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Dr.Sreeni Edakhlon, Dr.Gopal S Pillai,Dr. PRABHU SHANKER M.,Dr.Prakash V S

PURPOSE: To study the in vitro activity of Moxifloxacin against conjunctival flora in patients undergoing cataract surgery.

DESIGN: Descriptive study

MATERIALS AND METHOD :Conjunctival swabswere taken from 480 patients who were posted for cataract surgery between November 2016 and February 2018. Culture and sensitivity tests were done using these samples. Moxifloxacin resistance was studied in the samples which grew bacteria.

RESULTS: 181 samples grew Staphylococcus epidermidis (coagulase negative staphylococcus) of which 52 (28.72%) were resistant to Moxifloxacin , 39 samples grew Staphylococcus aureus of which 18 (46.15%) were resistant to Moxifloxacin. 12 samples grew Klebsiella pneumoniae  .50% (6/12) were resistant to Moxifloxacin . Two samples grew Pseudomonas Aeruginosa, of which 50% (1/2) were resistant to Moxifloxacin.

CONCLUSION: There is a high incidence of resistance to moxifloxacin in organisms cultured  from conjunctival sac. With such a high incidence of resistance, Moxifloxacin may not be a good choice antibiotic for cataract surgery either as preoperative topical prophylaxis or as routine intracameral injection to prevent postoperative endophthalmitis.

Endophthalmitis is one of the most dreaded complications of cataract surgery. Jury is still out on what is the best intervention to reduce the risk of post operative endophthalmitis.

A  prospective, randomized European Society ofCataract & Refractive Surgeons (ESCRS) study published in year 2007,  reported that intracameral(IC) cefuroxime at the conclusion of cataract surgery significantly decreased rate of acute-onset postoperative endophthalmitis 1. The efficacy of ICcefuroxime for endophthalmitis prophylaxis has beenconfirmed by multiple studies 2-14.In a 2013 follow-up to the 2006 ESCRS study(A series of 15,689 eyes undergoing cataract surgery by nine surgeons before and after institution of prophylactic intracameral antibiotics) not a single  case  of endophthalmitis wasreported in 13,390 cataract surgeries in which  intracameral cefuroxime was used 15.Still there was no consensus on the use of intracameral antibiotics for cataract surgery, and even in Europe the ESCRS guidelines were not universally followed 16

Survey done by American Society of Cataract and Refractive Surgery (ASCRS) in 2014 among its members  found that from 1147 global respondents 36% were injecting an IC antibiotic at the conclusion of surgery compared with 14% in the  survey done in year  2007. Among the 2014 respondents in addition to the 36% already giving  IC antibiotics another 11%  planned to initiate IC injections within 6months.17,18The  2014 ASCRS survey found that cefuroxime (26%), vancomycin (37%), and moxifloxacin (33%) were comparable preferences among those using IC antibiotic prophylaxis.17

The choice of intra cameral antibiotic vary from center to center and favorable results have been reported with the use of intracameral moxifloxacin 19-25Haripriya et al  compared the postoperative endophthalmitis rate before and after initiation of intracameral moxifloxacin prophylaxis for cataract sugery. It was seen that routine IC moxifloxacin prophylaxis reduced the overall endophthalmitis rate by 3.5-fold. 26

Studies have suggested that patient’s own ocular surface flora is the major source of organisms causing endophthalmitis27,28. In the presentstudy,we evaluated the sensitivity of bacteria grown from swabs taken from conjunctival sac to the fourth generation fluoroquinolone antibiotic Moxifloxacin.

MATERIALS & METHODS

Conjunctival swabs were taken from 480 patients who were posted for cataract surgery between November 2016 and February 2018. The swabs were taken before instillation of any ophthalmic solution in the eye. Culture and antibiotic susceptibility profiles were done  through standard microbiological techniques.

RESULT

181 samples grew Staphylococcus epidermidis (coagulase negative staphylococcus) of which 52 (28.72%) were resistant to Moxifloxacin , 39 samples grew Staphylococcus aureus of which 18 (46.15%) were resistant to Moxifloxacin. 12 samples grew Klebsiella pneumonia,of which 50% (6/12) were resistant to Moxifloxacin . Two samples grew Pseudomonas Aeruginosa, of which 50% (1/2) were resistant to Moxifloxacin. (Table1 & Table 2)

Table 1

Microbial isolates from the conjunctival  swabs  of patients posted for Cataract surgery

Conjunctival isolates Total Number (n=235) Percentage (48.95%) out of 480 swabs
Conjunctival isolates Number (n=235) Percentage (%)
Gram-positive bacteria 220 93.61
 Staphylococcus epidermidis 181 77.02
 S. aureus 39 16.59
Gram-negative bacteria 14 5.95
Klebsiella Pneumoniae 12 5.10
Pseudomonas aeruginosa 2 0.85
Fungus 1 0.42
 Yeast-like 1 0.42

