Purpose
To identify the resistance profiles of conjunctival and nasal bacterial isolates in patients undergoing intravitreal injections and to determine if frequent exposures to topical fluoroquinolones increased antimicrobial resistance among these organisms.
Design
Prospective cohort study.
Methods
Patients undergoing intravitreal injection at our institution were enrolled in this study. The conjunctiva and nares of both sides of the patient’s face were swabbed and cultured before antiseptic preparation for intravitreal injection. At the time of the study, all patients received 3 days of moxifloxacin eye drops after each intravitreal injection as prophylaxis against endophthalmitis. Resistance to antimicrobials was analyzed using the chi-square test and t test.
Results
Two hundred eight conjunctival and nasal specimens were cultured from 104 patients. Forty-two (45%) of 93 patients had at least 1 fluoroquinolone-resistant organism in the nose or conjunctiva. Twelve (48%) of 25 patients with no previous injections had at least 1 resistant organism; 14 (45%) of 31 patients with 1 to 4 previous injections had at least 1 resistant organism; 8 (33%) of 24 patients with 5 to 9 previous injections had at least 1 resistant organism; and 8 (62%) of 13 patients with 10 or more previous injections had at least 1 resistant organism ( P = .88; chi-square test, linear by linear association).
Conclusions
In this small study, there was no correlation between the number of exposures to topical fluoroquinolones and resistance to fluoroquinolones in nasal and conjunctival flora, but there was a high prevalence of fluoroquinolone resistance among all patient groups.
The use of intravitreal injection for the treatment of eye disease has increased exponentially since the advent of anti–vascular endothelial growth factor treatment methods. The incidence of endophthalmitis after intravitreal injections of various therapeutic agents ranges from 0.05% to 0.2%. A consensus statement published by Aiello and associates provides guidelines for the prevention of endophthalmitis after intravitreal injection. Current practice calls for an eyelid preparation with povidone iodine, the use of a sterile lid speculum, adequate anesthesia, application of povidone iodine to the bulbar conjunctival before injection, avoiding extensive eyelid manipulation, and avoiding paracentesis after injection. Prophylactic antibiotics are used by many clinicians before and after intravitreal injection without scientific evidence of their benefit. At the time of this study, fourth-generation fluoroquinolones were used routinely at our institution after all intravitreal injections: 1 drop immediately after injection followed by 1 drop 4 times daily for 3 days.
Nasal mucosa serves as a reservoir of organisms for the conjunctiva and nasolacrimal system. Alexandrou and associates noted a reduction of preoperative conjunctival bacterial flora with the nasal application of mupirocin ointment. Additionally, nasal flora has been implicated as a source for endophthalmitis. Speaker and associates determined that organisms isolated from the vitreous cavity of patients with endophthalmitis were genetically identical to organisms isolated from the eyelids, conjunctiva, and nares in 14 of 17 cases.
It remains to be elaborated whether repeated exposure to short-term topical antibiotics alters the antimicrobial susceptibility profile of normal flora in the eye and nose. The current study attempted to identify the conjunctival and nasal flora of patients undergoing intravitreal injections. This study also evaluated the antimicrobial susceptibility profiles of these isolates and their association with the number of exposures to fluoroquinolones.
Methods
Patients 18 years of age and older undergoing intravitreal injection were eligible for inclusion in this prospective study. After informed consent was obtained, 1 drop of 0.5% proparacaine hydrochloride was instilled onto the bulbar conjunctiva of each eye. Two sterile cotton-tipped applicators were moistened with trypticase soy broth and were placed in the right and left nostril (1 swab for each nostril). The swabs were rolled gently around the nasal mucosa and were placed on blood and chocolate agar plates. Two additional sterile cotton-tipped applicator swabs were moistened with trypticase soy broth and were placed in the right and left inferior forniceal conjunctiva (1 for each eye). The swabs were rolled gently around the mucosa and were plated on blood and chocolate agar plates. Patients then underwent complete ocular preparation for their intravitreal injection according to hospital protocol.
