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Ophthalmic Antibiotics and Antimicrobial Resistance
Ophthalmic Antibiotics and Antimicrobial Resistance A Randomized, Controlled Study of Patients Undergoing Intravitreal Injections Stephen J. Kim, MD, Hassanain S. Toma, MD Purpose: To determine whether repeated exposure of ocular and nasopharyngeal flora to ophthalmic antibiotics promotes antimicrobial resistance in patients undergoing intravitreal injections for choroidal neovascularization (CNV). Design: Prospective, randomized, controlled, clinical trial. Participants: Forty-eight eyes of 24 patients undergoing unilateral intravitreal injections for CNV. Methods: Patients were assigned randomly to 1 of 4 ophthalmic antibiotics (azithromycin 1%, ofloxacin 0.3%, gatifloxacin 0.3%, moxifloxacin 0.5%) to be used after each injection in the treatment eye only. Bilateral conjunctival and unilateral nasopharyngeal cultures on the treatment side were obtained at baseline and were repeated at each subsequent visit for 1 year. All bacterial isolates were tested for antibiotic susceptibility to 16 different antibiotics using the Kirby-Bauer disc diffusion technique. Genetic analysis of bacteria strains was performed using pulse-field gel electrophoresis. Main Outcome Measures: Changes in antibiotic susceptibility patterns of conjunctival and nasopharyngeal flora over time and emergence of resistant strains. Results: Eight subjects (33%) grew Staphylococcus aureus from the nasopharynx and 1 subject (13%) showed emergence of a resistant strain. Coagulase-negative staphylococci (CNS) cultured from eyes repeatedly exposed to fluoroquinolone antibiotics demonstrated significantly increased rates of resistance to third- and fourth-generation fluoroquinolones compared with untreated eyes. Resistance to ofloxacin and levofloxacin was roughly 85% (P ⫽ 0.003), and resistance to gatifloxacin and moxifloxacin approached 67% (P ⫽ 0.009) and 77% (P⬍0.001), respectively. In contrast, CNS isolated from eyes repeatedly exposed to azithromycin demonstrated significantly increased resistance (94%) to erythromycin and azithromycin when compared with control eyes (P ⫽ 0.009) and decreased resistance to third-generation (P⬍0.03) and fourth-generation (P⬍0.001) fluoroquinolones when compared with eyes exposed to fluoroquinolones. Conclusions: Repeated exposure of ocular and nasopharyngeal flora to ophthalmic antibiotics selects for resistant strains. Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references. Ophthalmology 2011;118:1358 –1363 © 2011 by the American Academy of Ophthalmology.
Age-related macular degeneration (AMD) is the leading cause of blindness among individuals older than 65 years in the United States and currently affects more than 8 million Americans.1 The overall prevalence of advanced AMD is projected to increase by more than 50% by the year 2020.2 Monthly intraocular injection of ranibizumab (Lucentis; Genentech, South San Francisco, CA) or off-labeled use of bevacizumab (Avastin; Genentech, South San Francisco, CA) has become the standard of care for the treatment of neovascular AMD.3,4 Consequently, the number of intraocular injections performed in the United States, estimated from Medicare procedure codes, has risen exponentially from fewer than 3000 per year in
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© 2011 by the American Academy of Ophthalmology Published by Elsevier Inc.
1999 to more than 1 million in 2008 and will continue to increase rapidly given the aging of the population and expanding applications.5 Endophthalmitis is the most severe complication after intraocular injection and results in substantial morbidity.6 Consequently, ophthalmic antibiotics are prescribed routinely after each injection by most treating eye specialists.7,8 Increasing resistance of normal ocular flora to older antibiotic classes in conjunction with widespread availability has led to more frequent use of fourth-generation fluoroquinolone antibiotics: gatifloxacin 0.3% (Zymar; Allergan Pharmaceuticals, Irvine, CA) and moxifloxacin 0.5% (Vigamox; Alcon, Fort Worth, TX),9,10 but ocular flora resistance to these antibiotics also may be increasing. ISSN 0161-6420/11/$–see front matter doi:10.1016/j.ophtha.2010.12.014
Kim and Toma 䡠 Ophthalmic Antibiotics and Antimicrobial Resistance Approximately 40% of a standard 50-l eye drop directly enters the highly vascular tear drainage apparatus and is absorbed by the nasopharyngeal mucosa.11 Staphylococcus aureus and Streptococcus pneumoniae colonize the nasopharynx of healthy individuals and are the most common cause of hospital-acquired and community-acquired pneumonia, respectively.12,13 Exposure to subinhibitory concentrations of antibiotic may promote resistance. Therefore, the repeated exposure of ocular and nasopharyngeal flora to ophthalmic antibiotics after intraocular injection may select for resistant bacterial strains. The Antibiotic Resistance of Conjunctiva and Nasopharynx Evaluation (ARCaNE) study is a randomized, controlled clinical study designed to determine changes in antibiotic resistance after repeated exposure of flora to ophthalmic antibiotics. Baseline resistance patterns of this study cohort already have been published.8 Herein are reported changes in antibiotic susceptibility and resistance over time.
Patients and Methods The Vanderbilt University Institutional Review Board approved this study, and all subjects gave informed consent before enrollment. The study complied with all aspects of the Health Insurance Portability and Accountability Act. The trial is registered at clinicaltrials.gov (identifier no. NCT00831961). Inclusion and exclusion criteria of the Antibiotic Resistance of Conjunctiva and Nasopharynx Evaluation study have been published previously.8 In brief, all adult patients 18 years of age or older with choroidal neovascularization (CNV) resulting from AMD or other causes in 1 eye only and planned treatment with intraocular injection were eligible for inclusion. Exclusion criteria consisted of previous intraocular injection in either eye, chronic use of ophthalmic medication, contact lens wear, ocular surgery, use of ophthalmic medications in either eye or ocular infection within the previous 3 months, use of systemic antibiotics within 30 days, and use of eye drops (e.g., artificial tears, saline solutions, vasoconstrictors) in either eye within 3 days of enrollment. As part of the study protocol, all enrolled patients received 4 consecutive monthly intraocular injections and then were treated as needed. Patients were assigned by permuted block randomization to 1 of 4 ophthalmic antibiotics: ofloxacin 0.3% (Ocuflox; Akorn, Inc., Somerset, NJ), azithromycin 1% (AzaSite; Inspire Pharmaceuticals, Inc., Durham, NC), gatifloxacin 0.3%, or moxifloxacin 0.5% and used only their assigned antibiotic after each injection. Before the application of any ophthalmic medication, conjunctival cultures of both eyes were obtained using the BBL CultureSwab collection and transport system (Becton, Dickinson and Co., Sparks, MD) in accordance with manufacturer instructions. Conjunctival cultures were obtained from the lower fornix in standardized fashion with every effort made to minimize contamination from the lids, lashes, or skin. Nasopharyngeal cultures were obtained on the same side as the treated eye with sterile calcium alginate swabs and were inoculated immediately onto 5% sheep blood media plates. Conjunctival culture swabs were inoculated onto 5% sheep blood and chocolate agar plates and were incubated with 5% carbon dioxide. All culture plates were incubated at 37° C for 3 days. Cultures were deemed positive if 1 or more colonyforming units were observed. For nasopharyngeal cultures, only S. aureus and S. pneumoniae were isolated if present.