Table 2:Comparison of Moxifloxacin susceptibilities

Total number. Sensitive Resistant Resistant %
Gram Positive organisms 220
Staphylococcus epidermidis 181 129 52 28.72
S.aureus 39 21 18 46.15
Gram negative organisms 14
Klebsiella Pneumoniae 12 6 6 50
Pseudomonas aeruginosa 2 1 1 50

DISCUSSION

Antibiotic prophylaxis is a common preventive measure to prevent endophthalmitis .Topical antibiotic prophylaxis is given preoperatively to reduce the conjunctival bacterial load, thus lowering the risk of intraocular contamination either intraoperatively or postoperatively. Studies have given conflicting results on efficacy of topical antibiotic prophylaxis to prevent endophthalmitis29-31.Some studies support use of topical antibiotics.29Another study says that there is no extra benefit in the use of topical antibiotics in addition to topical povidone Iodine when compared to povidone iodine alone30.Bhavsar AR et al, demonstratedthat cases that used topical antibiotics in addition to topical povidone iodine had a higher risk for endophthalmitis31. But vast majority of respondents in the 2014 American Society of Cataract and Refractive Surgery (ASCRS) survey (90%) used topical perioperative antibiotics and virtually all surgeons used it postoperatively (97%).Topical antibiotics are frequently used for up to 1–2 weeks postoperatively until the incision fully heals and should not be tapered as this would encourage emergence of resistant organisms17,18.

Though efficacy of IC antibiotic prophylaxis continues to remain controversial due to paucity of level 1 evidence,  many studies strongly support it.The large prospective, randomized clinical trial that has been completed on IC antibiotic use,the 2006 ESCRS study 1 and majority of the multiple clinical studies in which the efficacy of IC antibiotic prophylaxis has been evaluated 2-14 have reported a reduction in endophthalmitis rates with routine IC cefuroxime injection.

52% of US 2014 ASCRS survey respondents using IC antibiotics

were administering vancomycin, compared with 14% using

cefuroxime and 31% using moxifloxacin.17

With a 3.5 fold reduction seen with the use of IC Moxifloxacin in a study group of 600000, the study by Haripriya et al provides the strongest evidence in support of IC Moxifloxacin to prevent postoperative endophthalmitis after cataract surgery26. Haripriya et al, compared the postoperative endophthalmitis rate before and after initiation of intracameral moxifloxacin prophylaxis for cataract sugery.Overall, 302 815 eyes did not receive IC moxifloxacin and 314 638 eyes did, and there was a significant decline in the endophthalmitis rate, from 0.07% to 0.02%,with moxifloxacin. It was seen that routine IC moxifloxacin prophylaxis reduced the overall endophthalmitis rate by 3.5-fold 26.  But there were some lacunae in this study. The antibiotic used (thiswas given as topicaldrops) used in the control group was Ofloxacin. So one group received just Ofloxacin as perioperative antibiotic and the other i.e. the IC group received both Ofloxacin and Moxifloxacin. In this study there was no mention as  on when the topical antibiotics were started  postoperatively.

Starting topical antibiotics preoperatively and within 1-2 hours of surgery could help in achieving MIC concentrations of topically applied antibiotics32. Topical antibiotic, even if it was Ofloxacin alone, could have been effective in reducing chance of endophthalmitis in the control group, if it was given sufficiently early. Considering that bacterial sensitivity to Moxifloxacin in the area where the study was done was high, its protective effect as topical antibiotic could have been better than Ofloxacin. If topical Moxifloxacin had been given pre operatively and in the immediate post operative period in high concentration of Moxifloxacin,well above MIC could have been reached in the IC group without IC Moxifloxacin.

Study by Sharma et al 32 have shown Moxifloxacin to have good anterior chamber penetration. Topical Moxifloxacin, given as  one drop of 0.5% topical moxifloxacin four times, at 15 min intervals starting 75 min before the surgery  or a single tablet of 400 mg of moxifloxacin administered  12 h before the surgery achieved levels in aqeous which exceeded the MIC90 levels for most of the organisms causing endophthalmitis. Mean aqueous concentration of moxifloxacin attained in the oral group (n=21) was 0.504±0.30 μg/mL while that in the topical group (n=21) was 2.04±0.72 μg/mL

Use of topical Moxifloxacin pre operatively andstartedearly in the postoperative period could have achieved therapeutic concentration of Moxifloxacin in aqueous in the Non IC group. If topical Moxifloxacin was given in  Non IC group, then endophthalmitis rate in Non IC group could have been similar to IC group in Haripriya’s study.

But in a study by David PR et al, the bacteria cultured from aqueous taken from the anterior chamber(AC) lacked concordance with vitreous findings in cases of endophthalmitis.It was concluded that use of broad-spectrum antibiotics to the ocular surface to provide therapeutic levels in the AC may not prevent endophthalmitis. In this study, the finding of a sterile AC did not rule out vitreous infection. 33 Going by this argument, directly providing therapeutic levels of antibiotic in AC even through intracameral antibiotics might also not be beneficial.

