September 2017

RESIDENTS

EyeWorld journal club
Review of “Long-term effects of cataract surgery with topical levofloxacin on ocular bacterial flora”


by Brandon Wong, MD, Vivek Patel, MD, and J. Bradley Randleman, MD


Vivek Patel, MD, USC residency
program director


Vivek Patel, MD, Brandon Wong, MD, and J. Bradley Randleman, MD
Source: USC Roski Eye Institute

Emerging bacterial resistance due to topical antibiotic prophylaxis is an important consideration for cataract surgeons. This month, I invited the USC residents to review this study on the longer-term consequences of drug resistance in this setting, which appears in the September issue of JCRS.

—David F. Chang, MD,
EyeWorld journal club editor

 

The normal ocular flora in healthy individuals includes a diverse spectrum of bacteria, including Staphylococcus epidermidis (S. epidermidis) and Propionibacterium acnes (P. acnes), which have previously been identified as important pathogens causing endophthalmitis following cataract surgery. Preoperative measures to prevent endophthalmitis include routine disinfection of the ocular surface with direct povidone-iodine as well as preoperative antibiotics. In Japan, a recent survey of cataract surgeons revealed 99% of respondents used preoperative topical antibiotics; after cataract surgery 6% used postoperative drops for less than 2 weeks, 30% used them for 2–4 weeks, and 63% used postoperative antibiotics for 1 month or more.1 This prolonged use of antibiotics calls to question the potential effects this may have on bacterial resistance to antibiotics. Miyanaga et al. reported that 3-week continuous instillation of levofloxacin changed the normal bacterial flora and led to higher resistance rates in S. epidermidis through a possible induction of fluoroquinolone resistance.2 Similarly, after a 3-month follow-up, Nejima et al. found a 20% decrease in S. epidermidis susceptibility in patients with 1 month of postoperative levofloxacin treatment compared to 1-week postoperative treatment.3 While these studies indicate short-term alterations of the bacterial environment and antibiotics susceptibility, to date there have not been any studies looking at the long-term effects on normal ocular flora after topical antibiotic use.
In “Long-term effects of cataract surgery with topical levofloxacin on ocular bacterial flora,” Ono et al. conducted a single-center, prospective study evaluating the long-term effects of topical antibiotics on ocular bacterial flora after cataract surgery. The study looked at 50 patients undergoing cataract surgery who had topical levofloxacin 1.5% instilled in the eye four times per day from preoperative day 3 to 1 month postop. All patients additionally received 3 days of oral cefcapene pivoxil (third generation cephalosporin) immediately after surgery. Bacterial scrapings from the conjunctival sac were obtained before the start of topical levofloxacin, as well as at 0 (after last levofloxacin treatment), 3, 6, 9, and 12 months after postoperative levofloxacin instillation. Aerobic and anaerobic cultures were performed on scrapings, and each bacterial isolate underwent minimum inhibitory concentration (MIC) determinations of levofloxacin. The authors used mixed-effects models to compare the differences between number of bacterial species pre-surgery and other time points, as well as to compare the geometric mean MICs of levofloxacin on S. epidermidis and P. acnes at each visit pre-surgery.
The authors report that all 50 patients completed 6 months and 48 patients completed 1 year of follow-up after last topical levofloxacin instillation. Prior to administration of levofloxacin, bacteria were isolated from 48 eyes. S. epidermidis (33.3%) and P. acnes (33.3%) were the most common species isolated before treatment. After last treatment with topical levofloxacin (month 0) the percent of eyes positive for bacterial isolates was significantly decreased (p<0.01); P. acnes was the predominant bacterial species detected. Compared to pre-surgery, there was no statistical difference in percent of eyes positive for bacteria 3, 6, 9, or 12 months after last levofloxacin treatment or in the bacterial diversity. The mean geometric MIC for S. epidermidis was significantly higher at 0 months compared to pre-surgery; there were no statistical differences between the initial and other time points. The MIC of P. acnes was not significantly different before or after topical levofloxacin.
This study demonstrates the reduction of normal ocular flora diversity after extended levofloxacin use after cataract surgery as well as the ability of the ocular flora to regenerate after such use. There is a significant increase in the MIC of S. epidermis after topical levofloxacin administration for 1 month, and the MIC was not restored to retreatment levels until 6 months after last treatment. These findings not only indicate the potential for the development of antibiotic resistant bacteria (given the higher MIC after 1 month), they also demonstrate the long-term alterations in the microbial environment after long-term antibiotic use, which could have a significant impact on the normal flora. Interestingly, there was no observed change in MIC in P. acnes. The authors assert that the different MIC pattern observed between S. epidermidis and P. acnes could be attributed to differing replicating activity of the bacteria and bacterial location. They suggest the continuous turnover of susceptible P. acnes from the meibomian glands, as well as its transient movement through the conjunctival sac without replicating, may account for the lack of bacterial resistance seen after
extended levofloxacin use. While this particular study did not look at the short-term use of topical antibiotics, a study done by the same
authors evaluated the MIC of S. epidermidis after 1 week of postoperative levofloxacin compared to 1 month of postoperative levofloxacin; they found that at the 3-month follow-up the MIC of the 1-month group was twice that of the 1-week group, and there were 20% less susceptible strains in the 1-month group.3 The results of that study and this present one suggest that using postoperative antibiotics for a shorter period of time prevents the development of antibiotic resistant strains and prevents significant alteration to the normal ocular flora.
While the authors sensibly focus on the development of levofloxacin resistant strains after levofloxacin use in their study, the effects of prolonged antibiotic use may still have effects on the normal flora beyond development of resistance to one antibiotic alone. For example, it is interesting to note the sharp increase in methicillin resistant S. epidermidis species 3 and 6 months after antibiotics use, which is not emphasized by the authors. The ocular bacterial milieu is complex and antibiotic use may have other, unforeseen, or as of yet unidentified consequences on the ocular flora. A sub-analysis of patients specifically with S. epidermidis or P. acnes isolates would be interesting, especially to see what other isolates were noted in these patients and if those isolates had developed any indication of bacterial resistance. One notable confounding factor in this study that the authors acknowledge is the use of the oral cefcapene after surgery in conjunction with topical levofloxacin; this makes it difficult to ascertain the true effect of the topical levofloxacin on the perioperative surgical bacterial environment.
Although endophthalmitis is a rare complication after cataract surgery, the threat of infection and questions as to how to prevent such infections persist. Moreover, the risk of development of antibiotic resistant microbes is an ongoing concern that must also be simultaneously addressed. While newer approaches for endophthalmitis prophylaxis such as intracameral antibiotics have been more recently advocated, topical antibiotics have consistently been used to prevent infection with varying treatment durations. The Endophthalmitis Vitrectomy Study (EVS) showed that Gram-positive, coagulase negative species were the most common bacteria isolated in post-cataract endophthalmitis, and 61% of patients presented in the first week following cataract surgery.4 In the U.S. and Europe, the common practice after cataract surgery is to use postoperative topical antibiotics for 1 week or less, usually a fluoroquinolone that has broad Gram-positive and Gram-negative coverage.5
This study strengthens our knowledge about the long-term effects of topical levofloxacin on the normal ocular flora and its potential effect on the development of antibiotic resistant bacteria; specifically, there is an alteration in the normal flora for 6 months with a demonstrable increase in the MIC for S. epidermidis after long-term postoperative antibiotic use. These alterations and risk of antimicrobial resistance are not seen after short-term postoperative antibiotic regimens as commonly used in other countries. The potential adverse microbial consequences without any current evidence to establish benefit may have important implications on the value, effectiveness, and risk of long-term antibiotic use in Japan after cataract surgery and should promote a reevaluation of the country’s predominant practice pattern.

