Prevention and Treatment of Postoperative Endophthalmitis Using ...

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REVIEW ARTICLE ISSN: 1381-6128 eISSN: 1873-4286

Prevention and Treatment of Postoperative Endophthalmitis Using Povidone-Iodine

Volume 23, Number 4

no.

Impact Factor: 3.052

BENTHAM SCIENCE

Hiroyuki Shimada1,*, Hiroyuki Nakashizuka1 and Andrzej Grzybowski2,3 1

Department of Ophthalmology, School of Medicine, Nihon University, Tokyo, Japan; 2Department of Ophthalmology, University of Warmia and Mazury, Olsztyn, Poland; 3Department of Ophthalmology, Poznan City Hospital, Poznan, Poland

ARTICLE HISTORY

Current Pharmaceutical Design

Received: October 13, 2016 Accepted: November 25, 2016 DOI: 10.2174/13816128226661612051 05404

Abstract: Postoperative endophthalmitis is typically caused by patient’s conjunctival bacterial flora or contaminated solutions and instruments. Visual outcome is often poor in severe cases, and treatment is especially difficult when endophthalmitis is caused by multidrug resistant bacteria. Povidone-iodine is used worldwide due to its wide-spectrum antimicrobial activity, absence of resistant bacteria to povidone-iodine, and low cost. Furthermore, the effective concentration against microorganisms and safe concentration for ocular tissues have been well established. For ocular surface washing, the safe and highly bactericidal concentrations range from 0.050 to 0.500%. Repeated washing of the ocular surface with 0.250% povidone-iodine every 20-30 seconds during ophthalmic surgeries eliminates the conjunctival normal flora, minimizing the passage of bacteria into intraocular compartment, and is thus useful for the prevention of endophthalmitis. The concentration range of 0.013%-0.027% is effective for the treatment of endophthalmitis and nontoxic to intraocular tissues. In a small case series, 4 eyes with endophthalmitis were treated by vitrectomy using 0.025% povidone-iodine in Balanced Salt Solution (BSS) PLUS for vitreous irrigation. In all eyes, endophthalmitis was resolved with no ocular complications and visual acuity was improved. When performing ophthalmic surgeries, washing the ocular surface with saline containing 0.250% povidone-iodine every 20-30 seconds is safe for ocular tissues and effective for the prevention of endophthalmitis. A small case series suggested the effectiveness and safety of using irrigation solution containing 0.025% povidone-iodine in vitrectomy for the treatment of endophthalmitis, but this treatment method remains to be established.

Keywords: Bacterial flora in conjunctival sac, postoperative endophthalmitis, intravitreal irrigation, ocular surface irrigation, ocular toxicity, povidone-iodine, resistant bacteria, safe concentration. 1. INTRODUCTION Postoperative endophthalmitis is a serious complication of ocular surgeries, and remains a sight-threatening infection for many affected patients worldwide. The reported rates of endophthalmitis were 0.029-0.048% [1-3] after microincision cataract surgery; 0.030-0.058% [3-6] after microincision vitrectomy surgery (MIVS); and 0.049-0.056% [7, 8] after intravitreal injection (Fig. 1). Since intravitreal injection involves repeated injections into the same eye, the rate of endophthalmitis per eye is higher. Endophthalmitis after cataract surgery has poor visual outcome, with reported final visual acuity worse than 20/200 in 35.7% and 20/200 to 20/40 in 36.7% [2]. During vitrectomy and intravitreal injections (such as antiVEGF agents, triamcinolone, and dexamethasone), direct inoculation of bacteria directly into the vitreous may occur resulting in earlier retinal damage and even worse visual outcome compared to cataract surgery [9, 10]. Since many patients affected by endophthalmitis are at risk of vision loss, its prevention and treatment are important issues. 2. BACTERIA CAUSING DOPHTHALMITIS

