Accepted Manuscript

Povidone-Iodine Concentration and Dosing in Cataract Surgery

Jagger C. Koerner, MD, Mary J. George, PhD, Dale R. Meyer, MD, FACS, Michael G.
Rosco, BS, Matthew M. Habib, BS

PII: S0039-6257(17)30312-0
DOI: 10.1016/j.survophthal.2018.05.002
Reference: SOP 6796

To appear in: Survey of Ophthalmology

Received Date: 19 November 2017

Revised Date: 26 April 2018
Accepted Date: 7 May 2018

Please cite this article as: Koerner JC, George MJ, Meyer DR, Rosco MG, Habib MM, Povidone-
Iodine Concentration and Dosing in Cataract Surgery, Survey of Ophthalmology (2018), doi: 10.1016/
j.survophthal.2018.05.002.

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Title Page:

Title: Povidone-Iodine Concentration and Dosing in Cataract Surgery

Article type: Review article

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Keywords: povidone-iodine; endophthalmitis prevention; cataract surgery

Running head: Povidone-Iodine Concentration and Dosing in Cataract Surgery

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Order of Authors: Jagger C. Koerner, MD1, Mary J. George, PhD2, Dale R. Meyer, MD,
FACS1, Michael G. Rosco, BS1, Matthew M. Habib, BS1

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Corresponding Author: Jagger C. Koerner, Lions Eye Institute, Albany Medical College,

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1220 New Scotland Road, Suite 302, Slingerlands, NY 12159, Phone: (585) 506-7897,
Fax: (518) 533-6542, Email: jaggerkoerner@gmail.com
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Affiliations:
1
The Lions Eye Institute, Department of Ophthalmology, Albany Medical College,
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Albany, NY
2
Albany Medical College, Department of Microbiology Albany, NY
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Abstract:
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Iodine has been recognized as an effective bactericide since the 1800’s, and povidone-iodine (PI)
solution has been applied to the ocular surface and periocular skin since the 1980’s to prevent
endophthalmitis in cataract surgery. In vitro, PI solution kills bacteria very quickly at dilute
concentrations (0.05-1.0%). In many instances, PI kills bacteria more quickly at these dilute
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concentrations than more conventional (5%-10%) concentrations. This is due to greater availability of
diatomic free iodine in dilute solution, the bactericidal component of PI. The toxicity of PI, both in vitro
and clinically has been shown to be related to concentration. Current American Academy of
Ophthalmology (AAO) and the European Society of Cataract and Refractive Surgeons (ESCRS)
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recommendations regarding PI use suggest using 5% PI prior to surgery. An alternative dosing strategy
uses dilute PI repetitively throughout cataract surgery (0.25% every thirty seconds). We review the
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povidone-iodine literature with attention to basic science and use of dilute PI.
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Povidone-Iodine Concentration and Dosing in Cataract Surgery

I. Introduction

Iodine has been recognized as an effective bactericide since the 1800’s. Clinically, iodine is used as a

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complex of the polymer polyvinylpyrrolidone and iodine “povidone-iodine” to increase water solubility,

and decrease irritant and allergic reactions18. Povidone-iodine (PI) is routinely used as a surgical scrub

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for skin disinfection, and in preparation for ophthalmic surgery or intraocular injection. It has also been

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used in more limited applications such as to treat infectious keratitis, endophthalmitis, and as

ophthalmia neonatorum prophylaxis19,20,38. PI has been studied extensively in the ophthalmic setting,

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and evidence-based recommendations regarding its use to prevent endophthalmitis exist. We review
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the povidone-iodine literature with attention to basic science and use of dilute PI in cataract surgery.

II. Basics of povidone-iodine

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A. Initial use of PI in cataract surgery antisepsis

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PI was used as an antiseptic on the skin prior to ocular application. Two studies using iodine solution on
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the skin reported decreased flora on the periocular skin as well as ocular surface flora7,30. These studies

introduced iodine solution to the ophthalmic literature, and by the 1980’s PI was being applied to the
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ocular surface. The acceptance and worldwide use of PI solution in ophthalmic surgical site antisepsis is

attributed to its wide spectrum of activity, limited instances of microbial resistance, as well as more
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practical features such as affordability and availability. In 1984 Apt et al conducted a controlled trial of PI
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on the ocular surface and found it significantly reduced both bacterial species and colony counts on the

conjunctiva2.

