- Email: [email protected]
Long-term effects of cataract surgery with topical levofloxacin on ocular bacterial flora
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ARTICLE
Long-term effects of cataract surgery with topical levofloxacin on ocular bacterial flora Takashi Ono, MD, Ryohei Nejima, MD, Takuya Iwasaki, MD, PhD, Yosai Mori, MD, Yukari Noguchi, COT, Akiko Yagi, BS, Hideaki Hanaki, PhD, Kazunori Miyata, MD, PhD
Purpose: To clarify the long-term effect of topical antibiotics on the ocular bacterial flora after cataract surgery. Setting: Miyata Eye Hospital, Miyazaki, Japan. Design: Prospective case series. Methods: Patients who had cataract surgery between November 2014 and January 2015 were included. Levofloxacin 1.5% was administered 4 times a day by topical instillation from 3 days before surgery to 1 month postoperatively. The conjunctival sacs of patients were scraped before the procedure and 0, 3, 6, 9, and 12 months after the last instillation. The samples were cultured, and minimum inhibitory concentrations (MICs) of levofloxacin for Staphylococcus epidermidis and Propionibacterium acnes were evaluated using mixed-effects models.
T
he ocular surface of healthy individuals contains various bacteria such as Staphylococcus epidermidis and other coagulase-negative Staphylococcus, Propionibacterium acnes, and Corynebacterium.1 Staphylococcus epidermidis and other coagulase-negative Staphylococcus species are important causal pathogens for postoperative endophthalmitis.2–4 Based on molecular analyses, Speaker et al.5 and Bannerman et al.6 showed that these pathogens are derived from the ocular surface flora. To prevent postoperative endophthalmitis, the ocular surface is disinfected by the perioperative administration of topical antibiotics in addition to the direct application of iodine solution during surgery.7,8 In Japan, many patients having cataract surgery receive topical antibiotic instillations 3 days before to 1 month after surgery.9
Results: The study evaluated 50 patients. Diverse bacterial species, predominantly S epidermidis and P acnes, were isolated before the application of topical levofloxacin. Bacterial diversity was substantially reduced after the final topical levofloxacin application and subsequently increased after 3 months. However, the geometric mean levofloxacin MICs for S epidermidis isolates were still significantly higher at 0 months and 3 months than before treatment (P < .01 and P Z .03, respectively) and reached pretreatment levels 6 months and 12 months after the last application. Propionibacterium acnes did not show significant changes in the geometric mean levofloxacin MIC over time.
Conclusion: The restoration of the bacterial flora required more than 6 months after cataract surgery and topical levofloxacin. J Cataract Refract Surg 2017; 43:1129–1134 Q 2017 ASCRS and ESCRS
However, the resilience of the ocular surface flora after these clinical interventions for ophthalmologic surgery has not been well investigated. We recently reported that the duration of perioperative topical levofloxacin administration influences levofloxacin susceptibility of S epidermidis isolates from the ocular surface after cataract surgery.10 Bacterial resistance to antibiotics has become an important clinical and public health issue. The presence of oxacillin-resistant S aureus in the conjunctival sac is significantly associated with recent antibiotic use.11 Three-week administration of topical fluoroquinolones increases the rate of fluoroquinolone-resistant S epidermidis isolation from ocular surfaces.12 However, the fate of these antibiotic-resistant staphylococci after the last topical instillation of antibiotics is unclear.
Submitted: February 23, 2017 | Final revision submitted: June 9, 2017 | Accepted: June 15, 2017 From Miyata Eye Hospital (Ono, Nejima, Iwasaki, Mori, Noguchi, Yagi, Miyata), Miyakonojo, and the Kitasato Institute for Life Sciences (Hanaki), Kitasato University, Tokyo, Japan. Supported by Santen Pharmaceutical Co., Ltd., Osaka, Japan. Toshihito Furukawa performed the statistical analysis. Corresponding author: Takashi Ono, MD, Miyata Eye Hospital, Miyakonojo, Miyazaki 885-0051, Japan. E-mail: [email protected]. Q 2017 ASCRS and ESCRS Published by Elsevier Inc.
0886-3350/$ - see frontmatter http://dx.doi.org/10.1016/j.jcrs.2017.06.037
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LONG-TERM RESPONSE OF OCULAR BACTERIA TO LEVOFLOXACIN
The purpose of this paper is to clarify the long-term effect of topical antibiotics on the ocular bacterial flora after cataract surgery. PATIENTS AND METHODS This prospective case series study included patients who had cataract surgery in 2014 or 2015. Patients were excluded if they had a history of antibacterial or immunosuppressive medications or ophthalmic surgery within 3 months, ophthalmologic infection, systemic underlying disease, and hospitalization for any reason other than ophthalmic surgery. The study was approved by the Institutional Review Board, Miyata Eye Hospital, Miyazaki, Japan, and was performed in accordance with the tenets of the Declaration of Helsinki and ethical guidelines for clinical research. All patients provided written informed consent after discussion. Surgical Protocol and Medication Administration Before surgery, the ocular surfaces were disinfected using 1 minute of irrigation with polyvinyl alcohol–iodide solution and washed with sterile 0.9% sodium chloride. Topical instillation of levofloxacin 1.5% (Cravit) 4 times per day was initiated on the third preoperative day.13 On the day of surgery, eyedrops were administered in the morning and 1 hour before surgery. For 1 month after surgery, levofloxacin 1.5% was administered 4 times a day. Oral cefcapene pivoxil 300 mg/day (Flomox) was administered to the patients for 3 days after surgery. Bacteriologic Analysis A bacteriologic examination was performed on samples scraped from the conjunctival sac under surface anesthesia with preservative-free oxybuprocaine hydrochloride before the start of topical levofloxacin administration and 0 month (after the last levofloxacin treatment), 3 months, 6 months, 9 months, and 12 months after the postoperative instillation of antibiotics. This timing was equivalent to 1 month, 4 months, 7 months, 10 months, and 13 months after surgery, respectively. Specimens were examined by direct culture and liquid culture under aerobic and anaerobic conditions. The aerobic culture was performed at 36.5 C for 24 to 48 hours in trypticase soy agar with Columbia colistin, nalidixic acid agar, and 5% sheep blood (Becton Dickinson Co.), Columbia agar with 5% sheep blood (Becton Dickinson Co.), and chocolate agar (Kyokuto Pharmaceutical Industrial Co. Ltd.). The anaerobic culture was performed at 36.5 C for 24 to 120 hours using Columbia agar with 5% sheep blood under anaerobic conditions. The liquid culture was performed in thioglycolate broth at 36.5 C for 1 to 2 weeks. Each bacterial isolate was evaluated to determine the minimum inhibitory concentrations (MICs) of levofloxacin in accordance with the broth microdilution method described in the Clinical and Laboratory Standards Institute Standards.14 The MICs of levofloxacin were determined using antibiotic susceptibility tests with the SG17 plate (Eiken Chemical).15 For Staphylococcus species; the MIC of oxacillin was measured to identify isolates as methicillin-susceptible or methicillin-resistant. Statistical Analysis Data obtained from the pretreatment visit to the final 12-month visit were used for the analysis. To estimate the differences between the number of bacterial species before surgery and the counts at other timepoints, mixed-effects models were used with the number of bacterial species as a response variable, visit as a fixed effect, and patient as a random effect. To estimate the geometric mean MICs of levofloxacin on S epidermidis and P acnes at each visit and the mean changes from preoperatively, mixedeffects models were used with log-transformed MICs as a response variable, visit as a fixed effect, and patient as a random effect. The estimated geometric mean MICs are reported with 95% Volume 43 Issue 9 September 2017
confidence intervals. The influence of background factors on isolates was evaluated using a generalized estimating equation (GEE) logistic model. Statistical analyses were implemented in SAS software (version 9.4, SAS Institute, Inc.). A P value less than 0.05 was considered to indicate a statistically significant difference.