References

1. Matsuura K, et al. Survey of Japanese ophthalmic surgeons regarding perioperative disinfection and antibiotic prophylaxis in cataract surgery. Clin Ophthalmol. 2014;8:2013–8.
2. Miyanaga M, et al. Changes in drug susceptibility and the quinolone-resistance determining region of Staphylococcus epidermidis after administration of fluoroquinolones. J Cataract Refract Surg. 2009;35:1970–8.
3. Nejima R, et al. Effect of the administration period of perioperative topical levofloxacin on normal conjunctival bacterial flora. J Cataract Refract Surg. 2017;43:42–48.
4. Results of the Endophthalmitis Vitrectomy Study. A randomized trial of immediate vitrectomy and of intravenous antibiotics for the treatment of postoperative bacterial endophthalmitis. Endophthalmitis Vitrectomy Study Group. Arch Ophthalmol. 1995;113:1479–96.
5. Chang DF, et al. Antibiotic prophylaxis of postoperative endophthalmitis after cataract surgery: Results of the 2014 ASCRS member survey. J Cataract Refract Surg. 2015;41:1300–5.

Contact information

Patel: Vivek.Patel@med.usc.edu

Review of “Long-term effects of cataract surgery with topical levofloxacin on ocular bacterial flora” Review of “Long-term effects of cataract surgery with topical levofloxacin on ocular bacterial flora”
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