B. Chemistry
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Polyvinylpyrrolidone (also referred to as “povidone” or “PVP”) is a water-soluble polymer similar to

dextran with medical and industrial uses. Povidone is generally considered safe, though rare severe

allergic reactions have been described8. PI solution has a pH of approximately 5, and acidity decreases

with dilution4,46. The 10% commercial formulation consists of 90% water, 8.5% povidone, and 1%

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available iodine and iodide57. When povidone and iodine are mixed there is a chemical reaction between

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the two. While the chemistry of povidone-iodine is complex and not fully understood, iodine is thought

to be complexed with povidone and iodide through a hydrogen bond between two pyrroles; resulting in

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mostly povidone-iodine complex existing with a small amount of free iodine. Exposure to organic

substances reduces PI’s bactericidal activity by complexing the iodine and by reducing it to iodide58.

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C. Antimicrobial spectrum and mechanism of action
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PI acts on a variety of bacteria, fungi, protozoa, and viruses59. Povidone is hydrophilic and has an affinity
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for cell membranes, allowing it to act as a carrier transferring iodine to the target cell46,59. The delivery of

diatomic free iodine (I2) directly to the target cell surface is thought to be the crucial event of
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antimicrobial action4. For bacteria, PI targets the cytoplasmic membrane and cytoplasm with killing
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taking place in a matter of seconds12. Free iodine iodinates and oxidizes proteins, enzymes, and other

molecules essential for biologic viability8. In addition, PI inactivates pathogenic factors such as bacterial
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exotoxins, endotoxins and tissue destroying enzymes as well as microbial-induced cytokines27. PI is

bactericidal against drug resistant bacteria40,42. While PI has some efficacy against bacterial biofilms,
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biofilm producing species have contaminated PI solution and survived long exposure times18,23,36.
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D. Dilute povidone-iodine

In 1982 Berkelman et al demonstrated that dilute PI solution has greater bactericidal activity than stock

(10%) solution4. Various bacterial strains were tested and in two, Staphylococcus aureus and

Mycobacterium chelonei, the killing time varied significantly with different dilutions of PI. In these
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isolates, a 1:100 dilution (0.1%) produced the fastest killing time. This is due to an increase in free iodine

in dilute PI solution14. The somewhat counterintuitive increased availability of bactericidal free iodine in

dilute PI is thought to be a result of weaker iodine linkage to the carrier polymer in these solutions4.

Iodine chemistry is complex and the methods used to measure free iodine controversial. There are

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methods to measure iodine concentration, but determining how much is bactericidal “free” iodine,

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“tamed” iodine complexed with PVP, or iodide after chemical reduction is difficult. Given these

limitations, estimated free iodine concentration in PI solution has been described as a roughly bell-

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shaped curve with a peak around 0.1%-1%, an important corollary to Berkelman’s observations14.

Concentrations less than 0.05% lose their povidone-iodine complex characteristics and behave like

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aqueous iodine, though concentrations as low as 0.005% have been shown to be bactericidal in vitro4,59.
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III. Pharmacokinetics and toxicity
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A. Pharmacokinetics

The half-life of povidone-iodine on the ocular surface and in the anterior chamber have not been
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studied, though a rabbit model has been used to investigate the pharmacokinetics in the vitreous. This
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model demonstrated that PI has dose dependent (non-linear) pharmacokinetics and at a concentration

of 0.1% had a half-life of 3.27 hours24. Povidone and iodine can be absorbed systemically after topical
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application and iodine is primarily excreted by the kidneys9. Although systemic absorption can cause
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serious systemic toxicity including renal failure and death, the small amount of PI used in the ophthalmic
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setting make this less relevant59.

B. Toxicity

1. General considerations

PI solution does not have a known specificity for microorganisms, and can be expected to act on host

cells. PI toxicity in the ophthalmic setting has been studied in vitro, in animal models, and in clinical
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studies. PI solution applied to fresh surgical wounds (skin) inhibits fibroblastic activity, wound cellularity,

and migration of polymorphonuclear leukocytes. A 1% PI solution showed no significant difference

compared with application of normal saline, suggesting that at the cellular level, PI toxicity is related to

the concentration used55.