RESULTS This study enrolled 50 patients. The mean age of the 29 women and 21 men was 74.4 years G 7.4 (SD) (range 56 to 88 years). The initial operated eye was examined bacteriologically in patients who subsequently received contralateral surgery within the study period. All 50 patients were followed for at least 6 months after the last topical levofloxacin treatment. One patient could not be followed after 9 months, and 2 patients could not be followed after 12 months. No patient developed blepharitis or postsurgical infection. Bacterial Isolates
Before topical levofloxacin was administered, bacteria were isolated from 48 of 50 eyes by direct and/or liquid culture methods (Table 1). Single or multiple strains were isolated from many eyes at 3, 6, 9, and 12 months after the last levofloxacin treatment, but either no strains or single strains were isolated immediately after the last levofloxacin treatment (0 month). In a mixed-effects model, the percentage of eyes that were positive for bacterial isolates was significantly lower at 0 month (after the last levofloxacin treatment) than before antibiotic administration (P ! .01) (Figure 1). However, no significant changes were observed 3, 6, 9, or 12 months after the last levofloxacin treatment. Isolated Bacterial Species
Various species were frequently isolated from the conjunctival sac before the start of topical levofloxacin treatment (Tables 1 and 2). Staphylococcus epidermidis (33.3%) and P acnes (33.3%) were the predominant species detected. Immediately after the last levofloxacin treatment (0 month), the bacterial diversity of the conjunctival sac was substantially reduced and P acnes became the predominant isolate. Three months after the last levofloxacin treatment, bacterial diversity in the conjunctival sac was similar to that observed before the first levofloxacin treatment (Figure 2). In a GEE logistic model, a significant decrease in diversity was observed at 0 month only. Antibiotic Susceptibility of Isolates
Regarding changes in the levofloxacin MIC of S epidermidis, the mean geometric MIC was significantly higher at 0 month than before the initial levofloxacin treatment (Figure 3). Thereafter, the mean MIC values decreased and did not differ significantly from the initial value. The levofloxacin MIC of P acnes showed no significant differences before and after topical levofloxacin administration (Figure 3). In an analysis of the cumulative percentage of levofloxacin MICs for all S epidermidis isolates at each timepoint, single-step increases were consistently observed at approximately 4 mg/mL (Figure 4). The cumulative percentage was lower for isolates 3 months and 6 months after the last levofloxacin than for other isolates below 4 mg/mL.
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LONG-TERM RESPONSE OF OCULAR BACTERIA TO LEVOFLOXACIN
Table 1. Number of strains isolated from the conjunctival sac before and after the postoperative instillation of levofloxacin. Number of Isolated Strains Months After Topical LVFX
0
1
2
3
4
5
Pre (n Z 50) 0 mo (n Z 50) 3 mo (n Z 50) 6 mo (n Z 50) 9 mo (n Z 48) 12 mo (n Z 47)
2 18 3 3 6 7
18 26 19 15 13 17
22 5 25 24 20 20
7 1 4 5 8 1
1 0 0 2 1 2
0 0 0 1 0 0
LVFX Z levofloxacin
DISCUSSION In this study, we found the resilience of the bacterial flora of the conjunctival sacs of patients who had cataract surgery with 1 month of topical levofloxacin administration. The diversity of the bacteria flora in the conjunctival sac, which was lost after topical levofloxacin administration, recovered 3 months after the last levofloxacin treatment. The levofloxacin MICs of S epidermidis showed a transient but significant increase after treatment; however, P acnes did not change in terms of the mean levofloxacin MIC over time. The restoration of the levofloxacin MIC of S epidermidis in the conjunctival sac after the last levofloxacin treatment took more than 6 months after the last levofloxacin treatment. The predominance of S epidermidis and P acnes and the presence of multiple diverse strains before topical levofloxacin treatment were consistent with previous results obtained by aerobic and anaerobic microbiological analyses1 and suggest that the patients in this study were healthy. Few studies have reported the long-term effects of antibiotics in healthy patients. Levofloxacin resistance was based on the serum standards for systemic treatment, and there are no antibiotic breakpoint standards for topical antibiotic therapy. In this study, levofloxacin-resistant clones of S epidermidis increased within 6 months after topical levofloxacin administration and decreased thereafter. These findings
Figure 1. Percentage of samples in which bacteria were isolated at each point in the bacteriological analysis (* Z P ! .01).
are consistent with the presence of fluoroquinoloneresistant bacteria in the conjunctival sac of patients with a history of topical fluoroquinolone within 3 months.16 We recently reported that antibiotic-resistant S epidermidis are less frequent after the administration of perioperative topical levofloxacin for 1 week than after administration for 1 month.10 This suggests that the diversity and antibiotic susceptibility of ocular surface flora are not highly influenced by the ophthalmologic procedures in the United States and Europe, where antibiotics are typically administered for 1 week or less.8,17 Bacterial diversity in the conjunctival sac was highly reduced in response to topical levofloxacin and recovered at 3 months after the last levofloxacin treatment. The predominant isolates (ie, S epidermidis and P acnes) 3 months after the last levofloxacin treatment were similar to those isolated before the initial levofloxacin treatment. These species are also members of the bacterial flora of the skin,18,19 suggesting that the bacteria that reemerged in the conjunctival sac were from the surrounding skin. The mean levofloxacin MICs of S epidermidis and P acnes showed different patterns after the last levofloxacin
Table 2. Bacterial species isolated from the conjunctival sac of subjects before and 0, 3, 6, 9, and 12 months after the postoperative instillation of levofloxacin. Number of Isolated Species Species Gram-positive cocci Staphylococcus aureus Staphylococcus epidermidis Methicillin-susceptible S epidermidis Methicillin-resistant S epidermidis Other coagulase-negative Staphylococcus Streptococcus species Enterococcus faecalis Gram-positive bacilli Corynebacterium species Propionibacterium acnes Other gram-positive bacilli Gram-negative bacilli
Pre (n Z 50)
0 Mo (n Z 50)
3 Mo (n Z 50)
6 Mo (n Z 50)
9 Mo (n Z 48)
12 Mo (n Z 47)
2 29 13 16 5 4 4
0 4 3 1 2 3 0
6 32 10 22 3 3 1
5 34 14 20 3 2 2
6 23 12 11 5 3 5
4 20 10 10 3 1 3
5 29 6 3
1 28 1 0
4 29 2 1
13 26 3 3
13 23 3 0
8 25 3 1
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Figure 2. Diversity of bacterial species isolated at each point in the bacteriological analysis. Geometric mean of the number of bacterial species and 95% confidence interval (* Z P ! .01).