All intraocular injections were performed in standard fashion after obtaining informed consent. Briefly, subconjunctival or topical anesthesia was administered and 5% Betadine (Alcon Laboratories, Inc., Fort Worth, TX) was applied to the ocular surface and lids. Betadine was reapplied, and immediately afterward, the drug was injected into the eye approximately 3.5 mm from the limbus using a 32-gauge needle. Patients were instructed carefully to start using their assigned antibiotic beginning on the day of their injection and continued for the next 4 consecutive days. Ofloxacin 0.3%, gatifloxacin 0.3%, and moxifloxacin 0.5% were administered as 1 drop 4 times daily, and azithromycin 1% was administered twice daily. All patients were given written instructions on use of their antibiotic after each treatment and also were supplied with new samples of their antibiotic to ensure compliance and to reduce the possibility of contamination. After baseline cultures were obtained (visit 0), the first injection was administered and all subjects returned in 4 weeks (visit 1), 8 weeks (visit 2), 12 weeks (visit 3), and 16 weeks (visit 4). At visits 1, 2, and 3, subjects were recultured and reinjected and then resumed use of their assigned ophthalmic antibiotic. At visit 4, all subjects were recultured, but continued treatment was determined on an individual basis. If subjects were reinjected at visit 4, then they resumed use of their assigned antibiotic and were recultured at their next return appointment (visit 5). Some study participants received monthly injections throughout the 1-year of follow-up, and thus had as many as 13 culture results (baseline plus visits 1–12), whereas others had the minimum of 5 culture results (baseline plus visits 1– 4). To test resistance, the Kirby-Bauer disc diffusion technique was conducted in strict accordance with guidelines of the National Committee for Clinical Laboratory Standards. The following antibiotics were tested on all culture samples with positive results: amoxicillin/clavulanate, cefazolin, cefoxitin, erythromycin, azithromycin, ofloxacin, levofloxacin, gatifloxacin, moxifloxacin, trimethoprim/sulfamethoxazole, rifampin, gentamicin, doxycycline, linezolid, clindamycin, and vancomycin. The diameter of zone of inhibition was recorded and used to determine susceptibility. Resistance to cefoxitin was considered equivalent to methicillin resistance.14 Identification of bacteria strains was performed by gram staining and testing for the presence or absence of catalase and coagulase/agglutination. The API Staph kit (bioMérieux, Hazelwood, MO) was used further to speciate coagulase-negative staphylococci (CNS). Genetic analysis was performed using the well-established technique of pulse-field gel electrophoresis following restriction digest with SmaI (ARUP Laboratories, Salt Lake City, UT). Pulsefield gel electrophoresis involves use of restriction enzymes that selectively cleave (fragment) DNA at locations unique to each strain of bacteria, resulting in fragments of differing lengths. The DNA fragments then are run on a gel to create a so-called fingerprint of each strain of bacteria. Relatedness was determined on the basis of criteria developed by Bannerman et al15 and Tenover et al.16 Genetic analysis was performed on selected series of strains for which a change or lack of change in antibiotic susceptibility was potentially important.
Statistical Analysis Descriptive statistics, including mean, were calculated for case characteristics. Percentages were calculated for antibiotic susceptibility. Group comparisons were performed with the Fisher exact test. A P value of less than 0.05 was considered significant.
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Ophthalmology Volume 118, Number 7, July 2011 Table 1. Baseline Demographics of 24 Patients Receiving Unilateral Intraocular Injection for Choroidal Neovascularization Azithromycin
Ofloxacin
Gatifloxacin
Moxifloxacin
6 75 (42–86)
6 75 (64–83)
6 69 (49–86)
6 82 (68–97)
0 2
0 2
0 2
0 2
No. Age (range), yrs Nasopharyngeal flora Streptococcus pneumonia Staphylococcus aureus Indications for treatment, % AMD Myopic degeneration Ocular histoplasmosis Idiopathic Previous surgery in treatment eye, % Cataract surgery Glaucoma surgery Retinal surgery Corneal surgery Refractive surgery
5 (83) 0 0 1 (17)
5 (83) 1 (17) 0 0
4 (67) 1 (17) 1 (17) 0
6 (100) 0 0 0
4 (67) 0 0 0 0
3 (50) 0 0 0 1 (17)
3 (50) 0 0 0 0
3 (50) 0 0 0 0
AMD ⫽ age-related macular degeneration.
Results Baseline characteristics of the study cohort are summarized in Table 1. A total of 24 subjects were enrolled from February 2009 through November 2009, with a total of 6 patients randomized to each antibiotic. The average age of the cohort was 75 years (range, 42–97 years). No patient had a history of prior intraocular injection in either eye. Most patients (83%) were undergoing treatment for AMD. Among the 24 baseline nasopharyngeal cultures, no isolates of S. pneumoniae were identified, but 8 (33%) subjects showed positive results for S. aureus. One subject, who was randomized to moxifloxacin, had S. aureus that was sensitive to all 16 antibiotics and remained sensitive through visit 2 (Fig 1). However, by visit 4, genetic analysis demonstrated the emergence of a different strain of S. aureus that was resistant to ofloxacin, levofloxacin, and moxifloxacin and that showed intermediate resistance to gatifloxacin. Furthermore, this fluoroquinolone-resistant strain also was resistant to macrolides (azithromycin and erythromycin), and clindamycin and was the only strain isolated from the subject’s nasopharynx on subsequent visits. A total of 37 of the 57 bacterial isolates cultured from the conjunctiva from both eyes of 24 study participants at baseline were CNS, with most (73%) being Staphylococcus epidermidis. Of these 37 baseline CNS isolates, 23 were collected from eyes that had active CNV and received treatment. The antibiotic susceptibility of these 23 CNS isolates is shown in Figure 2 (available at http://aaojournal.org). Resistance to erythromycin and azithromycin was 57% and 65%, respectively, and resistance to ofloxacin and levofloxacin was 57% and approached 52% (43% resistant; 9% intermediate), respectively. Resistance to gatifloxacin and moxifloxacin approached 39% and 34%, respectively. Treated eyes randomized to fluoroquinolones demonstrated increased CNS resistance to fluoroquinolones that was observed as early as visit 1, but became more evident by visit 3. At this time point, resistance to both ofloxacin and levofloxacin approached 83%, whereas resistance to gatifloxacin and moxifloxacin roughly doubled from baseline levels approaching 66% (P ⫽ 0.28) and 75% (P ⫽ 0.07), respectively. Interestingly, resistance to both macrolides decreased sharply from 60% at baseline to 33% at visit 3. In contrast, CNS from eyes exposed to azithromycin showed increased resistance to both macrolides (80%) and decreased