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2. PI concentrations in clinical use

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Brief application of PI 5%-10% to the ocular surface is commonly used worldwide. Repetitive application

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of 0.25% PI, a two or three drop irrigation every 20-30 seconds throughout cataract surgery, is an

alternative dosing strategy reported by Shimada and colleagues in 201146. Bacterial corneal ulcers were

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treated with 1.25% PI four times daily and to prevent ophthalmia neonatorum 2.5% was used one
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time19,20. PI has not been used clinically in the anterior chamber. In a limited fashion PI has been used in

vitreoretinal surgery. In vitrectomy irrigating solution 0.025% was used in the treatment of
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endophthalmitis33.

3. Corneal epithelial toxicity of PI

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Corneal epithelial toxicity has been demonstrated in vitro, with concentrations as low as 0.0125%

producing cytotoxicity in human cultured cells57. Exposure to this low concentration killed about 30% of
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the cultured epithelial cells after thirty minutes of exposure. Toxicity has been shown to increase with

both increased concentration and exposure time57. A rabbit model demonstrated severe epithelial
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edema after exposure to 5% PI, and moderate-mild edema with concentrations of 1% or less. Repetitive
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0.25% PI irrigation during cataract surgery was well tolerated, though some epithelial injury was noted

when repetitive dilute PI followed a high concentration (2.5%) initial application11,46. The barrier function

of the epithelial cells is reduced by exposure to 1.25% PI for ten minutes57.

4. Corneal stromal toxicity of PI

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Free iodine from PI solutions can penetrate the cornea when applied topically, with the depth

depending on the exposure time and concentration. In donor corneas after topical application of PI

solution of greater than 5%, iodine was found from the epithelium to the mid-stroma. In concentrations

of 0.5-5% applied for two minutes, however, iodine was virtually absent from the stromal layers41. PI

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solution is toxic to corneal fibroblasts in vitro, exposure to a concentration of only 0.25% for two

minutes caused significant damage41.

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5. Corneal endothelial toxicity of PI

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PI 5%, solution injected directly into the anterior chamber producing a 0.8% intracameral concentration,

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caused endothelial damage in rabbits1. Two studies in rabbits found no evidence of endothelial cell
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damage with intracameral concentrations of 0.1% and 0.08%22,35. In vitro, 0.05% PI was not toxic to

cultured bovine endothelial cells with 12 hours of exposure1. During cataract surgery repetitive irrigation
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with 0.25% PI did not cause endothelial damage46. Topical 5% PI, with no surgery to introduce the

solution directly into the anterior chamber, demonstrated no endothelial toxicity22.

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6. Retinal toxicity of PI
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In a rabbit model 0.1% and 0.3% PI 0.1 ml intravitreal injections were found to be tolerable by ERG and
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histological examination24. Other investigators using rabbit models have found intravitreal

concentrations between 0.05% and 0.5% tolerable. 5% PI has been shown to uniformly cause severe
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retinal damage54,56. In humans, irrigation during vitrectomy with 0.025% PI in balanced salt solution was
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well tolerated33.

IV. PI and endophthalmitis prevention

A. How endophthalmitis prevention has been studied

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There are no randomized controlled trials of PI that use endophthalmitis rate as the primary end point.

In a large, open-label nonrandomized parallel trial, Speaker et al found that 5% PI applied to conjunctiva

prior to surgery reduced endophthalmitis rates from 0.24% to 0.06%50. Studies evaluating the

concentration, dose and other aspects of PI application have used the presence and concentration of

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bacteria on the conjunctiva and in the anterior chamber as proxy measures for reduced endophthalmitis

risk16,59. The reasons for this are the infrequent occurrence of endophthalmitis and evidence implicating

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ocular surface flora as the cause of postoperative endophthalmitis51.