treatment. The former showed a transient, but significant increase, and the latter showed no change. The appearance of levofloxacin-susceptible P acnes immediately after the last levofloxacin treatment suggests that the species continuously enters from the sebaceous glands,20 probably from the meibomian glands. In addition, the lack of emergence of levofloxacin-resistant P acnes suggests that anaerobic P acnes in the conjunctival sac was in a static condition, without active replication, and might be a transient passenger because the conjunctival sac is aerobic and levofloxacin acts on DNA replication by forming a complex with bacterial gyrase/topoisomerase.21 Only a few levofloxacinresistant S epidermidis were isolated immediately after the last levofloxacin treatment. The emergence of fluoroquinolone-resistant S epidermidis with mutations in the quinolone resistance–determining region of the genome in the conjunctival sac has been detected after 3 weeks of topical fluoroquinolone administration.22 These results strongly suggest that the skin bacterial flora surrounding the eyes also disappeared, except for P acnes in the sebaceous glands of the skin, in response to topical levofloxacin.
Figure 4. Cumulative percentage of S epidermidis isolates with respect to levofloxacin MIC at each point in the bacteriological analysis. Because of the small number of isolates, results for 0 month were not included in the plot.
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Figure 3. Generalized estimating equation analysis of the levofloxacin MIC of S epidermidis and P acnes isolated at each point in the bacteriological analysis. Geometric mean and 95% confidence interval (log scale) (* Z P ! .01; ** Z P Z .03; P acnes Z Propionibacterium acnes; S epidermidis Z Staphylococcus epidermidis).
This must be confirmed by further analyses of S epidermidis in the skin surrounding the eye. In this study, the ocular surface bacterial flora might be influenced by the 1month course of topical levofloxacin 1.5% and the 3-day course of oral cefcapene pivoxil to prevent infection. However, it is reasonable to infer that topical levofloxacin played an important role in this study. The bacteria of the ocular flora are directly influenced by topical antibiotics, and the administration of antibiotics beyond 5 days does not effectively suppress the antibiotic-resistant subpopulation of gram-positive cocci.23 Eyedrops frequently overflow after topical instillation. Topical prostaglandin eyedrops for glaucoma often cause pigmentation changes in the skin surrounding the eye.24 In a previous study,10 we showed that the MIC of levofloxacin against S epidermidis increases after 1 month of administration after cataract surgery. These findings suggest that cutaneous S epidermidis surrounding the eye might also be influenced by topical levofloxacin. Accordingly, levofloxacin-resistant clones of S epidermidis might be selected as a result of the lower concentration of levofloxacin in the periphery.25 Therefore, we believe that it takes more than 6 months for the entry of S epidermidis from the surrounding skin unaffected by topical levofloxacin into the conjunctival sac. Bacterial fitness is defined as the ability to adjust the metabolism according to environmental conditions to survive and grow.25 Under antibiotic pressure, clones that are resistant to a particular antibiotic might be better suited to survive in the region influenced by the antibiotic and accordingly increase in frequency by selection. After antibiotics are no longer present in the region, entering bacteria would form the bacterial flora. Laurent et al.26 determined the generation time of methicillin-susceptible and methicillin-resistant S aureus strains; the mean generation time of methicillin-sensitive S aureus was shorter (22.9 minutes) than that of methicillin-resistant S aureus (MRSA) strains
LONG-TERM RESPONSE OF OCULAR BACTERIA TO LEVOFLOXACIN
(23.7 to 32.5 minutes). Furthermore, they found that in mixed cultures of MRSA strains with different generation times, those with shorter generation times increased in frequency.26 According to another study,27 the growth of biofilm-forming S epidermidis is slower than that of S epidermidis without biofilm-forming ability. In this study, we did not measure the generation time of each isolate. In a literature search, we could not find previous estimates of the difference in generation time between levofloxacin-susceptible and levofloxacin-resistant strains of S epidermidis. However, our results suggest that levofloxacin-susceptible S epidermidis is more suited for the conditions of the conjunctival sac than antibiotic-resistant strains after the disappearance of levofloxacin. Further studies are required to confirm these findings. In this study, we showed the resilience of indigenous ocular bacterial flora after ophthalmologic interventions with topical antibiotics. This recovery of the ocular bacterial flora requires at least 6 months after the last topical levofloxacin. Only a few bacteria have been detected on the ocular surface immediately after disinfection.7 Bacterial species with high MIC levels initially appeared on the conjunctival sac under postoperative topical antibiotics, and species with low MIC levels gradually became predominant, within 1 year of the administration of topical antibiotics. These results are consistent with those in previous results indicating a low prevalence of antibiotic-resistant bacteria in the ocular surface flora in the absence of recent antibiotic use.11
4.
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8.
9.
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WHAT WAS KNOWN Staphylococcus epidermidis and other coagulase-negative Staphylococcus are pathogens of postoperative endophthalmitis, and disinfection of the ocular surface before surgery is important for the prevention of postoperative infection. The use of topical levofloxacin with cataract surgery influences the antibiotic susceptibility of S epidermidis on the conjunctival sac.
14.
WHAT THIS PAPER ADDS
16.
Recovery of the ocular bacterial flora requires at least 6 months after the last topical levofloxacin after cataract surgery from the viewpoint of bacterial diversity and the MIC of levofloxacin. Bacteria on the skin around the eyes might contribute to the reconstruction of the ocular surface flora after surgical intervention.