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resistance to second-generation (ofloxacin; 40%), third-generation (levofloxacin; 20%), and fourth-generation (gatifloxacin and moxifloxacin; 0%) fluoroquinolones. Fourteen CNS isolates were cultured from untreated (control) eyes at baseline. Fifty percent of these isolates were resistant to macrolides, whereas resistance to ofloxacin and levofloxacin approached 43% and resistance to gatifloxacin and moxifloxacin approached 21% and 35%, respectively (data not shown). A total of 70 CNS isolates subsequently were cultured from control eyes from visit 1 to 4. Overall, these 70 CNS isolates did not demonstrate significant differences in fluoroquinolone or macrolide resistance when compared with the 14 CNS isolates identified at baseline (Fig 3). In contrast, 48 CNS isolates were cultured from treated eyes (visit 1 to 4) exposed to fluoroquinolones and demonstrated significantly increased rates of resistance to second, third, and fourth-generation fluoroquinolones compared with control eyes. Resistance to ofloxacin and levofloxacin was roughly 85% (P ⫽ 0.003), and resistance to gatifloxacin and moxifloxacin approached 67% (P ⫽ 0.009) and 77% (P⬍0.001), respectively. Seventeen CNS isolates were identified in total (visit 1 to 4) from eyes exposed to azithromycin and demonstrated significantly increased resistance to macrolides (94%; P ⫽ 0.009) when compared with control eyes and decreased resistance to ofloxacin (59%; P ⫽ 0.029), levofloxacin (35%; P⬍0.001), gatifloxacin (0%; P⬍0.001), and moxifloxacin (13%; P⬍0.001) when compared with fluoroquinolone-exposed eyes. Emergence of resistant strains occurred rapidly in the conjunctiva of subjects with bacteria flora susceptible to their assigned antibiotic, but not in subjects with bacteria flora resistant to their assigned antibiotic. One representative subject, randomized to moxifloxacin, had a fluoroquinolone-sensitive strain of S. epidermidis that rapidly became supplanted by a fluoroquinolone-resistant strain of S. epidermidis (Fig 4, available at http://aaojournal.org). In contrast, 1 subject randomized to azithromycin had an azithromycin-resistant strain of S. epidermidis at baseline and continued to regrow this same strain on subsequent visits. All CNS isolates resistant to gatifloxacin or moxifloxacin also were resistant to ofloxacin and levofloxacin, indicating high levels of cross-resistance between fourth- and older-generation fluoroquinolone antibiotics. One subject, randomized to ofloxacin and with fluoroquinolone-sensitive CNS at baseline, subsequently
Kim and Toma 䡠 Ophthalmic Antibiotics and Antimicrobial Resistance
Figure 1. Antibiotic susceptibility and genetic fingerprint analysis of Staphylococcus aureus isolated from the nasopharynx of 1 subject randomized to moxifloxacin. Restriction enzyme digest of S. aureus DNA (left gel) demonstrates identical pattern of DNA fragments from isolates collected on visits 0, 1, and 2. This strain of S. aureus is sensitive to all 16 antibiotics tested (top right graph). Emergence of a different strain (left gel) of S. aureus (note change in genetic fingerprint pattern) is first observed at visit 4, and this new strain is resistant to fluoroquinolones, macrolides, and clindamycin (bottom right graph). S. aureus was not isolated on visit 3. Amox/Clav ⫽ amoxicillin/clavulanate; TMP/SMZ ⫽ trimethoprim/sulfamethoxazole.
grew CNS resistant to all fluoroquinolones tested. This high level of cross-resistance explains the increasing rate of levofloxacin resistance observed in this study despite absence of exposure.
Discussion Age-related macular degeneration is the leading cause of blindness in individuals older than 65 years, and its prevalence is rising. The advent of ranibizumab and bevacizumab has been a remarkable advance for the treatment of neovascular AMD, but is itself not curative and requires long-term, often monthly, administration by intraocular injection.3,4 Endophthalmitis is the most severe complication after intraocular injection, and consequently more than 80% of treating eye specialists use ophthalmic antibiotics after each injection.8 Emerging resistance of ocular flora to third- and fourthgeneration fluoroquinolones has been observed by recent surveillance studies.8 However, to the authors’ knowledge, this is the first study directly to establish ophthalmic antibiotic use with resistance and to characterize its progression. These results demonstrate that resistant strains in the conjunctiva emerge immediately after exposure to antibiotic and are maintained by periodic re-exposure. This finding has considerable implications because conjunctival flora, particularly CNS, is a common cause of ocular infections.17
At least 1 study has reported that resistant strains of S. epidermidis may be associated with greater ocular inflammation than susceptible strains.18 Furthermore, Miller et al19 reported higher rates of fluoroquinolone resistance in CNS recovered from patients with endophthalmitis than would have been predicted based on surveillance studies conducted during the same period. These studies suggest that antibiotic resistance may be associated with greater virulence and increased ocular infection rates. Although the ocular surface harbors bacteria that can cause systemic infection, its actual contribution to these infections is probably minor. In contrast, nasopharyngeal flora contributes too many systemic infections. S. aureus is a particularly virulent gram-positive cocci that is present on the skin and in the nasopharynx of approximately 30% to 50% of adults.20,21 S. aureus causes a wide spectrum of clinical disease, including skin and soft tissue infections, sepsis, and pneumonia. Nasal carriage is a major risk factor for lower respiratory infections, and S. aureus is the most common cause of hospitalacquired pneumonia, which accounts for 15% of all nosocomial infections and has a high mortality rate.22,23 For inpatient, non–intensive care unit pneumonia, monotherapy with a fluoroquinolone is recommended and may afford greater success of treatment in more severe cases.24,25 However, rapid emergence of fluoroquinolone-resistant S. aureus was observed with the use of fluoroquinolones in
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Figure 3. Graphs showing antibiotic susceptibility of coagulase-negative Staphylococcus (CNS) isolated from the conjunctiva from visits 1 to 4. A, Results of 70 CNS species isolated from untreated (control) eyes. Treated eyes exposed to (B) fluoroquinolone and (C) azithromycin antibiotics demonstrated significantly increased fluoroquinolone and macrolide resistance, respectively, when compared with control eyes (A). Amox/Clav ⫽ amoxicillin/clavulanate; TMP/SMZ ⫽ trimethoprim/sulfamethoxazole.
