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Dr. Sangeet Mittal, M09477, Dr. Apoorva Mittal, Dr. Kanwaljeet H Madan

ABSTRACT:Treatment of endophthalmitis is difficult if caused by multi-drug resistant bacteria. Povidone Iodine (PI) has wide spectrum anti-microbial activity. 20 eyes with endophthalmitis not responding to intravitreal antibiotics were divided equally into two groups. In Group I, 3 port sutureless 25G central vitrectomy was done with infusion of 0.025% PI & in Group II, with plain ringer lactate solution. Posterior Vitreous Detachment (PVD) was induced in all eyes. Intravitreal Vancomycin, Ceftazidime & Dexamethasone was given at the end of surgery in both groups. In Group I, all eyes had inflammation resolved with no adverse events. No recurrence was seen. Mean BCVA improved to 6/24. In Group II, 3 eyes had recurrence. Mean BCVA improved to 6/60. Endothelial Cell Count & Electroretinogram at 4 weeks was comparable in both groups. One patient in each group required silicon oil injection due to retinal detachment. 0.025% Povidone Iodine infusion during vitrectomy is safe & effective in preventing recurrent episodes of endophthalmitis.

Introduction: Endophthalmitis is a vision threatening complication following intra-ocular surgery or penetrating trauma. Intravitreal injection of vancomycin and ceftazidime is the recommended treatment of endophthalmitis. [1] 5.2% cases of multi-drug resistant& vancomycin resistant bacteria were isolated from bacterial cultures in 1 report and these cases were found to have poor visual outcome after intravitreal injections &vitrectomy.[2]Moreover there is a rise seen in fungal infections especially after frequent use of intravitreal injections.[3]Povidone–iodine exhibits diverse microbicidalactions against multi-drugresistant bacteria, candida,viruses, acanthamoebaand is also activeagainst biofilms.[4]Povidone–iodine has additional advantages of low cost, absence of drug resistanceandrapid bactericidal effect.[4] The safe concentration and toxicity for intraocular tissues of Povidone Iodine had been studied. Trost et al found no ERG abnormalities and toxicity of Povidone Iodine used intravitreally in rabbit eyes with concentrations less than 0.027%.[5] Use of 0.025% Povidone Iodine in irrigating solutions for anterior chamber irrigation had been found to be useful.[6] We aim to study efficacy and safety of Povidone Iodine infusion during vitrectomy for eyes with endophthalmitis not responding to conventional treatment.

Methods: The design of the study was a randomized comparative clinical trial. 20 consecutive eyes with endophthalmitis which had not responded to conventional treatment given elsewhere (intravitreal antibiotics/vitrectomy) and presented to our outpatient department from 1/1/2017 to 31/10/2017 were included in the study and divided equally in two groups randomly by draw of chits. In Group I (Study Group), 10 eyes underwent Vitrectomy with infusion of 0.025% povidone iodine in Ringers Lactate solution. In Group II (Control Group), 10 eyes underwent Vitrectomy with infusion of plain Ringers Lactate solution. Pre-operative evaluation included Best Corrected Visual Acuity (BCVA), Intra-Ocular Pressure (IOP), Slit Lamp examination (SLE), Fundus Examination, Endothelial Cell Count (ECC) when possible and Electro-retinography (ERG). Patients with b/a ratio less than one on ERG were not included in the study. All eyes underwent standard 3 port Micro-incision Vitrectomy (MIVS) with 25G or 27G instruments. A central core vitrectomy was performed and Posterior Vitreous Detachment was induced in all eyes. Vitreous was removed to the extent possible without causing extra strain on the retinal tissues. Endolaser, membrane peeling or silicon oil tamponade was done whenever required. Intravitreal injection of Vancomycin, Ceftazidime and Dexamethasone was given at the end of surgery in all eyes. All surgeries were performed by single surgeon (SM). Povidone Iodine infusion was prepared by adding 2.5 ml of 5% w/v of Povidone Iodine to 500 ml of Ringers Lactate just before the start of surgery. Post-operative BCVA, IOP, SLE & Fundus examination was done in retina clinic by KM at days 1, 3, 7, 14, 30, 90 and later if required. ECC and ERG were repeated 1 month after surgery. The person performing these tests (AM) was blinded to the pre, intra and postoperative status of the patients. During ERG, patient was dark adapted for 30 minutes after pupillary dilation. Unipolar contact lens was placed in the eye to be evaluated. Negative electrode was placed on the forehead and ground electrodes to the earlobes. Three types of responses were evaluated including dark adapted scotopic response (rod response), Scotopic flash response (cones and rods) and Photopic response (cone response). Mean amplitudes of a and b wave were calculated for all the responses and the average value was used for final analysis. Difference of a and b (b-a) waves was calculated for each eye and compared to response 4 weeks after surgery. Decrease in post vitrectomy response greater than 30% was considered significant.[7]