REFERENCES 1. Singer TR, Isenberg SJ, Apt L. Conjunctival anaerobic and aerobic bacterial flora in paediatric versus adult subjects. Br J Ophthalmol 1988; 72:448–451. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1041480 /pdf/brjopthal00610-0049.pdf. Accessed July 14, 2017 2. Miller JJ, Scott IU, Flynn HW Jr, Smiddy WE, Newton J, Miller D. Acuteonset endophthalmitis after cataract surgery (2000–2004): incidence, clinical settings, and visual acuity outcomes after treatment. Am J Ophthalmol 2005; 139:983–987 3. Lalwani GA, Flynn HW Jr, Scott IU, Quinn CM, Berrocal AM, Davis JL, Murray TG, Smiddy WE, Miller D. Acute-onset endophthalmitis after clear
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corneal cataract surgery (1996–2005); clinical features, causative organisms, and visual acuity outcomes. Ophthalmology 2008; 115:473–476 Pijl BJ, Theelen T, Tilanus MAD, Rentenaar R, Crama N. Acute endophthalmitis after cataract surgery: 250 consecutive cases treated at a tertiary referral center in the Netherlands. Am J Ophthalmol 2010; 149:482–487 Speaker MG, Milch FA, Shah MK, Eisner W, Kreiswirth BN. Role of external bacterial flora in the pathogenesis of acute postoperative endophthalmitis. Ophthalmology 1991; 98:639–649; discussion by J Baum, 650 Bannerman TL, Rhoden DL, McAllister SK, Miller JM, Wilson LA, for the Endophthalmitis Vitrectomy Study Group. The source of coagulase-negative staphylococci in the Endophthalmitis Vitrectomy Study; a comparison of eyelid and intraocular isolates using pulsed-field gel electrophoresis. Arch Ophthalmol 1997; 115:357–361 Inoue Y, Usui M, Ohashi Y, Shiota H, Yamazaki T. Preoperative disinfection of the conjunctival sac with antibiotics and iodine compounds: a prospective randomized multicenter study; for the Preoperative Disinfection Study Group. Jpn J Ophthalmol 2008; 52:151–161 Chang DF, Braga-Mele R, Henderson BA, Mamalis N, Vasavada A, for the ASCRS Cataract Clinical Committee. Antibiotic prophylaxis of postoperative endophthalmitis after cataract surgery: results of the 2014 ASCRS member survey. J Cataract Refract Surg 2015; 41:1300–1305. Available at: http://www.ascrs.org/sites/default/files/resources/endopthalmitis-survey -Chang.pdf. Accessed July 14, 2017 Matsuura K, Mori T, Miyamoto T, Suto C, Saeki Y, Tanaka S, Kawamura H, Ohkubo S, Tanito M, Inoue Y. Survey of Japanese ophthalmic surgeons regarding perioperative disinfection and antibiotic prophylaxis in cataract surgery. Clin Ophthalmol 2014; 8:2013–2018. Available at: https://www.ncbi .nlm.nih.gov/pmc/articles/PMC4189719/pdf/opth-8-2013.pdf. Accessed July 14, 2017 Nejima R, Shimizu K, Ono T, Noguchi Y, Yagi A, Iwasaki T, Shoji N, Miyata K. Effect of the administration period of perioperative topical levofloxacin on normal conjunctival bacterial flora. J Cataract Refract Surg 2017; 43:42–48 Hsu HY, Lind JT, Miller D, Tseng L. Assessment of risk factors for oxacillinresistant ocular flora in eyes having cataract surgery. J Cataract Refract Surg 2015; 41:387–392 Miyanaga M, Nejima R, Miyai T, Miyata K, Ohashi Y, Inoue Y, Tokyokawa M, Asari S. Changes in drug susceptibility and the quinolone-resistance determining region of Staphylococcus epidermidis after administration of fluoroquinolones. J Cataract Refract Surg 2009; 35:1970–1978 Suzuki T, Tanaka H, Toriyama K, Okamoto S, Urabe K, Hashida M, Shinkai Y, Ohashi Y. Prospective clinical evaluation of 1.5% levofloxacin ophthalmic solution in ophthalmic perioperative disinfection. J Ocul Pharmacol Ther 2013; 29:887–892 Clinical and Laboratory Standards Institute. Performance Standards for Antimicrobial Susceptibility Testing; Twenty-Second Informational Supplement, M100–S22. Wayne, PA, Clinical and Laboratory Standards Institute, 2012; Available at: http://zums.ac.ir/files/health/pages/ill/azmayeshghah /clsi_2013.pdf. Accessed July 14, 2017 Tou N, Nejima R, Ikeda Y, Hori Y, Araki-Sasaki K, Miyata K, Inoue Y, Tawara A. Clinical utility of antimicrobial susceptibility measurement plate covering formulated concentrations of various ophthalmic antimicrobial drugs. Clin Ophthalmol 2016; 10:2251–2257. Available at: https://www.ncbi.nlm.nih.gov/pmc /articles/PMC5108616/pdf/opth-10-2251.pdf. Accessed July 14, 2017 Ishihara K, Shimokubo N, Sakagami A, Ueno H, Muramatsu Y, Kadosawa T, Yanagisawa C, Hanaki H, Nakajima C, Suzuki Y, Tamura Y. Occurrence and molecular characteristics of methicillin-resistant Staphylococcus aureus and methicillin-resistant Staphylococcus pseudointermedius in an academic veterinary hospital. Appl Environ Microbiol 2010; 76:5165–5174. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles /PMC2916498/pdf/2780-09.pdf. Accessed July 14, 2017 €ell J, Kodjikian L, Mencucci R, Nuijts R, Behndig A, Cochener-Lamard B, Gu Pleyer U, Rosen P, Szaflik J, Tassignon M-J. Surgical, antiseptic, and antibiotic practice in cataract surgery: results from the European Observatory in 2013. J Cataract Refract Surg 2015; 41:2635–2643. Available at: http://www.jcrsjournal.org/article/S0886-3350(15)01134-7/pdf. Accessed July 14, 2017 Fintelmann RE, Hoskins EN, Lietman TM, Keenan JD, Gaynor BD, Cevallos V, Acharya NR. Topical fluoroquinolone use as a risk factor in vitro fluoroquinolone resistance in ocular culture. Arch Ophthalmol 2011; 129:399–402. Available at: https://www.ncbi.nlm.nih.gov/pmc /articles/PMC3830547/pdf/nihms-525034.pdf. Accessed July 14, 2017 Cogen AL, Nizet V, Gallo RL. Skin microbiota: a source of disease or defense? Br J Dermatol 2008; 158:442–455 Grice EA, Kong HH, Conlan S, Deaming CB, Davis J, Young AC, NISC Comparative Sequencing Program, Bouffard GG, Blakesley RW, Murray PR, Green ED, Turner ML, Segre JA. Topographical and temporal diversity of the human skin microbiome. Science 2009; 324:1190–1192.