the 1980s. After the introduction of ciprofloxacin, several United States hospitals reported resistance rates as high as 80% and strikingly higher in methicillin-resistant strains.26 Fluoroquinolone resistance in staphylococci results from the stepwise acquisition of chromosomal point mutations in the subunits of the 2 intracellular target enzymes, topoisomerase IV and DNA gyrase, and less commonly with overexpression of a multidrug efflux protein.22 Exposure to subinhibitory concentrations of fluoroquinolones or cross-resistance to older generations may promote resistance.20,22,26 Genetic analysis demonstrated the emergence of a fluoroquinolone-resistant strain of S. aureus in the nasopharynx of 1 subject exposed to moxifloxacin. Although this conversion was observed in only 1 (13%) of 8 subjects who grew S. aureus at baseline, some subjects did not regrow S. aureus on subsequent visits and others had S. aureus that had baseline resistance to their assigned antibiotic. More importantly, this 1 subject had no other antibiotic exposure that could account for this observation and grew only this resistant strain on subsequent visits. Approximately 40% of a standard eye drop directly enters the nasolacrimal duct and is absorbed by the
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nasopharyngeal mucosa.11 The high bacterial density in the nasopharynx in combination with the likely preexistence of resistant subpopulations and subinhibitory concentration of antibiotic after ophthalmic application may create an environment that favors selection of resistant strains.26 In addition to S. aureus, S. pneumonia also was examined. S. pneumonia is a gram-positive cocci that is the most common cause of community-acquired pneumonia, which is the leading infectious cause of death in the United States.27 S. pneumonia adheres to and replicates in the nasopharynx of approximately 5% to 10% of adults, but invasive infection is more common in older individuals.28 Although we did not detect any isolates of S. pneumonia in our small cohort of patients, similar selective pressure in the nasopharynx of patients repeatedly exposed to ophthalmic antibiotic also may select for resistant strains. More concerning, fluoroquinolone-resistant strains of S. pneumonia also tend to have resistance to other classes of antibiotics.29 Despite the lack of evidence that topical antibiotics reduce the rate of postinjection endophthalmitis, recent surveys have suggested that 40% of retinal specialists use topical antibiotics before and 86% of retinal specialists use topical antibiotics after intraocular injections.8 Nevertheless, there is still rationale to support their use. Presumed mechanisms of infection include direct inoculation of bacteria into the vitreous at the time of injection or subsequent entry of bacteria through a wound track potentially mediated by vitreous incarceration.8 Therefore, both preinjection and postinjection antibiotic use theoretically may reduce the risk of infection via these mechanisms. In addition, there are medicolegal concerns and patient expectations that favor their use in certain circumstances. For these reasons and others, topical antibiotics will continue to be used commonly in relation to intraocular injections, despite growing concerns of antibiotic resistance. As with all longitudinal studies, these results should be taken with caution. Resistance found in vitro does not always correlate with clinical resistance. A combination of pharmacokinetics and pharmacodynamics of drug, infection site, and minimum inhibitory concentration is needed to properly predict in vivo efficacy of antibiotics against target pathogens. Resistant strains also may be less virulent than sensitive strains. However, in the case of S. aureus, fluoroquinolone-resistant strains show increased expression of fibronectin, which facilitates attachment and spread and may have greater methicillin resistance.26,30 Despite the small sample size, these results are convincing because of the longitudinal nature of the data collection and the consistency of the observations. Nevertheless, independent verification of these findings is strongly encouraged. In conclusion, the repeated use of ophthalmic antibiotics may select for resistant strains in the conjunctiva and nasopharynx. These findings indicate the need for greater thought and rationale regarding the use of antibiotics after intraocular injection to reduce the emergence of antimicrobial resistance.
Kim and Toma 䡠 Ophthalmic Antibiotics and Antimicrobial Resistance
References 1. Jager RD, Mieler WF, Miller JW. Age-related macular degeneration. N Engl J Med 2008;358:2606 –17. 2. Eye Diseases Prevalence Research Group. Prevalence of agerelated macular degeneration in the United States. Arch Ophthalmol 2004;122:564 –72. 3. Rosenfeld PJ, Brown DM, Heier JS, et al, MARINA Study Group. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med 2006;355:1419 –31. 4. Brown DM, Kaiser PK, Michels M, et al, ANCHOR Study Group. Ranibizumab vs verteporfin for neovascular age-related macular degeneration. N Engl J Med 2006;355:1432– 44. 5. Campbell RJ, Bronskill SE, Bell CM, et al. Rapid expansion of intravitreal drug injection procedures, 2000 to 2008: a population-based analysis. Arch Ophthalmol 2010;128: 359 – 62. 6. Jager RD, Aiello LP, Patel SC, Cunningham ET Jr. Risks of intravitreous injection: a comprehensive review. Retina 2004; 24:676 –98. 7. Ta CN. Topical antibiotic prophylaxis in intraocular injections. Arch Ophthalmol 2007;125:972– 4. 8. Kim SJ, Toma HS, Mida NK, et al. Antibiotic resistance of conjunctiva and nasopharynx evaluation study: a prospective study of patients undergoing intravitreal injections. Ophthalmology 2010;117:2372– 8. 9. Hwang DG. Fluoroquinolone resistance in ophthalmology and the potential role for newer ophthalmic fluoroquinolones. Surv Ophthalmol 2004;49(suppl):S79 – 83. 10. Moss JM, Sanislo SR, Ta CN. A prospective randomized evaluation of topical gatifloxacin on conjunctival flora in patients undergoing intravitreal injections. Ophthalmology 2009;116:1498 –501. 11. Shell JW. Pharmacokinetics of topically applied ophthalmic drugs. Surv Ophthalmol 1982;26:207–18. 12. File TM Jr. Streptococcus pneumoniae and communityacquired pneumonia: a cause of concern. Am J Med 2004; 117(suppl):39S–50S. 13. Costa SF, Newbaer M, Santos CR, et al. Nosocomial pneumonia: importance of recognition of aetiological agents to define an appropriate initial empirical therapy. Int J Antimicrob Agents 2001;17:147–50. 14. Fernandes CJ, Fernandes LA, Collignon P, Australian Group on Antimicrobial Resistance (AGAR). Cefoxitin resistance as a surrogate marker for the detection of methicillin-resistant Staphylococcus aureus. J Antimicrob Chemother 2005;55: 506 –10. 15. Bannerman TL, Hancock GA, Tenover FC, Miller JM. Pulsedfield gel electrophoresis as a replacement for bacteriophage
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typing of Staphylococcus aureus. J Clin Microbiol 1995; 33:551–5. Tenover FC, Arbeit RD, Goering RV, et al. Interpreting chromosomal DNA restriction patterns produced by pulsed-field gel electrophoresis: criteria for bacterial strain typing. Clin Microbiol 1995;33:2233–9. Speaker M, Milch F, Shah M, et al. Role of external bacterial flora in the pathogenesis of acute postoperative endophthalmitis. Ophthalmology 1991;98:639 – 49. Mino de Kasper H, Hoepfner AS, Engelbert M, et al. Antibiotic resistance pattern and visual outcome in experimentallyinduced Staphylococcus epidermidis endophthalmitis in a rabbit model. Ophthalmology 2001;108:470 – 8. Miller D, Flynn PM, Scott IU, et al. In vitro fluoroquinolone resistance in staphylococcal endophthalmitis isolates. Arch Ophthalmol 2006;124:479 – 83. Lowy FD. Staphylococcus aureus infections. N Engl J Med 1998;3339:520 –32. Noble WC, Valkenburg HA, Wolters CH. Carriage of Staphylococcus aureus in random samples of a normal population. J Hyg (Lond) 1967;65:567–73. Lowy FD. Antimicrobial resistance: the example of Staphylococcus aureus. J Clin Invest 2003;111:1265–73. Lynch JP. Hospital-acquired pneumonia: risk factors, microbiology, and treatment. Chest 2001;119:373S– 84S. Mandell LA, Wunderink RG, Anzueto A, et al. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis 2007;44(suppl):S27–72. Vardakas KM, Siempos IM, Grammatikos AM, et al. Respiratory fluoroquinolones for the treatment of communityacquired pneumonia: a meta-analysis of randomized controlled trials. CMAJ 2008;179:1269 –77. Hooper DC. Fluoroquinolone resistance among Gram-positive cocci. Lancet Infect Dis 2002;2:530 – 8. Lister PD. Emerging resistance problems among respiratory tract pathogens. Am J Manag Care 2000;6(suppl):S409 –18. Furuya EY, Lowy FD. Antimicrobial-resistant bacteria in the community setting. Nat Rev Microbiol 2006;4:36 – 45. Whitney CG, Farley MM, Hadler J, et al, Active Bacterial Core Surveillance Program of the Emerging Infections Program Network. Increasing prevalence of multidrug-resistant Streptococcus pneumonia in the United States. N Engl J Med 2000;343:1917–24. Bisognano C, Vaudaux P, Rohner P, et al. Induction of fibronectin-binding proteins and increased adhesion of quinolone-resistant Staphylococcus aureus by subinhibitory levels of ciprofloxacin. Antimicrob Agents Chemother 2000;44:1428 –37.