The plates were transported to the Bascom Palmer Eye Institute Ocular Microbiology laboratory for analysis. Cultures were grown and identified according to standard microbiologic protocol. In vitro susceptibility was determined using the Kirby Bauer disk method. Two to 3 colonies were inoculated into 2 mL trypticase soy broth and incubated at 350 C for 2 to 4 hours. Alternatively, 2 to 3 colonies were selected from a plate swabbed within the prior 24 hours, were inoculated into trypticase soy broth, and were adjusted to a 0.5 McFarland standard (10 8 cfu/mL). A cotton swab was used to inoculate Mueller Hinton agar plates with the standardized inoculum of each isolate. Ten antibiotic disks (penicillin, ciprofloxacin, gatifloxacin, moxifloxacin, trimethoprim-sulfamethoxazole, bacitracin, erythromycin, tetracycline, gentamicin, and oxacillin) were placed on the agar surface and the plates were incubated for 18 to 24 hours at 350 C in a non-CO 2 incubator. At the end of incubation, the zones of inhibition around the disks were measured, recorded, and interpreted as susceptible, intermediate, or resistant in accordance with the Clinical Laboratory Standards Institute guidelines. A quality control strain, Staphylococcus aureus ATCC 25923, was used to validate and monitor results.
Isolates with fewer than 10 colonies (light growth) or those with no Clinical and Laboratory Standards Institute interpretative standards ( Moraxella species, Corynebacterium species) were excluded from in vitro susceptibility testing. Those isolates meeting criteria for in vitro susceptibility testing were referred to as significant organisms.
Data collected include age, diagnosis, past medical history, drug injected, eye injected, type of topical fourth-generation antibiotic used (moxifloxacin or gatifloxacin), and number of prior intravitreal injections. Resistance of ocular and nasal flora to antimicrobials was analyzed using the chi-square test and t test.
Results
One hundred four patients were enrolled in this study. Two hundred eight conjunctival and nasal specimens were cultured. The patient population comprised 55 women and 49 men with a mean age of 72 years (standard deviation [SD], 14.5 years; range, 35 to 103 years). Patients had an average of 2.1 previous injections in the right eye (SD, 2.9 injections; range, 0 to 11 injections) and 2.7 previous injections in the left eye (SD, 5.5 injections; range, 0 to 39 injections). The main indication for intravitreal injection was wet age-related macular degeneration (59/104; 57%). Table 1 identifies other indications for injections. Endophthalmitis did not develop in any of the patients enrolled in this study. Ninety-three of 104 patients (89%) had at least 1 significant organism isolated from any the nares or conjunctiva for which antimicrobial sensitivity profiles were obtained.