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Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2805064 /pdf/nihms162584.pdf. Accessed July 14, 2017 Achermann Y, Goldstein EJC, Coenye T, Shirtliff ME. Propionibacterium acnes: from commensal to opportunistic biofilm-associated implant pathogen. Clin Microbiol Rev 2014; 27:419–440. Available at: https://www .ncbi.nlm.nih.gov/pmc/articles/PMC4135900/pdf/zcm419.pdf. Accessed July 14, 2017 Wolfson JS, Hooper DC. Fluoroquinolone antimicrobial agents. Clin Microbiol Rev 1989; 2:378–424. Available at: https://www.ncbi.nlm.nih.gov/pmc /articles/PMC358131/pdf/cmr00054-0058.pdf. Accessed July 14, 2017 Tam VH, Louie A, Fritsche TR, Deziel M, Liu W, Brown DL, Deshpande L, Leary R, Jones RN, Drusano GL. Impact of drug-exposure intensity and duration of therapy on the emergence of Staphylococcus aureus resistance to a quinolone antimicrobial. J Infect Dis 2007; 195:1818–1827. Available at: https://academic.oup.com/jid/article-lookup/doi/10.1086/518003. Accessed July 14, 2017 Johnstone MA. Hypertrichosis and increased pigmentation of eyelashes and adjacent hair in the region of the ipsilateral eyelids of patients treated with unilateral topical latanoprost. Am J Ophthalmol 1997; 124:544–547 Gullberg E, Cao S, Berg OG, Ilback C, Sandegren L, Hughes D, Anderson DI. Selection of resistant bacteria at very low antibiotic concentration. PloS Pathog 2010; 7:e1002158. https://www.ncbi.nlm.nih.gov/pmc /articles/PMC3141051/pdf/ppat.1002158.pdf Laurent F, Lelievre H, Cornu M, Vandensch F, Carret G, Etienne J, Flandrois JP. Fitness and competitive growth advantage of new gentamicin-susceptible MRSA clones spreading in French Hospitals. J Antimicrob Chemother 2001; 47:277–283 Ali H, Greco-Stewart VS, Jacobs MR, Yomtovian RA, Rood IGH, de Korte D, Ramirez-Arcos SM. Characterization of the growth dynamics and biofilm formation of Staphylococcus epidermidis strains isolated from contaminated platelet units. J Med Microbiol 2014; 63:884–891
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Disclosures: Dr. Ono receives grants from Santen Pharmaceutical Co., Ltd. and lecture fees from Senju Pharmaceutical Co., Ltd. Dr. Nejima receives grants and lecture fees from Santen Pharmaceutical Co., Ltd. and lecture fees from Senju Pharmaceutical Co., Ltd. Drs. Iwasaki, Noguchi, and Yagi receive grants from Santen Pharmaceutical Co., Ltd. Dr. Mori receives grants from Abbott Medical Optics, Inc., Beaver-Visitec International, Inc., Mitsubishi Chemical Medience, and Santen Pharmaceutical Co., Ltd.; grants and lecture fees from Alcon Laboratories, Inc., Hoya Corp., Otsuka Pharmaceutical Co., Ltd., and Senju Pharmaceutical Co., Ltd.; and lecture fees from Kowa Pharmaceutical Co Ltd. and Pfizer Inc. Dr. Miyata receives grants from Santen Pharmaceutical Co., Ltd.; lecture fees and consultation fees from Alcon Laboratories, Inc.; grants and lecture fees from Senju Pharmaceutical Co., Ltd.; and lecture fees from Otsuka Pharmaceutical Co., Ltd. Dr. Hanaki has no financial or proprietary interest in any material or method mentioned.
First author: Takashi Ono, MD Miyata Eye Hospital, Miyakonojo, Japan
ARTICLE
Long-term effects of cataract surgery with topical levofloxacin on ocular bacterial flora Takashi Ono, MD, Ryohei Nejima, MD, Takuya Iwasaki, MD, PhD, Yosai Mori, MD, Yukari Noguchi, COT, Akiko Yagi, BS, Hideaki Hanaki, PhD, Kazunori Miyata, MD, PhD
Purpose: To clarify the long-term effect of topical antibiotics on the ocular bacterial flora after cataract surgery. Setting: Miyata Eye Hospital, Miyazaki, Japan. Design: Prospective case series. Methods: Patients who had cataract surgery between November 2014 and January 2015 were included. Levofloxacin 1.5% was administered 4 times a day by topical instillation from 3 days before surgery to 1 month postoperatively. The conjunctival sacs of patients were scraped before the procedure and 0, 3, 6, 9, and 12 months after the last instillation. The samples were cultured, and minimum inhibitory concentrations (MICs) of levofloxacin for Staphylococcus epidermidis and Propionibacterium acnes were evaluated using mixed-effects models.
T
he ocular surface of healthy individuals contains various bacteria such as Staphylococcus epidermidis and other coagulase-negative Staphylococcus, Propionibacterium acnes, and Corynebacterium.1 Staphylococcus epidermidis and other coagulase-negative Staphylococcus species are important causal pathogens for postoperative endophthalmitis.2–4 Based on molecular analyses, Speaker et al.5 and Bannerman et al.6 showed that these pathogens are derived from the ocular surface flora. To prevent postoperative endophthalmitis, the ocular surface is disinfected by the perioperative administration of topical antibiotics in addition to the direct application of iodine solution during surgery.7,8 In Japan, many patients having cataract surgery receive topical antibiotic instillations 3 days before to 1 month after surgery.9
Results: The study evaluated 50 patients. Diverse bacterial species, predominantly S epidermidis and P acnes, were isolated before the application of topical levofloxacin. Bacterial diversity was substantially reduced after the final topical levofloxacin application and subsequently increased after 3 months. However, the geometric mean levofloxacin MICs for S epidermidis isolates were still significantly higher at 0 months and 3 months than before treatment (P < .01 and P Z .03, respectively) and reached pretreatment levels 6 months and 12 months after the last application. Propionibacterium acnes did not show significant changes in the geometric mean levofloxacin MIC over time.
Conclusion: The restoration of the bacterial flora required more than 6 months after cataract surgery and topical levofloxacin. J Cataract Refract Surg 2017; 43:1129–1134 Q 2017 ASCRS and ESCRS
However, the resilience of the ocular surface flora after these clinical interventions for ophthalmologic surgery has not been well investigated. We recently reported that the duration of perioperative topical levofloxacin administration influences levofloxacin susceptibility of S epidermidis isolates from the ocular surface after cataract surgery.10 Bacterial resistance to antibiotics has become an important clinical and public health issue. The presence of oxacillin-resistant S aureus in the conjunctival sac is significantly associated with recent antibiotic use.11 Three-week administration of topical fluoroquinolones increases the rate of fluoroquinolone-resistant S epidermidis isolation from ocular surfaces.12 However, the fate of these antibiotic-resistant staphylococci after the last topical instillation of antibiotics is unclear.
Submitted: February 23, 2017 | Final revision submitted: June 9, 2017 | Accepted: June 15, 2017 From Miyata Eye Hospital (Ono, Nejima, Iwasaki, Mori, Noguchi, Yagi, Miyata), Miyakonojo, and the Kitasato Institute for Life Sciences (Hanaki), Kitasato University, Tokyo, Japan. Supported by Santen Pharmaceutical Co., Ltd., Osaka, Japan. Toshihito Furukawa performed the statistical analysis. Corresponding author: Takashi Ono, MD, Miyata Eye Hospital, Miyakonojo, Miyazaki 885-0051, Japan. E-mail: [email protected]. Q 2017 ASCRS and ESCRS Published by Elsevier Inc.
