111; [email protected]. for IntraLase. Uncorrected and best corrected visual acuity Paul Sanghera, MD, is senior resident in ophthalmology in in high and low contrast conditions were equivalent at one the Department of Ophthalmology and Vision Sciences at month, however, 92% of the XP Microkeratome eyes were the University of Toronto. He states that he holds no finan- within +/-.50D of intended refraction versus 87% of the cial interest in any product mentioned herein. Dr. Sanghera IntraLase eyes. This study was good news to me; upgrading may be reached at (416) 666-7115; [email protected]. to the Zyoptix XP Microkeratome is cost effective without Renée Solomon, MD, is an ophthalmology fellow at Oph- compromising precision or predictability. thalmic Consultants of Long Island in New York. She states thatshe holds no financial interest in any product mentioned herein. 1 Cheng AC, Rao SK, Yu EY, et al. Reproducibility of corneal flap Dr. Solomon may be reached at [email protected]. thickness in laser in situ keratomileusis using the Hansatome Tracy Swartz, OD, MS, states that she holds no financial microkeratome. J Cataract Refract Surg 2001; 27:1712 interest in any product mentioned herein. She may be reached 2 Data on file at Bausch & Lomb at (615) 321-8881; [email protected]. Ming Wang, MD, PhD, states that he holds no financial interest in any product mentioned herein. He may be reachedat (615) 321-8881; [email protected].

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