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In vitro studies have used bacterial suspensions in balanced salt solution, sterile water, and on plated

agar media4,48. There is no standard model that is used to represent the ocular surface. Consequently,

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there is uncertainty about translating these studies to in vivo use. Silas at el reported using an organics
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rich agar plate system with a high bacterial load to simulate the ocular surface with subclinical

infection26,32.
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B. Basics of postoperative endophthalmitis pathophysiology and microbiology

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1. Postoperative endophthalmitis has multifactorial etiology

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The anterior chamber contamination rate after cataract surgery ranges from 5-20%46,49. Given the orders

of magnitude lower endophthalmitis rate, entry of bacteria into the anterior chamber is only one
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contributing factor29. The virulence of specific microbes, differences in host defense and mechanical
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changes related to surgery are additional risk factors. An epidemiologic study of greater than four-
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hundred thousand patients identified diabetes mellitus, older age, large incision extracapsular cataract

extraction, and perioperative communication with the vitreous as risk factors21.

2. Commensal ocular surface bacteria cause postoperative endophthalmitis

Studies of conjunctival flora have found the most common organism cultured is Staphylococcus

epidermidis. Staphylococcus aureus, Streptococcus viridans, and many additional organisms are
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occasionally found16,51. Genetic work confirmed that in Staphylococcus epidermidis endophthalmitis the

causative organism comes from commensal bacteria on the ocular surface that gain entry into the eye

as a result of surgery51. The mechanism of bacterial entry was further studied using porcine eyes and

fluorescent microspheres, similar in size to bacteria, to visualize entry into the eye during common

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surgical maneuvers. Vitrectomy, intraocular lens insertion, and intravitreal injection all caused

microspheres on the ocular surface to enter the eye25.

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Postoperative endophthalmitis is caused by gram positive organisms in more than 90% of cases.

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Staphylococcus epidermidis, Streptococcus viridians, and Staphylococcus aureus are the most common

organisms. The most common molds are Fusarium and Aspergillus, the most common yeast species is

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Candida34. PI solution has been shown to be effective against these organisms13,40. Fluoroquinolone
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antibiotics are commonly used perioperatively in cataract surgery. The common bacterial causes of

endophthalmitis, including Staphylococcus epidermidis, Staphylococcus aureus, and Streptococcus

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viridans are not infrequently resistant to this class of antibiotics when living commensally on the
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conjunctiva53,44. In cases of endophthalmitis, multidrug resistance has been reported in approximately

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5% of bacteria, dilute PI solution has been shown to effectively kill bacteria that are resistant to

antibiotics39,40.
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C. Current recommendations for PI use in cataract surgery

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The American Academy of Ophthalmology’s (AAO) guideline recommends 5% PI applied to the

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conjunctival cul de sac prior to surgery. Application for three minutes was described by a supporting

reference; no specific duration or volume is specifically recommended6,37. Additionally, this guideline

cautions against lower concentrations of PI and states there is no convincing evidence that preoperative

antibiotics provide additional benefit37. Similarly, the European Society of Cataract and Refractive
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Surgeons (ESCRS) recommends 5-10% PI prior to surgery for a duration of a least three minutes3. Neither

of these guidelines discuss the frequent application of dilute PI.

D. Evidence that PI reduces bacterial load of the ocular surface

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The efficacy of PI was established by finding significant reduction in the percent culture positives and

decreased colony forming units (CFUs) from swabs of the conjunctiva. A 2009 prospective controlled

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study of 54 eyes demonstrated significant decrease in culture positive swabs, number of species, and

bacterial growth after exposure to 5% PI for three minutes6. Many additional studies show that PI

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reduces bacterial load on the ocular surface. They generally use a swab of the conjunctiva before and

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after single application of PI, from one drop to a 10ml irrigation. Irrigation was shown to reduce positive
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cultures more than application of two drops of equivalent concentration PI31. The time the post

application swab was taken varied between studies, from one minute after application to after surgery
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was complete. Prior to disinfection with PI, swabs were culture positive in the 25-70% range6,16. The

bacterial load before PI application varies significantly between individuals. No study reporting
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‘sterilization’ of the ocular surface was found. The lowest percentage of culture positive swabs found
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post PI application, 5% PI for three minutes, was three percent16. The identification of new bacterial

species and increased CFU’s has also been reported after PI application, suggesting contamination after
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application10. Application of gel formulations of topical anesthesia before PI leads to increased microbial

survivability, probably due to a barrier mechanism5. There have been many studies regarding the
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combined use of antibiotics and PI with mixed results, it is not clear that pre-operative antibiotics
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provide additional benefit16,37.