In the 2014 online survey of the American Society of Cataract and Refractive Surgery members it was seen that for topical perioperative antibiotic prophylaxis, there was a declining trend toward use of fourth-generation fluoroquinolones (60%, down from 81% in 2007) and greater use of topical ofloxacin and ciprofloxacin (21%, up from 9% in 2007) 17

Coagulase-negative Staphylococcus is the most common cause of postcataract surgery endophthalmitis 33,,34.But the microbial flora and resistance patterns may vary in different parts of the world.Before recommending routine use of  topical and IC Moxifloxacin, one should consider the antimicrobial efficacy of Moxifloxacin. Fluoroquinolone (including moxifloxacin) resistance rates among coagulase-negative Staphylococcus endophthalmitis isolates have been reported as high as 40% to 60%. 34Studies have suggested that patient’s own ocular surface flora is the major source of organisms causing endophthalmitis.27,28A very high percentage of cultures taken from samples from normal eyes have grown Staphylococcus epidermidis ( Coagulase Negative Staphylococcus) and Staphylococcus aureus35,36. Study by Ravee Ratnumnoi et al, showed that coagulase negative Staphylococcus  was the commonest isolate from conjunctival swab and there was a 100% sensitivity to Moxifloxacin35. Another study by Keshav BR et al in eyes of Omanis, demonstrated Coagulase Negative Staphylococcus to be the most common bacteria isolated from conjunctival swab. In their study Vancomycin followed by gentamycin and ciprofloxacin were the most effective antibiotics against normal conjunctival flora, and fusidic acid was the most ineffective of all the antibiotics tested36.

The results of these studies on bacterial flora from ocular surface is similar to culture results from of postcataract surgery endophthalmitis 33,,34.Speaker et al have shown that in 17 cases of Staphylococcus epidermidis endophthalmitis the organisms grown from intraocular sources were genetically similar to organisms isolated from ocular surface of the eye in 82% of the cases27. In another study by Bannerman et al using pulse field gel electrophoresis, it was shown that in cases of endophthalmitis, 67.7% of eyelid and intraocular specimens were identical28. These studies prove that for post operative endophthalmitis, conjunctival and eyelid micro organisms serve as the most common source.

We took Conjunctival swabsfrom 480 patients posted for cataract surgery before instillation of any ophthalmic solutions. Culture and antibiotic susceptibility profiles were done through standard microbiological techniques.232 samples grew bacteria (48.33%) .The most common isolate (78%) was Staphylococcus epidermidis (coagulase negative staphylococcus).181 samples grew Staphylococcus epidermidis(coagulase negative staphylococcus).  39 samples grew Staphylococcus aureus (16.8%).12 samples grew Klebsiella (5.17%). Two samples grew Pseudomonas aerogenosa (0.85%).

Of the 181 samples that grew Staphylococcus epidermidis(coagulase negative staphylococcus), 52 (28.72%) were resistant to Moxifloxacin . Of the 39 samples that grew Staphylococcus aureus 18 (46.15%) were resistant to Moxifloxacin. Of the 12 samples that grew Klebsiella pneumoniae  50% (6/12) were resistant to Moxifloxacin . Of the two samples that grew Pseudomonas Aeruginosa, of which 50% (1/2) was resistant to Moxifloxacin.

A significant degree of bacterial resistance to Moxifloxacin was noticed in our study.

Gatifloxacin and moxifloxacin demonstrated an in vitro efficacy of less than 80% for coagulase-negative staphylococci endophthalmitisin a study by Miller D et al37.Increasing resistance to fluoroquinolones was reported in a review of microbiological records of 111 coagulase-negative staphylococci isolates recovered over 15 years in a single center. Susceptibility to gatifloxacin and moxifloxacin declined from 96.6% to 65.4% during this time frame34.

The risk of post cataract surgery endophthalmitis in the study by Haripriya et al, without the use of intracameral antibiotics is about

0.07% (reduced to  0.02% with IC) 26. If we use a 0.1% incidence rate for calculations, to prevent one case of endophthalmitis, 999 cases have to be needlessly exposed to intracameral injection of Moxifloxacin. The number of needlessly exposed looks even worse when you consider the fact Moxifloxacin is going to be ineffective in a significant number of patients considering the high incidence of bacterial resistance to Moxifloxacin.

CONCLUSION

With a very high incidence of resistance developing to Moxifloxacin, it might not be a good idea to use IC Moxifloxacin routinely in all cases. Patients should not be needlessly exposed to the inherent risk of IC injection including contamination of Moxifloxacin by pathogenic organisms. It would be best to restrict the use of IC Moxifloxacin to cases in which there were complications like vitreous loss since these cases have a higher risk of endophthalmitis unlike uncomplicated cases38-40. Even in these cases it would be better to use an antibiotic with a much better sensitivity profile.

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