| Characteristic | |
|---|---|
| Mean age (SD), range (years) | 72.3 (4.5), 35 to 103 |
| No. of males (%) | 49 (47%) |
| Race, no. (%) | |
| Hispanic | 43 (54%) |
| White | 30 (38%) |
| Black | 7 (9%) |
| Unknown | 24 |
| Diabetes mellitus, no. (%) | 30 (29%) |
| Cancer, no. (%) | 10 (10%) |
| Chronic oral steroid use, no. (%) | 3 (3%) |
| Indication, no. (%) | |
| Wet age related macular degeneration | 59 (57%) |
| Proliferative diabetic retinopathy | 5 (5%) |
| Clinically significant diabetic macular edema | 13 (13%) |
| Central/Branch retinal vein occlusion | 5 (5%) |
| Cystoid macular edema | 11 (11%) |
| Radiation retinopathy | 5 (5%) |
| CNVM from POHS | 2 (2%) |
| Hypotony | 2 (2%) |
| Other | 2 (2%) |
| No. of Previous Injections (%) | |
| Right eye | |
| 0 | 49 (47%) |
| 1 to 4 | 36 (35%) |
| 5 to 9 | 17 (16%) |
| 10+ | 2 (2%) |
| Mean ± SD (range) | 2.1 ± 2.9 (0 to 11) |
| Left eye | |
| 0 | 57 (55%) |
| 1 to 4 | 28 (27%) |
| 5 to 9 | 12 (12%) |
| 10+ | 7 (7%) |
| Mean ± SD (range) | 2.7 ± 5.5 (0 to 39) |
| Both eyes | |
| 0 | 26 (25%) |
| 1 to 4 | 38 (37%) |
| 5 to 9 | 26 (25%) |
| 10+ | 14 (13%) |
| Mean ± SD (range) | 4.8 ± 6.0 (0 to 39) |
Of 301 organisms isolated from the nares and conjunctiva, 292 (97%) were sensitive to gentamicin. The prevalence of resistance to penicillin (244/301; 81%) was the highest among conjunctival and nasal isolates tested in this study; this was followed by erythromycin (139/301; 46%) and the fluoroquinolones (ciprofloxacin, 119/301 [40%]; gatifloxacin, 95/301 [32%]; and moxifloxacin, 95/301 [32%]; Table 2 ). Staphylococcus epidermidis was the most frequently isolated organism in both the conjunctiva and nose ( Table 3 ). One hundred six (51%) of 208 conjunctival cultures did yield any significant organisms. Fluoroquinolone resistance among S. epidermis isolates cultured from the conjunctiva ranged from 31% to 50% ( Table 4 ). Similar findings were observed among nasal S. epidermis isolates in the nose, with resistance to various generations of fluoroquinolones ranging from 37% to 46%. S. aureus antimicrobial resistance profiles from ocular and nasal isolates are displayed in Table 5 . All but one of the 52 (98%) S. aureus isolates exhibited resistance to penicillin, and a smaller number were resistant to oxacillin and methicillin (8/52; 15%). Table 6 presents fluoroquinolone resistance of isolates by number of previous injections (0, 1 to 4, 5 to 9, and 10 or more). Resistance was not related to the number of previous injections ( P = .052 to 0.8, chi-square, linear-by-linear association). A trend for resistance was noted in the left nare in which all isolates in patients with more than 10 injections were resistant to fluoroquinolones. Forty-two (45%) of 93 patients had at least 1 organism in the nose or conjunctiva that demonstrated fluoroquinolone resistance. Twelve (48%) of 25 patients with no previous injections had at least 1 fluoroquinolone-resistant organism; 14 (45%) of 31 patients with 1 to 4 previous injections had at least 1 fluoroquinolone-resistant organism; 8 (33%) of 24 patients with 5 to 9 previous injections had at least 1 fluoroquinolone-resistant organism; and 8 (62%) of 13 patients with 10 or more previous injections had at least 1 fluoroquinolone-resistant organism ( P = .88, chi-square test, linear by linear association). When accounting for immunocompromised patients (those with diabetes mellitus, those with cancer, or those with chronic steroid use), resistance profiles to fluoroquinolones did not differ from those who were not immunocompromised. Eighteen (46%) of 39 immunocompromised patients harbored an organism resistant to fluoroquinolones, versus 24 (44%) of 54 patients who were not immunocompromised ( P = 1.00, chi-square test). Table 7 shows the mean number of injections at sites without any fluoroquinolone-resistant organisms as compared with sites with at least 1 fluoroquinolone-resistant organism. Patients harboring at least 1 fluoroquinolone-resistant isolate did not exhibit a significant difference in the number of intravitreal injections (5.6 vs 4.3 injections; P = .3, t test). The patients with at least 1 fluoroquinolone-resistant organism had 1.4 more injections. This was not statistically significant, and the 95% confidence interval (−1.2 to 4.0) indicates that if there is a difference, it is small (from 1.2 fewer injections to 4.0 more injections in resistant patients).