POSTOPERATIVE

EN-

2.1. Passage of Conjunctival Normal Flora into Intraocular Compartment In postoperative endophthalmitis, species identification and genetic analysis of the causative bacteria implicated the normal flora of the conjunctiva or eyelid as the source of the infecting organisms [11]. The higher incidence of bacterial contamination of *Address correspondence to this author at the Department of Ophthalmology, Nihon University Hospital, 1-6 Surugadai, Kanda, Chiyodaku, Tokyo 101-8309, Japan; Tel: +81-3-3293-1711; Ext: 3526; Fax: +81-3-3293-2880; E-mail: [email protected] 1873-4286/17 $58.00+.00

Fig. (1). Endophthalmitis observed after ophthalmic surgeries. A: Endophthalmitis after vitrectomy; B: endophthalmitis after cataract surgery. (Authors’ unpublished images).

the vitreous cavity at the beginning of 25-gauge vitrectomy suggests the increasing risk of direct inoculation of ocular surface flora into the vitreous cavity through the transconjunctival trocar-cannula system [12]. An experimental study was conducted to examine how microscopic objects such as bacteria enter intraocular compartment during various ophthalmic procedures [13]. In this experiment, 1µm fluorescent microspheres (Polysciences, Warrington, Pennsylvania, USA) with the same size as bacteria were spread on the conjunctiva of porcine eye. When vitrectomy was conducted, the fluorescent microspheres on the conjunctiva were observed to gain access into the peripheral vitreous after the trocar was inserted and irrigation was started (Fig. 2). Intravitreal injection using a 30gauge needle also resulted in passage of fluorescent microspheres into the vitreous by adhering to the needle tip. The number of fluorescent microspheres in the vitreous was significantly higher when a 27-gauge needle was used compared to a 30- gauge or 32-gauge needle [13]. It should be noted that even a 32-gauge needle may not prevent entry of conjunctival normal flora into the intraocular

© 2017 Bentham Science Publishers


Fig. (2). Fluorescent microspheres (1 µm) applied on the surface of porcine eye are introduced into the vitreous via insertion of instrument. A: a trocar is inserted for 25-gauge vitrectomy. B: Fluorescent microspheres are carried into the vitreous by the trocar (arrow). C: A 30-gauge needle is used for intravitreal injection. D: Fluorescent microsphere is carried into the vitreous by the 30-gauge needle (arrow). (Authors’ unpublished images).

cavity. When cataract surgery was conducted, fluorescent microspheres on the conjunctiva were pressed into the eye together with viscoelastic material during foldable intraocular lens implantation (Fig. 3). In addition, as the intraocular lens was inserted, fluorescent microspheres were observed around the whole lens. These findings show the need to wash not only the anterior surface but also the posterior surface of the lens during cataract surgery. When scleral buckling was conducted, adhesion of fluorescent microspheres around the silicon sponge, solid silicone and suture was observed. Examination of the cut end of the silicon sponge showed adhesion of fluorescent microspheres inside the pit. In scleral buckling, careful washing of the buckling material and suture is necessary.

Fig. (3). Fluorescent microspheres (1 µm) applied on the surface of porcine eye during cataract surgery and scleral buckling. A: In cataract surgery, fluorescent microspheres (arrow) are introduced into the eye during foldable intraocular lens implantation. B: As the intraocular lens is inserted, fluorescent microspheres (arrow) appear to surround the lens. C: In scleral buckling, fluorescent microspheres adhering to silicon sponge, solid silicone, and suture are observed (arrow). D: At the cut end of the silicon sponge, fluorescent microspheres adhering inside the pit are found (arrow). (Authors’ unpublished images).