Results:The mean age of patients in Group I was 59.7±15.5 and in group II was 63.4±14.6 (p>0.5). Primary procedure causing endophthalmitis in Group I was cataract surgery (7 eyes), trabeculectomy (1 eye) and penetrating trauma (2 eyes). Primary procedure causing endophthalmitis in Group II was cataract surgery (8 eyes), penetrating trauma (1 eye) and intravitreal injection of Anti-VEGF (1 eye). Mean pre-operative BCVA was 3/60 in Group I and 2/60 in Group II. 5 patients in each group had BCVA less than counting fingers close to face. Mean postoperative BCVA improved to 6/24 in Group I and 6/60 in Group II. Increased IOP was seen in 3 eyes on first post-operative day in both groups. Late IOP rise was seen in 2 eyes in each group. Hypotony was seen in 3 eyes in Group I and 2 eyes in Group II on first postoperative day. Hypotony persisted in one eye in Group 2 at 3 months follow up. Mean postoperative ECC was 1632±243.3 in Group I & 1520±364.7 in Group II which was not statistically significant (p<0.05). None of the eyes in both the groups showed a decrease of 30% in values of b-a wave on ERG (Table-1& Table-2). Maximum decrease seen in Group I was 14.53% and in Group II was 16.01%. 3 eyes in Group II had recurrence of infection which needed a repeat vitrectomy. 1out of these 3 eyes in Group II ended in Phthisis Bulbi.

Discussion:Povidone Iodine has a broad spectrum microbicidal action against bacteria (including multi-drug resistant bacteria), viruses, fungi, acanthamoeba and biofilms.[4]Other than its excellent microbicidal activity, it also has the advantages of being low cost, no drug resistance and rapid bactericidal action. Intra-Ocular use of Povidone Iodine has been found to be useful in controlling and treating infections after cataract surgery.[4-6] Concentrations of less than 0.027% of Povidone Iodine in irrigating solutions had been found to be non-toxic to retina in various studies.[3,8] However the efficacy and safety of Povidone Iodine in the treatment of endophthalmitis needs to be studied in a clinical setting. Whitacre et al[8] in a series of experiments on rabbit eyes injected concentrations of 0.3%, 0.03% and 0.025%. They had estimated 0.027% concentration of Povidone Iodine as safe for intravitreal use. In our study we used 0.025% Povidone Iodine in Ringers Lactate during vitrectomy and compared its safety with plain Ringers lactate infusion with help of ERG using analytical methods as described by Peyman et al.[7] They have suggested that a decrease in 30% of b-a wave on ERG to be considered significant test for retinal toxicity. In our study none of the eyes in both the Groups had more than 30% decrease in b-a wave postoperatively. The maximum fall seen in Group I (Study Group) was 14.53% (Table 1) and in Group II (control group) was 16.01% (table-2)(p<0.05). Thus use of Povidone Iodine did not appear to be toxic to retina in our study. Also the difference in postoperative ECC was also not significant in the 2 groups indicating no toxicity to corneal endothelium with the use of Povidone Iodine.

Brozou et al[9]performed intravitreal injection of Povidone Iodine in rabbit eyes with Staphylococcusepidermidis endophthalmitis (n = 10) and reported thatatan intravitreal PI concentration of 0.013%  inflammation regressed gradually and vitreous culture after 1 month shows no S. epidermidis. From these findings, theeffective intravitreal PI concentration for controllingendophthalmitis was estimated to be 0.013% or above. In our study, all eyes that underwent vitrectomy with Povidone Iodine infusion showed resolution of inflammation without any recurrence. Whereas in Group II, eyes that underwent Vitrectomy with plain ringers lactate, 3 incidences of recurrence of infection was seen and one eye ultimately ended with phthisis bulbi. This shows that 0.025% povidone Iodine infusion helps in controlling infection and prevents recurrences in eyes with endophthalmitis.