| Antibiotic | Right Conjunctiva (n = 18) | Left Conjunctiva (n = 22) | Right Nare (n = 130) | Left Nare (n = 131) | All Sites (n = 301) |
|---|---|---|---|---|---|
| Penicillin | 16 (89%) | 16 (73%) | 106 (82%) | 106 (81%) | 244 (81%) |
| Oxacillin | 1 (6%) | 6 (27%) | 25 (19%) | 26 (20%) | 58 (19%) |
| Ciprofloxacin | 8 (44%) | 6 (27%) | 53 (41%) | 52 (40%) | 119 (40%) |
| Gatifloxacin | 6 (33%) | 7 (32%) | 40 (31%) | 42(32%) | 95 (32%) |
| Moxifloxacin | 6 (33%) | 5 (23%) | 42 (32%) | 42 (32%) | 95 (32%) |
| Trimethoprim/Sulfamethoxazole | 6 (33%) | 3 (14%) | 31 (24%) | 31 (24%) | 71 (24%) |
| Bacitracin | 5 (28%) | 6 (27%) | 27 (21%) | 23 (18%) | 61 (20%) |
| Erythromycin | 7 (39%) | 8 (36%) | 62 (48%) | 62 (47%) | 139 (46%) |
| Tetracycline | 2 (11%) | 4 (18%) | 25 (19%) | 27 (21%) | 58 (19%) |
| Gentamicin | 5 (28%) | 1 (5%) | 1 (1%) | 2 (2%) | 9 (3%) |
| Any fluoroquinolone | 8 (44%) | 7 (32%) | 54 (42%) | 54 (41%) | 123 (41%) |
| Organism | Right Conjunctiva | Left Conjunctiva | Right Nare | Left Nare |
|---|---|---|---|---|
| Staphylococcus epidermidis | 12 | 13 | 67 | 69 |
| Other CNS | 1 | 1 | 31 | 30 |
| Staphylococcus aureus | 4 | 5 | 21 | 22 |
| Citrobacter | 0 | 0 | 1 | 1 |
| Micrococcus | 0 | 0 | 2 | 2 |
| Proteus | 1 | 1 | 4 | 4 |
| α-hemolytic Streptococcus | 0 | 2 | 4 | 3 |
| Not tested for resistance | ||||
| Mold | 0 | 0 | 0 | 1 |
| Bacillus | 0 | 0 | 1 | 1 |
| Gram-negative rods | 0 | 0 | 2 | 2 |
| Moraxella | 0 | 0 | 5 | 5 |
| Corynebacterium | 1 | 2 | 28 | 26 |
| Insignificant CNS | 37 | 30 | 14 | 13 |
| None | 52 | 54 | 0 | 0 |
| Antibiotic | Right Conjunctiva (n = 12) | Left Conjunctiva (n = 13) | Right Nare (n = 67) | Left Nare (n = 69) |
|---|---|---|---|---|
| Penicillin | 10 (83%) | 10 (77%) | 57 (85%) | 58 (84%) |
| Oxacillin | 1 (8%) | 4 (31%) | 15 (22%) | 16 (23%) |
| Ciprofloxacin | 6 (50%) | 5 (38%) | 31 (46%) | 32 (46%) |
| Gatifloxacin | 5 (42%) | 6 (46%) | 25 (37%) | 26 (38%) |
| Moxifloxacin | 5 (42%) | 4 (31%) | 25 (37%) | 26 (38%) |
| Trimethoprim-Sulfamethoxazole | 6 (50%) | 3 (23%) | 18 (27%) | 18 (26%) |
| Bacitracin | 3 (25%) | 4 (31%) | 12 (18%) | 10 (14%) |
| Erythromycin | 6 (50%) | 6 (46%) | 33 (49%) | 34 (49%) |
| Tetracycline | 1 (8%) | 3 (23%) | 11 (16%) | 11 (16%) |
| Gentamicin | 4 (33%) | 1 (8%) | 1 (1%) | 1 (1%) |
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