0886-3350/$ - see frontmatter http://dx.doi.org/10.1016/j.jcrs.2017.06.037
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LONG-TERM RESPONSE OF OCULAR BACTERIA TO LEVOFLOXACIN
The purpose of this paper is to clarify the long-term effect of topical antibiotics on the ocular bacterial flora after cataract surgery. PATIENTS AND METHODS This prospective case series study included patients who had cataract surgery in 2014 or 2015. Patients were excluded if they had a history of antibacterial or immunosuppressive medications or ophthalmic surgery within 3 months, ophthalmologic infection, systemic underlying disease, and hospitalization for any reason other than ophthalmic surgery. The study was approved by the Institutional Review Board, Miyata Eye Hospital, Miyazaki, Japan, and was performed in accordance with the tenets of the Declaration of Helsinki and ethical guidelines for clinical research. All patients provided written informed consent after discussion. Surgical Protocol and Medication Administration Before surgery, the ocular surfaces were disinfected using 1 minute of irrigation with polyvinyl alcohol–iodide solution and washed with sterile 0.9% sodium chloride. Topical instillation of levofloxacin 1.5% (Cravit) 4 times per day was initiated on the third preoperative day.13 On the day of surgery, eyedrops were administered in the morning and 1 hour before surgery. For 1 month after surgery, levofloxacin 1.5% was administered 4 times a day. Oral cefcapene pivoxil 300 mg/day (Flomox) was administered to the patients for 3 days after surgery. Bacteriologic Analysis A bacteriologic examination was performed on samples scraped from the conjunctival sac under surface anesthesia with preservative-free oxybuprocaine hydrochloride before the start of topical levofloxacin administration and 0 month (after the last levofloxacin treatment), 3 months, 6 months, 9 months, and 12 months after the postoperative instillation of antibiotics. This timing was equivalent to 1 month, 4 months, 7 months, 10 months, and 13 months after surgery, respectively. Specimens were examined by direct culture and liquid culture under aerobic and anaerobic conditions. The aerobic culture was performed at 36.5 C for 24 to 48 hours in trypticase soy agar with Columbia colistin, nalidixic acid agar, and 5% sheep blood (Becton Dickinson Co.), Columbia agar with 5% sheep blood (Becton Dickinson Co.), and chocolate agar (Kyokuto Pharmaceutical Industrial Co. Ltd.). The anaerobic culture was performed at 36.5 C for 24 to 120 hours using Columbia agar with 5% sheep blood under anaerobic conditions. The liquid culture was performed in thioglycolate broth at 36.5 C for 1 to 2 weeks. Each bacterial isolate was evaluated to determine the minimum inhibitory concentrations (MICs) of levofloxacin in accordance with the broth microdilution method described in the Clinical and Laboratory Standards Institute Standards.14 The MICs of levofloxacin were determined using antibiotic susceptibility tests with the SG17 plate (Eiken Chemical).15 For Staphylococcus species; the MIC of oxacillin was measured to identify isolates as methicillin-susceptible or methicillin-resistant. Statistical Analysis Data obtained from the pretreatment visit to the final 12-month visit were used for the analysis. To estimate the differences between the number of bacterial species before surgery and the counts at other timepoints, mixed-effects models were used with the number of bacterial species as a response variable, visit as a fixed effect, and patient as a random effect. To estimate the geometric mean MICs of levofloxacin on S epidermidis and P acnes at each visit and the mean changes from preoperatively, mixedeffects models were used with log-transformed MICs as a response variable, visit as a fixed effect, and patient as a random effect. The estimated geometric mean MICs are reported with 95% Volume 43 Issue 9 September 2017
confidence intervals. The influence of background factors on isolates was evaluated using a generalized estimating equation (GEE) logistic model. Statistical analyses were implemented in SAS software (version 9.4, SAS Institute, Inc.). A P value less than 0.05 was considered to indicate a statistically significant difference.
RESULTS This study enrolled 50 patients. The mean age of the 29 women and 21 men was 74.4 years G 7.4 (SD) (range 56 to 88 years). The initial operated eye was examined bacteriologically in patients who subsequently received contralateral surgery within the study period. All 50 patients were followed for at least 6 months after the last topical levofloxacin treatment. One patient could not be followed after 9 months, and 2 patients could not be followed after 12 months. No patient developed blepharitis or postsurgical infection. Bacterial Isolates
Before topical levofloxacin was administered, bacteria were isolated from 48 of 50 eyes by direct and/or liquid culture methods (Table 1). Single or multiple strains were isolated from many eyes at 3, 6, 9, and 12 months after the last levofloxacin treatment, but either no strains or single strains were isolated immediately after the last levofloxacin treatment (0 month). In a mixed-effects model, the percentage of eyes that were positive for bacterial isolates was significantly lower at 0 month (after the last levofloxacin treatment) than before antibiotic administration (P ! .01) (Figure 1). However, no significant changes were observed 3, 6, 9, or 12 months after the last levofloxacin treatment. Isolated Bacterial Species
Various species were frequently isolated from the conjunctival sac before the start of topical levofloxacin treatment (Tables 1 and 2). Staphylococcus epidermidis (33.3%) and P acnes (33.3%) were the predominant species detected. Immediately after the last levofloxacin treatment (0 month), the bacterial diversity of the conjunctival sac was substantially reduced and P acnes became the predominant isolate. Three months after the last levofloxacin treatment, bacterial diversity in the conjunctival sac was similar to that observed before the first levofloxacin treatment (Figure 2). In a GEE logistic model, a significant decrease in diversity was observed at 0 month only. Antibiotic Susceptibility of Isolates
Regarding changes in the levofloxacin MIC of S epidermidis, the mean geometric MIC was significantly higher at 0 month than before the initial levofloxacin treatment (Figure 3). Thereafter, the mean MIC values decreased and did not differ significantly from the initial value. The levofloxacin MIC of P acnes showed no significant differences before and after topical levofloxacin administration (Figure 3). In an analysis of the cumulative percentage of levofloxacin MICs for all S epidermidis isolates at each timepoint, single-step increases were consistently observed at approximately 4 mg/mL (Figure 4). The cumulative percentage was lower for isolates 3 months and 6 months after the last levofloxacin than for other isolates below 4 mg/mL.
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LONG-TERM RESPONSE OF OCULAR BACTERIA TO LEVOFLOXACIN
Table 1. Number of strains isolated from the conjunctival sac before and after the postoperative instillation of levofloxacin. Number of Isolated Strains Months After Topical LVFX
0
1
2
3
4
5
Pre (n Z 50) 0 mo (n Z 50) 3 mo (n Z 50) 6 mo (n Z 50) 9 mo (n Z 48) 12 mo (n Z 47)
2 18 3 3 6 7
18 26 19 15 13 17
22 5 25 24 20 20
7 1 4 5 8 1
1 0 0 2 1 2
0 0 0 1 0 0
LVFX Z levofloxacin
DISCUSSION In this study, we found the resilience of the bacterial flora of the conjunctival sacs of patients who had cataract surgery with 1 month of topical levofloxacin administration. The diversity of the bacteria flora in the conjunctival sac, which was lost after topical levofloxacin administration, recovered 3 months after the last levofloxacin treatment. The levofloxacin MICs of S epidermidis showed a transient but significant increase after treatment; however, P acnes did not change in terms of the mean levofloxacin MIC over time. The restoration of the levofloxacin MIC of S epidermidis in the conjunctival sac after the last levofloxacin treatment took more than 6 months after the last levofloxacin treatment. The predominance of S epidermidis and P acnes and the presence of multiple diverse strains before topical levofloxacin treatment were consistent with previous results obtained by aerobic and anaerobic microbiological analyses1 and suggest that the patients in this study were healthy. Few studies have reported the long-term effects of antibiotics in healthy patients. Levofloxacin resistance was based on the serum standards for systemic treatment, and there are no antibiotic breakpoint standards for topical antibiotic therapy. In this study, levofloxacin-resistant clones of S epidermidis increased within 6 months after topical levofloxacin administration and decreased thereafter. These findings
Figure 1. Percentage of samples in which bacteria were isolated at each point in the bacteriological analysis (* Z P ! .01).