At the end of surgerythat takes approximately 30-40, visual inspection ofthe 0.025% Povidone Iodine solution shows the beginning of discoloration (originally pale yellow), suggesting attenuation of bactericidal effect. Marked bactericidal effect occurs when bacteria are exposed to 0.01% Povidone Iodine for 15 seconds to 15 minutes.The bactericidal effect is weakened after 30 minutes orlonger.[4] Therefore, when using 0.025% PI–BSS, thesolution should be prepared in the operation roomimmediately before surgery and used for irrigationwithin 15 minutes. In our study we prepared the 0.025% Povidone Iodine Infusion in the Operation Theatre immediately before starting the infusion by adding 2.5 ml of 5%Povidone Iodine to 500 ml of Ringers Lactate solution.

At the end of surgery intravitreal injection of Vancomycin and Ceftazidime were given in all eyes after reducing their dose to 50%. This was done because of the presence of air/silicon oil tamponade in the eyes.

Limitations of the study include small sample size, therefore complications may have been missed and significance could be erroneous. Multifocal ERG could be better in evaluating central as well as peripheral toxicity of Povidone Iodine. Also toxicity of Povidone Iodine to the retina has to be evaluated in eyes other than endophthalmitis because endophthalmitis itself could have effected he function of photoreceptors.

Despite these shortcomings, we can safely conclude that 0.025% Povidone Iodine did not appear to be toxic to retina or cornea when used during vitrectomy. It may be beneficial in control of infection and prevention of recurrences in patients not responding to conventional treatment. However its use as a primary treatment needs to be evaluated in larger and multicentric trials.

References:

  1. Endophthalmitis Vitrectomy Study Group. Results of the Endophthalmitis Vitrectomy Study. A randomized trial of immediate vitrectomy and of intravenous antibiotics for the treatment of postoperative bacterial endophthalmitis. Arch Ophthalmol 1995; 113: 1479-96.
  2. Pathengay A, Moreker MR, Puthussery R, et al. Clinical andmicrobiologic review of culture-proven endophthalmitiscaused by multidrug-resistant bacteria in patients seen at a tertiary eye care centre in southern India. Retina 2011;31:1806–1811.
  3. Schimel AM, Miller D, Flynn HW Jr.Endophthalmitis isolatesand antibiotic susceptibilities: a 10-year review of culture-proven cases. Am J Ophthalmol 2013;156:50–52.
  4. Nakashizuka H, Shimada H, Hattori T et al. Vitrectomy using 0.025% Povidone–iodine in balanced saltsolution plus for the treatmentof postoperative endophthalmitis. Retina 2015; 0: 1-8
  5. Trost LW, Kivilcim M, Peyman GA, et al. The effect of intravitreally injected Povidone-iodine on Staphylococcus epidermidisin rabbit eyes. J OculPharmacolTher 2007;23:70–77.
  6. Otani K, Shimada H, Nakashizuka H et al: Capsular bag irrigation using 0.025% povidone-iodine in balanced salt solution PLUS for the treatment of postoperative endophthalmitis. Int Ophthalmol 2018; 38: 1787-90
  7. Manzano RPA, Peyman GA, Khan P. Testing intravitreal toxicity of Bevacizumab (Avastin). Retina 2006; 26: 257-61
  8. Whitacre MM, Crockett RS. Tolerance of intravitreal povidone-iodine in rabbit eyes. Curr Eye Res 1990; 9: 725–732
  9. Brozou CG, Karabatakis V, Giannousis M, et al. The efficacyof intravitreal povidone iodine application in experimentalStaphylococcus epidermidis endophthalmitis. Ophthalmic Res 2009; 41: 181-85.

Table 1: ERG observations (b-a wave amplitudes) for Group I

Group I (PI infusion) Pre-operative Post-operative Change (%)
Case 1 90.3 104.57 13.65
Case 2 140.25 126.23 -11.10
Case 3 139.47 185.63 24.87
Case 4 108.24 143.34 24.48
Case 5 165.71 142.64 -16.17
Case 6 174.87 180.14 2.93
Case 7 165.89 150.49 -10.23
Case 8 206.56 204.64 -0.94
Case 9 101.13 151.29 33.15
Case 10 160.42 140.06 -14.53

Table 2: ERG observations (b-a wave amplitudes) for Group II

Group II (Plain RL) Pre-operative Post-Operative Change (%)
Case 1 192.14 167.73 -14.55
Case 2 119.25 120.50 1.03
Case 3 177.45 152.96 -16.01
Case 4 94.87 111.53 14.93
Case 5 150.01 175.64 14.59
Case 6 172.48 149.39 -15.39
Case 7 101.32 99.54 -1.79

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