Footnotes and Financial Disclosures Originally received: July 21, 2010. Final revision: December 8, 2010. Accepted: December 13, 2010. Available online: March 21, 2011.
Financial Disclosure(s): The author(s) have made the following disclosure(s):
From the Department of Ophthalmology, Vanderbilt University School of Medicine, Nashville, Tennessee.
Stephen J. Kim - Consultant – Ophthotech Supported by an unrestricted grant from Research to Prevent Blindness, Inc., New York, New York, to the Vanderbilt University School of Medicine Department of Ophthalmology and Visual Sciences.
Presented in part at: American Society of Retinal Specialists Annual Meeting, 2010, Vancouver, Canada. This paper will also be presented at the 34th Annual Macula Society Meeting, March 2011, Boca Raton, FL.
Correspondence: Stephen J. Kim, MD, Vanderbilt Eye Institute, 2311 Pierce Avenue, Nashville, TN 37232. E-mail: [email protected].
Manuscript no. 2010-1007.
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Age-related macular degeneration (AMD) is the leading cause of blindness among individuals older than 65 years in the United States and currently affects more than 8 million Americans.1 The overall prevalence of advanced AMD is projected to increase by more than 50% by the year 2020.2 Monthly intraocular injection of ranibizumab (Lucentis; Genentech, South San Francisco, CA) or off-labeled use of bevacizumab (Avastin; Genentech, South San Francisco, CA) has become the standard of care for the treatment of neovascular AMD.3,4 Consequently, the number of intraocular injections performed in the United States, estimated from Medicare procedure codes, has risen exponentially from fewer than 3000 per year in
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1999 to more than 1 million in 2008 and will continue to increase rapidly given the aging of the population and expanding applications.5 Endophthalmitis is the most severe complication after intraocular injection and results in substantial morbidity.6 Consequently, ophthalmic antibiotics are prescribed routinely after each injection by most treating eye specialists.7,8 Increasing resistance of normal ocular flora to older antibiotic classes in conjunction with widespread availability has led to more frequent use of fourth-generation fluoroquinolone antibiotics: gatifloxacin 0.3% (Zymar; Allergan Pharmaceuticals, Irvine, CA) and moxifloxacin 0.5% (Vigamox; Alcon, Fort Worth, TX),9,10 but ocular flora resistance to these antibiotics also may be increasing. ISSN 0161-6420/11/$–see front matter doi:10.1016/j.ophtha.2010.12.014
Kim and Toma 䡠 Ophthalmic Antibiotics and Antimicrobial Resistance Approximately 40% of a standard 50-l eye drop directly enters the highly vascular tear drainage apparatus and is absorbed by the nasopharyngeal mucosa.11 Staphylococcus aureus and Streptococcus pneumoniae colonize the nasopharynx of healthy individuals and are the most common cause of hospital-acquired and community-acquired pneumonia, respectively.12,13 Exposure to subinhibitory concentrations of antibiotic may promote resistance. Therefore, the repeated exposure of ocular and nasopharyngeal flora to ophthalmic antibiotics after intraocular injection may select for resistant bacterial strains. The Antibiotic Resistance of Conjunctiva and Nasopharynx Evaluation (ARCaNE) study is a randomized, controlled clinical study designed to determine changes in antibiotic resistance after repeated exposure of flora to ophthalmic antibiotics. Baseline resistance patterns of this study cohort already have been published.8 Herein are reported changes in antibiotic susceptibility and resistance over time.
Patients and Methods The Vanderbilt University Institutional Review Board approved this study, and all subjects gave informed consent before enrollment. The study complied with all aspects of the Health Insurance Portability and Accountability Act. The trial is registered at clinicaltrials.gov (identifier no. NCT00831961). Inclusion and exclusion criteria of the Antibiotic Resistance of Conjunctiva and Nasopharynx Evaluation study have been published previously.8 In brief, all adult patients 18 years of age or older with choroidal neovascularization (CNV) resulting from AMD or other causes in 1 eye only and planned treatment with intraocular injection were eligible for inclusion. Exclusion criteria consisted of previous intraocular injection in either eye, chronic use of ophthalmic medication, contact lens wear, ocular surgery, use of ophthalmic medications in either eye or ocular infection within the previous 3 months, use of systemic antibiotics within 30 days, and use of eye drops (e.g., artificial tears, saline solutions, vasoconstrictors) in either eye within 3 days of enrollment. As part of the study protocol, all enrolled patients received 4 consecutive monthly intraocular injections and then were treated as needed. Patients were assigned by permuted block randomization to 1 of 4 ophthalmic antibiotics: ofloxacin 0.3% (Ocuflox; Akorn, Inc., Somerset, NJ), azithromycin 1% (AzaSite; Inspire Pharmaceuticals, Inc., Durham, NC), gatifloxacin 0.3%, or moxifloxacin 0.5% and used only their assigned antibiotic after each injection. Before the application of any ophthalmic medication, conjunctival cultures of both eyes were obtained using the BBL CultureSwab collection and transport system (Becton, Dickinson and Co., Sparks, MD) in accordance with manufacturer instructions. Conjunctival cultures were obtained from the lower fornix in standardized fashion with every effort made to minimize contamination from the lids, lashes, or skin. Nasopharyngeal cultures were obtained on the same side as the treated eye with sterile calcium alginate swabs and were inoculated immediately onto 5% sheep blood media plates. Conjunctival culture swabs were inoculated onto 5% sheep blood and chocolate agar plates and were incubated with 5% carbon dioxide. All culture plates were incubated at 37° C for 3 days. Cultures were deemed positive if 1 or more colonyforming units were observed. For nasopharyngeal cultures, only S. aureus and S. pneumoniae were isolated if present.