V. Concentration and dosing

A. Evidence supporting use of concentrated (>1%) PI

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There is no consensus definition of “dilute” or “concentrated” PI solution for endophthalmitis

prophylaxis. In this discussion, greater than 1% PI solution is considered “concentrated”; 2.5%, 5%, and

10% PI solutions are the most common. Dilute PI describes concentrations of 1% or less. Several studies

support the use of concentrated PI prior to cataract surgery. A study evaluating conjunctival swabs

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before and after application of 5% or 1% PI prior to surgery concluded that 5% PI more effectively

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reduced bacterial load on the ocular surface. This study found that as initial bacterial load increased, 5%

PI more effectively decreased the bacteria on the ocular surface than 1% PI. With low initial bacterial

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load, there was no significant difference10. Using a similar conjunctival swab evaluation, 10% PI solution

was found to reduce ocular surface bacteria more than lower concentrations after a 10 ml irrigation

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prior to surgery with concomitant use of topical antibiotics preoperatively28. A third study supporting
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the efficacy of higher PI concentrations found that post cataract surgery endophthalmitis bacterial

isolates were killed more effectively in vitro with higher concentrations of PI and longer exposure
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times17. None of these studies evaluated frequent application of dilute povidone iodine. Organic
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substances commonly found in the operative field have been shown to inhibit PI’s bactericidal activity.

The greater amount of total iodine supplied by higher concentrations could therefore be helpful17.
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B. Evidence supporting use of frequently applied dilute (<1%) PI

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As discussed in section II, basic science studies have shown the greatest concentration of bactericidal

free iodine to be present in 0.1-1% solutions. Additionally, at low concentration PI has a fast killing time,
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less than 30 seconds, and is effective on a wide variety of organisms. Higher concentration PI solutions
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presumably take longer to kill bacteria because the free iodine concentration is lower. In vitro, repetitive

0.7% PI application was found to be equivalent to single application of 5% PI using an organics rich agar

medium to simulate subclinical infection48.

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Shimada et al evaluated anterior chamber contamination rates after repetitive pre-and intraoperative

surface irrigation of 0.25% PI during cataract surgery in Japan46. Topical and intravenous antibiotics were

used and the ocular surface was disinfected with 0.25% PI. The experimental arm of the study yielded a

0% anterior chamber contamination rate in the 202 eyes studied. A similar study using repetitive 0.025%

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PI irrigation also achieved a 0% anterior chamber contamination rate in 100 eyes45. In both studies, the

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reduction of anterior chamber contamination was significant compared with the BSS irrigation controls.

In Japan, approximately 7% of cataract surgeons use repetitive irrigation with 0.25% PI and use is

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increasing at academic centers (Dr. Shimada, personal communication). No significant epithelial injury

was observed and there was no change in endothelial cell count. When 0.25% PI is applied in this way,

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the concentration in the anterior chamber at the end of surgery is 0.008%47.
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In a rabbit model of endophthalmitis repetitive low dose 0.1% and 0.3% intravitreal injections were

effective as a treatment24. Prior rabbit model studies to establish the safe intraocular concentration
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found no treatment benefit with a single intravitreal injection56. Additional studies of dilute povidone
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iodine include one study in dogs and a small study in humans which showed equivalency between dilute
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and more conventional PI concentrations15,43. A second application of 5% PI ten minutes after the first

further reduces the conjunctival bacterial flora52.

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VI. Discussion
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No antiseptic regimen has been found to consistently sterilize the ocular surface. Additionally, bacteria
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move onto the operative field during surgery. These bacteria from the conjunctiva and eyelids enter the

eye during surgery and cause infection. The ideal antiseptic regimen would sterilize the ocular surface

throughout the perioperative period. Consequently, reducing bacterial load has been an area of active

study. Bacterial colony counts and species number have been the outcome measures for studies both in

vitro, using various media, and in vivo, from the conjunctiva and anterior chamber.
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The AAO and ESCRS guidelines recommend 5% PI prior to cataract surgery. The use of frequently applied

dilute PI is not discussed in these guidelines. Frequent dilute application of PI provides a ‘reservoir’ of

iodine that can kill microorganisms and interact with other organic substances and host tissue. Dilute PI

provides a highly available, though small amount of free iodine. The toxicity of PI, both in clinical

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practice and experimentally, appears related to its concentration. Given this, one strategy to maximize

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delivery of free iodine to the cell membrane of microorganisms on the ocular surface, while minimizing

damage to host tissue, is frequent application of low concentration PI solution. An additional benefit of

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this strategy is that frequent applications also kill bacteria introduced onto the field after the start of

surgery.