are consistent with the presence of fluoroquinoloneresistant bacteria in the conjunctival sac of patients with a history of topical fluoroquinolone within 3 months.16 We recently reported that antibiotic-resistant S epidermidis are less frequent after the administration of perioperative topical levofloxacin for 1 week than after administration for 1 month.10 This suggests that the diversity and antibiotic susceptibility of ocular surface flora are not highly influenced by the ophthalmologic procedures in the United States and Europe, where antibiotics are typically administered for 1 week or less.8,17 Bacterial diversity in the conjunctival sac was highly reduced in response to topical levofloxacin and recovered at 3 months after the last levofloxacin treatment. The predominant isolates (ie, S epidermidis and P acnes) 3 months after the last levofloxacin treatment were similar to those isolated before the initial levofloxacin treatment. These species are also members of the bacterial flora of the skin,18,19 suggesting that the bacteria that reemerged in the conjunctival sac were from the surrounding skin. The mean levofloxacin MICs of S epidermidis and P acnes showed different patterns after the last levofloxacin
Table 2. Bacterial species isolated from the conjunctival sac of subjects before and 0, 3, 6, 9, and 12 months after the postoperative instillation of levofloxacin. Number of Isolated Species Species Gram-positive cocci Staphylococcus aureus Staphylococcus epidermidis Methicillin-susceptible S epidermidis Methicillin-resistant S epidermidis Other coagulase-negative Staphylococcus Streptococcus species Enterococcus faecalis Gram-positive bacilli Corynebacterium species Propionibacterium acnes Other gram-positive bacilli Gram-negative bacilli
Pre (n Z 50)
0 Mo (n Z 50)
3 Mo (n Z 50)
6 Mo (n Z 50)
9 Mo (n Z 48)
12 Mo (n Z 47)
2 29 13 16 5 4 4
0 4 3 1 2 3 0
6 32 10 22 3 3 1
5 34 14 20 3 2 2
6 23 12 11 5 3 5
4 20 10 10 3 1 3
5 29 6 3
1 28 1 0
4 29 2 1
13 26 3 3
13 23 3 0
8 25 3 1
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LONG-TERM RESPONSE OF OCULAR BACTERIA TO LEVOFLOXACIN
Figure 2. Diversity of bacterial species isolated at each point in the bacteriological analysis. Geometric mean of the number of bacterial species and 95% confidence interval (* Z P ! .01).
treatment. The former showed a transient, but significant increase, and the latter showed no change. The appearance of levofloxacin-susceptible P acnes immediately after the last levofloxacin treatment suggests that the species continuously enters from the sebaceous glands,20 probably from the meibomian glands. In addition, the lack of emergence of levofloxacin-resistant P acnes suggests that anaerobic P acnes in the conjunctival sac was in a static condition, without active replication, and might be a transient passenger because the conjunctival sac is aerobic and levofloxacin acts on DNA replication by forming a complex with bacterial gyrase/topoisomerase.21 Only a few levofloxacinresistant S epidermidis were isolated immediately after the last levofloxacin treatment. The emergence of fluoroquinolone-resistant S epidermidis with mutations in the quinolone resistance–determining region of the genome in the conjunctival sac has been detected after 3 weeks of topical fluoroquinolone administration.22 These results strongly suggest that the skin bacterial flora surrounding the eyes also disappeared, except for P acnes in the sebaceous glands of the skin, in response to topical levofloxacin.
Figure 4. Cumulative percentage of S epidermidis isolates with respect to levofloxacin MIC at each point in the bacteriological analysis. Because of the small number of isolates, results for 0 month were not included in the plot.
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Figure 3. Generalized estimating equation analysis of the levofloxacin MIC of S epidermidis and P acnes isolated at each point in the bacteriological analysis. Geometric mean and 95% confidence interval (log scale) (* Z P ! .01; ** Z P Z .03; P acnes Z Propionibacterium acnes; S epidermidis Z Staphylococcus epidermidis).
This must be confirmed by further analyses of S epidermidis in the skin surrounding the eye. In this study, the ocular surface bacterial flora might be influenced by the 1month course of topical levofloxacin 1.5% and the 3-day course of oral cefcapene pivoxil to prevent infection. However, it is reasonable to infer that topical levofloxacin played an important role in this study. The bacteria of the ocular flora are directly influenced by topical antibiotics, and the administration of antibiotics beyond 5 days does not effectively suppress the antibiotic-resistant subpopulation of gram-positive cocci.23 Eyedrops frequently overflow after topical instillation. Topical prostaglandin eyedrops for glaucoma often cause pigmentation changes in the skin surrounding the eye.24 In a previous study,10 we showed that the MIC of levofloxacin against S epidermidis increases after 1 month of administration after cataract surgery. These findings suggest that cutaneous S epidermidis surrounding the eye might also be influenced by topical levofloxacin. Accordingly, levofloxacin-resistant clones of S epidermidis might be selected as a result of the lower concentration of levofloxacin in the periphery.25 Therefore, we believe that it takes more than 6 months for the entry of S epidermidis from the surrounding skin unaffected by topical levofloxacin into the conjunctival sac. Bacterial fitness is defined as the ability to adjust the metabolism according to environmental conditions to survive and grow.25 Under antibiotic pressure, clones that are resistant to a particular antibiotic might be better suited to survive in the region influenced by the antibiotic and accordingly increase in frequency by selection. After antibiotics are no longer present in the region, entering bacteria would form the bacterial flora. Laurent et al.26 determined the generation time of methicillin-susceptible and methicillin-resistant S aureus strains; the mean generation time of methicillin-sensitive S aureus was shorter (22.9 minutes) than that of methicillin-resistant S aureus (MRSA) strains
LONG-TERM RESPONSE OF OCULAR BACTERIA TO LEVOFLOXACIN
(23.7 to 32.5 minutes). Furthermore, they found that in mixed cultures of MRSA strains with different generation times, those with shorter generation times increased in frequency.26 According to another study,27 the growth of biofilm-forming S epidermidis is slower than that of S epidermidis without biofilm-forming ability. In this study, we did not measure the generation time of each isolate. In a literature search, we could not find previous estimates of the difference in generation time between levofloxacin-susceptible and levofloxacin-resistant strains of S epidermidis. However, our results suggest that levofloxacin-susceptible S epidermidis is more suited for the conditions of the conjunctival sac than antibiotic-resistant strains after the disappearance of levofloxacin. Further studies are required to confirm these findings. In this study, we showed the resilience of indigenous ocular bacterial flora after ophthalmologic interventions with topical antibiotics. This recovery of the ocular bacterial flora requires at least 6 months after the last topical levofloxacin. Only a few bacteria have been detected on the ocular surface immediately after disinfection.7 Bacterial species with high MIC levels initially appeared on the conjunctival sac under postoperative topical antibiotics, and species with low MIC levels gradually became predominant, within 1 year of the administration of topical antibiotics. These results are consistent with those in previous results indicating a low prevalence of antibiotic-resistant bacteria in the ocular surface flora in the absence of recent antibiotic use.11
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
WHAT WAS KNOWN Staphylococcus epidermidis and other coagulase-negative Staphylococcus are pathogens of postoperative endophthalmitis, and disinfection of the ocular surface before surgery is important for the prevention of postoperative infection. The use of topical levofloxacin with cataract surgery influences the antibiotic susceptibility of S epidermidis on the conjunctival sac.