All intraocular injections were performed in standard fashion after obtaining informed consent. Briefly, subconjunctival or topical anesthesia was administered and 5% Betadine (Alcon Laboratories, Inc., Fort Worth, TX) was applied to the ocular surface and lids. Betadine was reapplied, and immediately afterward, the drug was injected into the eye approximately 3.5 mm from the limbus using a 32-gauge needle. Patients were instructed carefully to start using their assigned antibiotic beginning on the day of their injection and continued for the next 4 consecutive days. Ofloxacin 0.3%, gatifloxacin 0.3%, and moxifloxacin 0.5% were administered as 1 drop 4 times daily, and azithromycin 1% was administered twice daily. All patients were given written instructions on use of their antibiotic after each treatment and also were supplied with new samples of their antibiotic to ensure compliance and to reduce the possibility of contamination. After baseline cultures were obtained (visit 0), the first injection was administered and all subjects returned in 4 weeks (visit 1), 8 weeks (visit 2), 12 weeks (visit 3), and 16 weeks (visit 4). At visits 1, 2, and 3, subjects were recultured and reinjected and then resumed use of their assigned ophthalmic antibiotic. At visit 4, all subjects were recultured, but continued treatment was determined on an individual basis. If subjects were reinjected at visit 4, then they resumed use of their assigned antibiotic and were recultured at their next return appointment (visit 5). Some study participants received monthly injections throughout the 1-year of follow-up, and thus had as many as 13 culture results (baseline plus visits 1–12), whereas others had the minimum of 5 culture results (baseline plus visits 1– 4). To test resistance, the Kirby-Bauer disc diffusion technique was conducted in strict accordance with guidelines of the National Committee for Clinical Laboratory Standards. The following antibiotics were tested on all culture samples with positive results: amoxicillin/clavulanate, cefazolin, cefoxitin, erythromycin, azithromycin, ofloxacin, levofloxacin, gatifloxacin, moxifloxacin, trimethoprim/sulfamethoxazole, rifampin, gentamicin, doxycycline, linezolid, clindamycin, and vancomycin. The diameter of zone of inhibition was recorded and used to determine susceptibility. Resistance to cefoxitin was considered equivalent to methicillin resistance.14 Identification of bacteria strains was performed by gram staining and testing for the presence or absence of catalase and coagulase/agglutination. The API Staph kit (bioMérieux, Hazelwood, MO) was used further to speciate coagulase-negative staphylococci (CNS). Genetic analysis was performed using the well-established technique of pulse-field gel electrophoresis following restriction digest with SmaI (ARUP Laboratories, Salt Lake City, UT). Pulsefield gel electrophoresis involves use of restriction enzymes that selectively cleave (fragment) DNA at locations unique to each strain of bacteria, resulting in fragments of differing lengths. The DNA fragments then are run on a gel to create a so-called fingerprint of each strain of bacteria. Relatedness was determined on the basis of criteria developed by Bannerman et al15 and Tenover et al.16 Genetic analysis was performed on selected series of strains for which a change or lack of change in antibiotic susceptibility was potentially important.
Statistical Analysis Descriptive statistics, including mean, were calculated for case characteristics. Percentages were calculated for antibiotic susceptibility. Group comparisons were performed with the Fisher exact test. A P value of less than 0.05 was considered significant.
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Ophthalmology Volume 118, Number 7, July 2011 Table 1. Baseline Demographics of 24 Patients Receiving Unilateral Intraocular Injection for Choroidal Neovascularization Azithromycin
Ofloxacin
Gatifloxacin
Moxifloxacin
6 75 (42–86)
6 75 (64–83)
6 69 (49–86)
6 82 (68–97)
0 2
0 2
0 2
0 2
No. Age (range), yrs Nasopharyngeal flora Streptococcus pneumonia Staphylococcus aureus Indications for treatment, % AMD Myopic degeneration Ocular histoplasmosis Idiopathic Previous surgery in treatment eye, % Cataract surgery Glaucoma surgery Retinal surgery Corneal surgery Refractive surgery
5 (83) 0 0 1 (17)
5 (83) 1 (17) 0 0
4 (67) 1 (17) 1 (17) 0
6 (100) 0 0 0
4 (67) 0 0 0 0
3 (50) 0 0 0 1 (17)
3 (50) 0 0 0 0
3 (50) 0 0 0 0
AMD ⫽ age-related macular degeneration.
Results Baseline characteristics of the study cohort are summarized in Table 1. A total of 24 subjects were enrolled from February 2009 through November 2009, with a total of 6 patients randomized to each antibiotic. The average age of the cohort was 75 years (range, 42–97 years). No patient had a history of prior intraocular injection in either eye. Most patients (83%) were undergoing treatment for AMD. Among the 24 baseline nasopharyngeal cultures, no isolates of S. pneumoniae were identified, but 8 (33%) subjects showed positive results for S. aureus. One subject, who was randomized to moxifloxacin, had S. aureus that was sensitive to all 16 antibiotics and remained sensitive through visit 2 (Fig 1). However, by visit 4, genetic analysis demonstrated the emergence of a different strain of S. aureus that was resistant to ofloxacin, levofloxacin, and moxifloxacin and that showed intermediate resistance to gatifloxacin. Furthermore, this fluoroquinolone-resistant strain also was resistant to macrolides (azithromycin and erythromycin), and clindamycin and was the only strain isolated from the subject’s nasopharynx on subsequent visits. A total of 37 of the 57 bacterial isolates cultured from the conjunctiva from both eyes of 24 study participants at baseline were CNS, with most (73%) being Staphylococcus epidermidis. Of these 37 baseline CNS isolates, 23 were collected from eyes that had active CNV and received treatment. The antibiotic susceptibility of these 23 CNS isolates is shown in Figure 2 (available at http://aaojournal.org). Resistance to erythromycin and azithromycin was 57% and 65%, respectively, and resistance to ofloxacin and levofloxacin was 57% and approached 52% (43% resistant; 9% intermediate), respectively. Resistance to gatifloxacin and moxifloxacin approached 39% and 34%, respectively. Treated eyes randomized to fluoroquinolones demonstrated increased CNS resistance to fluoroquinolones that was observed as early as visit 1, but became more evident by visit 3. At this time point, resistance to both ofloxacin and levofloxacin approached 83%, whereas resistance to gatifloxacin and moxifloxacin roughly doubled from baseline levels approaching 66% (P ⫽ 0.28) and 75% (P ⫽ 0.07), respectively. Interestingly, resistance to both macrolides decreased sharply from 60% at baseline to 33% at visit 3. In contrast, CNS from eyes exposed to azithromycin showed increased resistance to both macrolides (80%) and decreased