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Repetitive application of dilute PI solution is supported by in vitro studies, its mechanism of action and
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some clinical evidence. In clinical practice, both brief application of 5% PI and repetitive irrigation of the

ocular surface with 0.25% cause minimal epithelial damage. The combination of a higher ‘loading
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concentration’ PI irrigation followed by 0.25% repetitive irrigation can cause more noticeable injury to
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the corneal epithelium10. The concentration of PI in the anterior chamber at the end of surgery, 0.008%,
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is less than the concentration required to cause endothelial damage. The safety in different scenarios,

such as when there is no epithelium, e.g. after corneal epithelial debridement in retinal surgery, has not
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been reported. Additionally, no studies examining the effect of dilute PI on the trabecular meshwork

were found. PI can be toxic to eye tissues even in low concentrations, and further study of repetitive
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exposure to PI is necessary. For example, toxicity to corneal fibroblasts was observed after exposure to a
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concentration of only 0.25% for 2 minutes in vitro41.

There is no validated model of the ocular surface to use for in vitro studies comparing various

concentrations of PI. Concentrations as low as 0.005% are bactericidal in some systems23. Silas et al

reported significant (3 log unit) reduction of bacterial load using three applications of 0.7% PI with a

virulent slime producing bacteria in an organics rich media to simulate the “worst case scenario” of
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subclinical infection46,45. The lowest effective concentration of PI for repetitive use is unknown. A better

understanding of the pharmacokinetics of PI on the ocular surface, and evaluation of interindividual

variation would help inform this.

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Shimada et al demonstrated efficacy with 0.25% and 0.025% PI using dilute repetitive PI in two

randomized trials45,46. These studies achieved a combined anterior chamber contamination rate of 0% in

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302 eyes, compared with a rate of approximately 5% in the BSS irrigation control groups46. Adjunctive

antisepsis measures included a topical fluoroquinolone, intravenous antibiotic, and single application of

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dilute PI in the control group. This is not similar to most pre-operative regimens. Nonetheless, this

technique produced the largest series of anterior chamber culture negative patients ever reported.

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Repetitive irrigation of dilute PI should be compared to single application of 5% PI both with and without
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concurrent use of topical antibiotics. Additionally, further in vitro study of endophthalmitis isolates

could help identify any mechanism of resistance, and determine if PI at these dilute concentrations kill
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the bacteria that actually cause endophthalmitis. This is important given the ability of some
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endophthalmitis isolates to survive extended PI exposure as reported by Hosseini et al17. Expanded

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application of PI solution from endophthalmitis prophylaxis to treatment is also being explored. A case

of primarily anterior post-operative endophthalmitis treated with dilute (0.025%) PI irrigation was
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recently reported38.

VII. Conclusions
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Dilute PI solution is widely available, easy to make, inexpensive and has been studied extensively. Basic

science studies and some clinical studies support using repetitive irrigation of dilute PI. Endophthalmitis

rate is a difficult primary end point because of its infrequent occurrence. Repetitive dilute PI yielded the

lowest rate (0%) of anterior chamber contamination reported in a large series. Areas of further study
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include the toxicity of repetitive PI application, direct comparison to single application 5% PI, and further

study of dilute PI’s ability to kill isolates from endophthalmitis cases.

Method of Literature Search

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In order to identify the literature on the topics of povidone iodine and endophthalmitis prevention, we

performed a PubMed search of published English-language papers. Literature in PubMed prior to

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August 2017 was reviewed without a date limit in the past. The terms “povidone-iodine” and

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“endophthalmitis” were combined with the terms “prevention,” “toxicity,” “pharmacokinetics,”

“cataract surgery,” “anterior chamber contamination,” “resistance,” and “antisepsis protocol”. The

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reference lists of relevant papers were reviewed to identify additional papers, this process was iterated
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several times.
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References:

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