14.
WHAT THIS PAPER ADDS
16.
Recovery of the ocular bacterial flora requires at least 6 months after the last topical levofloxacin after cataract surgery from the viewpoint of bacterial diversity and the MIC of levofloxacin. Bacteria on the skin around the eyes might contribute to the reconstruction of the ocular surface flora after surgical intervention.
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Preoperative disinfection of the conjunctival sac with antibiotics and iodine compounds: a prospective randomized multicenter study; for the Preoperative Disinfection Study Group. Jpn J Ophthalmol 2008; 52:151–161 Chang DF, Braga-Mele R, Henderson BA, Mamalis N, Vasavada A, for the ASCRS Cataract Clinical Committee. Antibiotic prophylaxis of postoperative endophthalmitis after cataract surgery: results of the 2014 ASCRS member survey. J Cataract Refract Surg 2015; 41:1300–1305. Available at: http://www.ascrs.org/sites/default/files/resources/endopthalmitis-survey -Chang.pdf. Accessed July 14, 2017 Matsuura K, Mori T, Miyamoto T, Suto C, Saeki Y, Tanaka S, Kawamura H, Ohkubo S, Tanito M, Inoue Y. Survey of Japanese ophthalmic surgeons regarding perioperative disinfection and antibiotic prophylaxis in cataract surgery. Clin Ophthalmol 2014; 8:2013–2018. Available at: https://www.ncbi .nlm.nih.gov/pmc/articles/PMC4189719/pdf/opth-8-2013.pdf. Accessed July 14, 2017 Nejima R, Shimizu K, Ono T, Noguchi Y, Yagi A, Iwasaki T, Shoji N, Miyata K. Effect of the administration period of perioperative topical levofloxacin on normal conjunctival bacterial flora. J Cataract Refract Surg 2017; 43:42–48 Hsu HY, Lind JT, Miller D, Tseng L. Assessment of risk factors for oxacillinresistant ocular flora in eyes having cataract surgery. J Cataract Refract Surg 2015; 41:387–392 Miyanaga M, Nejima R, Miyai T, Miyata K, Ohashi Y, Inoue Y, Tokyokawa M, Asari S. Changes in drug susceptibility and the quinolone-resistance determining region of Staphylococcus epidermidis after administration of fluoroquinolones. J Cataract Refract Surg 2009; 35:1970–1978 Suzuki T, Tanaka H, Toriyama K, Okamoto S, Urabe K, Hashida M, Shinkai Y, Ohashi Y. Prospective clinical evaluation of 1.5% levofloxacin ophthalmic solution in ophthalmic perioperative disinfection. J Ocul Pharmacol Ther 2013; 29:887–892 Clinical and Laboratory Standards Institute. Performance Standards for Antimicrobial Susceptibility Testing; Twenty-Second Informational Supplement, M100–S22. Wayne, PA, Clinical and Laboratory Standards Institute, 2012; Available at: http://zums.ac.ir/files/health/pages/ill/azmayeshghah /clsi_2013.pdf. Accessed July 14, 2017 Tou N, Nejima R, Ikeda Y, Hori Y, Araki-Sasaki K, Miyata K, Inoue Y, Tawara A. Clinical utility of antimicrobial susceptibility measurement plate covering formulated concentrations of various ophthalmic antimicrobial drugs. Clin Ophthalmol 2016; 10:2251–2257. Available at: https://www.ncbi.nlm.nih.gov/pmc /articles/PMC5108616/pdf/opth-10-2251.pdf. Accessed July 14, 2017 Ishihara K, Shimokubo N, Sakagami A, Ueno H, Muramatsu Y, Kadosawa T, Yanagisawa C, Hanaki H, Nakajima C, Suzuki Y, Tamura Y. Occurrence and molecular characteristics of methicillin-resistant Staphylococcus aureus and methicillin-resistant Staphylococcus pseudointermedius in an academic veterinary hospital. Appl Environ Microbiol 2010; 76:5165–5174. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles /PMC2916498/pdf/2780-09.pdf. Accessed July 14, 2017 €ell J, Kodjikian L, Mencucci R, Nuijts R, Behndig A, Cochener-Lamard B, Gu Pleyer U, Rosen P, Szaflik J, Tassignon M-J. Surgical, antiseptic, and antibiotic practice in cataract surgery: results from the European Observatory in 2013. J Cataract Refract Surg 2015; 41:2635–2643. Available at: http://www.jcrsjournal.org/article/S0886-3350(15)01134-7/pdf. Accessed July 14, 2017 Fintelmann RE, Hoskins EN, Lietman TM, Keenan JD, Gaynor BD, Cevallos V, Acharya NR. Topical fluoroquinolone use as a risk factor in vitro fluoroquinolone resistance in ocular culture. Arch Ophthalmol 2011; 129:399–402. Available at: https://www.ncbi.nlm.nih.gov/pmc /articles/PMC3830547/pdf/nihms-525034.pdf. Accessed July 14, 2017 Cogen AL, Nizet V, Gallo RL. Skin microbiota: a source of disease or defense? 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Disclosures: Dr. Ono receives grants from Santen Pharmaceutical Co., Ltd. and lecture fees from Senju Pharmaceutical Co., Ltd. Dr. Nejima receives grants and lecture fees from Santen Pharmaceutical Co., Ltd. and lecture fees from Senju Pharmaceutical Co., Ltd. Drs. Iwasaki, Noguchi, and Yagi receive grants from Santen Pharmaceutical Co., Ltd. Dr. Mori receives grants from Abbott Medical Optics, Inc., Beaver-Visitec International, Inc., Mitsubishi Chemical Medience, and Santen Pharmaceutical Co., Ltd.; grants and lecture fees from Alcon Laboratories, Inc., Hoya Corp., Otsuka Pharmaceutical Co., Ltd., and Senju Pharmaceutical Co., Ltd.; and lecture fees from Kowa Pharmaceutical Co Ltd. and Pfizer Inc. Dr. Miyata receives grants from Santen Pharmaceutical Co., Ltd.; lecture fees and consultation fees from Alcon Laboratories, Inc.; grants and lecture fees from Senju Pharmaceutical Co., Ltd.; and lecture fees from Otsuka Pharmaceutical Co., Ltd. Dr. Hanaki has no financial or proprietary interest in any material or method mentioned.
First author: Takashi Ono, MD Miyata Eye Hospital, Miyakonojo, Japan