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resistance to second-generation (ofloxacin; 40%), third-generation (levofloxacin; 20%), and fourth-generation (gatifloxacin and moxifloxacin; 0%) fluoroquinolones. Fourteen CNS isolates were cultured from untreated (control) eyes at baseline. Fifty percent of these isolates were resistant to macrolides, whereas resistance to ofloxacin and levofloxacin approached 43% and resistance to gatifloxacin and moxifloxacin approached 21% and 35%, respectively (data not shown). A total of 70 CNS isolates subsequently were cultured from control eyes from visit 1 to 4. Overall, these 70 CNS isolates did not demonstrate significant differences in fluoroquinolone or macrolide resistance when compared with the 14 CNS isolates identified at baseline (Fig 3). In contrast, 48 CNS isolates were cultured from treated eyes (visit 1 to 4) exposed to fluoroquinolones and demonstrated significantly increased rates of resistance to second, third, and fourth-generation fluoroquinolones compared with control eyes. Resistance to ofloxacin and levofloxacin was roughly 85% (P ⫽ 0.003), and resistance to gatifloxacin and moxifloxacin approached 67% (P ⫽ 0.009) and 77% (P⬍0.001), respectively. Seventeen CNS isolates were identified in total (visit 1 to 4) from eyes exposed to azithromycin and demonstrated significantly increased resistance to macrolides (94%; P ⫽ 0.009) when compared with control eyes and decreased resistance to ofloxacin (59%; P ⫽ 0.029), levofloxacin (35%; P⬍0.001), gatifloxacin (0%; P⬍0.001), and moxifloxacin (13%; P⬍0.001) when compared with fluoroquinolone-exposed eyes. Emergence of resistant strains occurred rapidly in the conjunctiva of subjects with bacteria flora susceptible to their assigned antibiotic, but not in subjects with bacteria flora resistant to their assigned antibiotic. One representative subject, randomized to moxifloxacin, had a fluoroquinolone-sensitive strain of S. epidermidis that rapidly became supplanted by a fluoroquinolone-resistant strain of S. epidermidis (Fig 4, available at http://aaojournal.org). In contrast, 1 subject randomized to azithromycin had an azithromycin-resistant strain of S. epidermidis at baseline and continued to regrow this same strain on subsequent visits. All CNS isolates resistant to gatifloxacin or moxifloxacin also were resistant to ofloxacin and levofloxacin, indicating high levels of cross-resistance between fourth- and older-generation fluoroquinolone antibiotics. One subject, randomized to ofloxacin and with fluoroquinolone-sensitive CNS at baseline, subsequently
Kim and Toma 䡠 Ophthalmic Antibiotics and Antimicrobial Resistance
Figure 1. Antibiotic susceptibility and genetic fingerprint analysis of Staphylococcus aureus isolated from the nasopharynx of 1 subject randomized to moxifloxacin. Restriction enzyme digest of S. aureus DNA (left gel) demonstrates identical pattern of DNA fragments from isolates collected on visits 0, 1, and 2. This strain of S. aureus is sensitive to all 16 antibiotics tested (top right graph). Emergence of a different strain (left gel) of S. aureus (note change in genetic fingerprint pattern) is first observed at visit 4, and this new strain is resistant to fluoroquinolones, macrolides, and clindamycin (bottom right graph). S. aureus was not isolated on visit 3. Amox/Clav ⫽ amoxicillin/clavulanate; TMP/SMZ ⫽ trimethoprim/sulfamethoxazole.
grew CNS resistant to all fluoroquinolones tested. This high level of cross-resistance explains the increasing rate of levofloxacin resistance observed in this study despite absence of exposure.
Discussion Age-related macular degeneration is the leading cause of blindness in individuals older than 65 years, and its prevalence is rising. The advent of ranibizumab and bevacizumab has been a remarkable advance for the treatment of neovascular AMD, but is itself not curative and requires long-term, often monthly, administration by intraocular injection.3,4 Endophthalmitis is the most severe complication after intraocular injection, and consequently more than 80% of treating eye specialists use ophthalmic antibiotics after each injection.8 Emerging resistance of ocular flora to third- and fourthgeneration fluoroquinolones has been observed by recent surveillance studies.8 However, to the authors’ knowledge, this is the first study directly to establish ophthalmic antibiotic use with resistance and to characterize its progression. These results demonstrate that resistant strains in the conjunctiva emerge immediately after exposure to antibiotic and are maintained by periodic re-exposure. This finding has considerable implications because conjunctival flora, particularly CNS, is a common cause of ocular infections.17
At least 1 study has reported that resistant strains of S. epidermidis may be associated with greater ocular inflammation than susceptible strains.18 Furthermore, Miller et al19 reported higher rates of fluoroquinolone resistance in CNS recovered from patients with endophthalmitis than would have been predicted based on surveillance studies conducted during the same period. These studies suggest that antibiotic resistance may be associated with greater virulence and increased ocular infection rates. Although the ocular surface harbors bacteria that can cause systemic infection, its actual contribution to these infections is probably minor. In contrast, nasopharyngeal flora contributes too many systemic infections. S. aureus is a particularly virulent gram-positive cocci that is present on the skin and in the nasopharynx of approximately 30% to 50% of adults.20,21 S. aureus causes a wide spectrum of clinical disease, including skin and soft tissue infections, sepsis, and pneumonia. Nasal carriage is a major risk factor for lower respiratory infections, and S. aureus is the most common cause of hospitalacquired pneumonia, which accounts for 15% of all nosocomial infections and has a high mortality rate.22,23 For inpatient, non–intensive care unit pneumonia, monotherapy with a fluoroquinolone is recommended and may afford greater success of treatment in more severe cases.24,25 However, rapid emergence of fluoroquinolone-resistant S. aureus was observed with the use of fluoroquinolones in
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Figure 3. Graphs showing antibiotic susceptibility of coagulase-negative Staphylococcus (CNS) isolated from the conjunctiva from visits 1 to 4. A, Results of 70 CNS species isolated from untreated (control) eyes. Treated eyes exposed to (B) fluoroquinolone and (C) azithromycin antibiotics demonstrated significantly increased fluoroquinolone and macrolide resistance, respectively, when compared with control eyes (A). Amox/Clav ⫽ amoxicillin/clavulanate; TMP/SMZ ⫽ trimethoprim/sulfamethoxazole.
the 1980s. After the introduction of ciprofloxacin, several United States hospitals reported resistance rates as high as 80% and strikingly higher in methicillin-resistant strains.26 Fluoroquinolone resistance in staphylococci results from the stepwise acquisition of chromosomal point mutations in the subunits of the 2 intracellular target enzymes, topoisomerase IV and DNA gyrase, and less commonly with overexpression of a multidrug efflux protein.22 Exposure to subinhibitory concentrations of fluoroquinolones or cross-resistance to older generations may promote resistance.20,22,26 Genetic analysis demonstrated the emergence of a fluoroquinolone-resistant strain of S. aureus in the nasopharynx of 1 subject exposed to moxifloxacin. Although this conversion was observed in only 1 (13%) of 8 subjects who grew S. aureus at baseline, some subjects did not regrow S. aureus on subsequent visits and others had S. aureus that had baseline resistance to their assigned antibiotic. More importantly, this 1 subject had no other antibiotic exposure that could account for this observation and grew only this resistant strain on subsequent visits. Approximately 40% of a standard eye drop directly enters the nasolacrimal duct and is absorbed by the
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nasopharyngeal mucosa.11 The high bacterial density in the nasopharynx in combination with the likely preexistence of resistant subpopulations and subinhibitory concentration of antibiotic after ophthalmic application may create an environment that favors selection of resistant strains.26 In addition to S. aureus, S. pneumonia also was examined. S. pneumonia is a gram-positive cocci that is the most common cause of community-acquired pneumonia, which is the leading infectious cause of death in the United States.27 S. pneumonia adheres to and replicates in the nasopharynx of approximately 5% to 10% of adults, but invasive infection is more common in older individuals.28 Although we did not detect any isolates of S. pneumonia in our small cohort of patients, similar selective pressure in the nasopharynx of patients repeatedly exposed to ophthalmic antibiotic also may select for resistant strains. More concerning, fluoroquinolone-resistant strains of S. pneumonia also tend to have resistance to other classes of antibiotics.29 Despite the lack of evidence that topical antibiotics reduce the rate of postinjection endophthalmitis, recent surveys have suggested that 40% of retinal specialists use topical antibiotics before and 86% of retinal specialists use topical antibiotics after intraocular injections.8 Nevertheless, there is still rationale to support their use. Presumed mechanisms of infection include direct inoculation of bacteria into the vitreous at the time of injection or subsequent entry of bacteria through a wound track potentially mediated by vitreous incarceration.8 Therefore, both preinjection and postinjection antibiotic use theoretically may reduce the risk of infection via these mechanisms. In addition, there are medicolegal concerns and patient expectations that favor their use in certain circumstances. For these reasons and others, topical antibiotics will continue to be used commonly in relation to intraocular injections, despite growing concerns of antibiotic resistance. As with all longitudinal studies, these results should be taken with caution. Resistance found in vitro does not always correlate with clinical resistance. A combination of pharmacokinetics and pharmacodynamics of drug, infection site, and minimum inhibitory concentration is needed to properly predict in vivo efficacy of antibiotics against target pathogens. Resistant strains also may be less virulent than sensitive strains. However, in the case of S. aureus, fluoroquinolone-resistant strains show increased expression of fibronectin, which facilitates attachment and spread and may have greater methicillin resistance.26,30 Despite the small sample size, these results are convincing because of the longitudinal nature of the data collection and the consistency of the observations. Nevertheless, independent verification of these findings is strongly encouraged. In conclusion, the repeated use of ophthalmic antibiotics may select for resistant strains in the conjunctiva and nasopharynx. These findings indicate the need for greater thought and rationale regarding the use of antibiotics after intraocular injection to reduce the emergence of antimicrobial resistance.
Kim and Toma 䡠 Ophthalmic Antibiotics and Antimicrobial Resistance
References 1. Jager RD, Mieler WF, Miller JW. Age-related macular degeneration. N Engl J Med 2008;358:2606 –17. 2. Eye Diseases Prevalence Research Group. Prevalence of agerelated macular degeneration in the United States. Arch Ophthalmol 2004;122:564 –72. 3. Rosenfeld PJ, Brown DM, Heier JS, et al, MARINA Study Group. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med 2006;355:1419 –31. 4. Brown DM, Kaiser PK, Michels M, et al, ANCHOR Study Group. Ranibizumab vs verteporfin for neovascular age-related macular degeneration. N Engl J Med 2006;355:1432– 44. 5. Campbell RJ, Bronskill SE, Bell CM, et al. Rapid expansion of intravitreal drug injection procedures, 2000 to 2008: a population-based analysis. Arch Ophthalmol 2010;128: 359 – 62. 6. Jager RD, Aiello LP, Patel SC, Cunningham ET Jr. Risks of intravitreous injection: a comprehensive review. Retina 2004; 24:676 –98. 7. Ta CN. Topical antibiotic prophylaxis in intraocular injections. Arch Ophthalmol 2007;125:972– 4. 8. Kim SJ, Toma HS, Mida NK, et al. Antibiotic resistance of conjunctiva and nasopharynx evaluation study: a prospective study of patients undergoing intravitreal injections. Ophthalmology 2010;117:2372– 8. 9. Hwang DG. Fluoroquinolone resistance in ophthalmology and the potential role for newer ophthalmic fluoroquinolones. Surv Ophthalmol 2004;49(suppl):S79 – 83. 10. Moss JM, Sanislo SR, Ta CN. A prospective randomized evaluation of topical gatifloxacin on conjunctival flora in patients undergoing intravitreal injections. Ophthalmology 2009;116:1498 –501. 11. Shell JW. Pharmacokinetics of topically applied ophthalmic drugs. Surv Ophthalmol 1982;26:207–18. 12. File TM Jr. Streptococcus pneumoniae and communityacquired pneumonia: a cause of concern. Am J Med 2004; 117(suppl):39S–50S. 13. Costa SF, Newbaer M, Santos CR, et al. Nosocomial pneumonia: importance of recognition of aetiological agents to define an appropriate initial empirical therapy. Int J Antimicrob Agents 2001;17:147–50. 14. Fernandes CJ, Fernandes LA, Collignon P, Australian Group on Antimicrobial Resistance (AGAR). Cefoxitin resistance as a surrogate marker for the detection of methicillin-resistant Staphylococcus aureus. J Antimicrob Chemother 2005;55: 506 –10. 15. Bannerman TL, Hancock GA, Tenover FC, Miller JM. Pulsedfield gel electrophoresis as a replacement for bacteriophage
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Footnotes and Financial Disclosures Originally received: July 21, 2010. Final revision: December 8, 2010. Accepted: December 13, 2010. Available online: March 21, 2011.
Financial Disclosure(s): The author(s) have made the following disclosure(s):
From the Department of Ophthalmology, Vanderbilt University School of Medicine, Nashville, Tennessee.
Stephen J. Kim - Consultant – Ophthotech Supported by an unrestricted grant from Research to Prevent Blindness, Inc., New York, New York, to the Vanderbilt University School of Medicine Department of Ophthalmology and Visual Sciences.
Presented in part at: American Society of Retinal Specialists Annual Meeting, 2010, Vancouver, Canada. This paper will also be presented at the 34th Annual Macula Society Meeting, March 2011, Boca Raton, FL.
Correspondence: Stephen J. Kim, MD, Vanderbilt Eye Institute, 2311 Pierce Avenue, Nashville, TN 37232. E-mail: [email protected].
Manuscript no. 2010-1007.
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