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In a study on patients scheduled for intraocular surgery, normal bacterial flora was isolated from the conjunctiva in 82.1% of the subjects at baseline. The rate decreased to 74.6% after receiving preoperative antibiotic eye drops, and decreased further to 11.9% after irrigation of the eyelid and conjunctiva with povidone-iodine (Fig. 4) [14]. At the beginning of surgery, immediately after disinfecting the eyelid and conjunctiva with povidone-iodine, the conjunctival normal flora is transiently eliminated. However, after draping and placing the eyelid speculum, bacteria once again emerge on the conjunctiva, and these bacteria are introduced into the eye via surgical instruments. In a prospective study of 200 eyes in which the ocular surface was washed repeatedly with infusion fluid during cataract surgery, bacteria were detected at a rate of 5.5% (11/200 eyes) on the eye surface at the beginning of surgery, and at a rate of 5.0% (10/200 eyes) in the anterior chamber at the end of surgery [15] (Table 1). In another prospective study of 103 eyes in which the ocular surface was washed repeatedly with infusion fluid during 25-gauge vitrectomy, bacteria were detected at a rate of 5.5% on the ocular surface at the beginning, and at a rate of 2.0% in the vitreous at the end of surgery [16] (Table 2).

Fig. (4). Rate of detection of conjunctival bacterial flora when antibiotic ophthalmic solutions are used before and after ophthalmic surgery. The proportion of resistant bacteria in the normal bacterial flora isolated from the conjunctival sac increases before and after surgery when antibiotic ophthalmic solution is used. During surgery, resistant bacteria are also isolated from the conjunctiva, indicating the risk of resistant bacteria entering the intraocular compartment via surgical instruments. (Authors’ unpublished data).

2.2. Causative Bacteria of Postoperative Endophthalmitis The most common causative bacteria of endophthalmitis are Staphylococcus epidermidis (30.1%), Streptococcus viridians group (10.9%), and Staphylococcus aureus (7.8%) [17]. Broad-spectrum fluoroquinolone ophthalmic solution is commonly used in ophthalmic procedures. However, while bacteria resistance to fluoroquinolones are found in 32.1% of healthy individuals, repeated use of topical antibiotics for intravitreal injections resulted in an increase to 63.6% [18]. Another study isolated multidrug resistant bacteria from 42 of 807 eyes (5.2%) with endophthalmitis; some of the bacteria were also resistant to vancomycin [19]. Moreover, a recent study of over 170,000 intravitreal injections showed that in the group using antibiotics, 40% of culture-positive endophthamitis cases grew bacteria resistant to the prescribed prophylactic antibiotic. On the other hand, none of culture-positive cases in the group not using antibiotics were resistent to those antibiotics [20]. Visual outcome was poor in eyes infected by multidrug resistant bacteria, because effective antibacterial agents are not available [19]. There is also a tendency of increase in the proportion of Candida albicans among microorganisms causing endophthalmitis [17], and fungal endophthalmitis after intravitreal injection has become a clinical issue [21]. Therefore, development of agents that are also

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Table 1. Bacterial contamination rate and corneal endothelial cell density when infusion fluid or 0.25% povidone-iodine was used to repeatedly irrigate the ocular surface during cataract surgery. Microbial contamination (%)

Solution used in ocular surface irrigation (no. of eyes)

Corneal endothelial cell density (/mm2)

Start of surgery

End of surgery

ocular surface fluid

anterior chamber fluid

11/200 (5.5%)*

10/200 (5.0%)**

CNS (7)

CNS (6)

Infusion fluid

Preop

Day 7 postop

2614±233+

2463±269++

(n=200)

Micrococcus sp. (1)

Enterococcus sp. (1)

Enterococcus faecalis (1)

Enterococcus faecalis (1)

Staphylococcus aureus (1)


Corynebacterium spp. (1)

Klebsiella pneumoniae (1)

12/200 (6.0%)*

0/200 (0%)**

2534±173+

2338±204++

0.0017**

0.2254+

0.4044++

0.25% povidone-iodine (n=200)

CNS (8) Staphylococcus aureus (2) Micrococcus sp. (1) Klebsiella spp. (1) P

>0.99 *

CNS=coagulase-negative Staphylococcus sp. *, **; Fisher exact probability test. + ++ , ; Mann-Whitney U test. Data extracted from [15].

Table 2. Bacterial contamination rate when 0.25% povidone-iodine was used to repeatedly irrigate the ocular surface during vitrectomy. Method of ocular surface irrigation

Vitreous contamination

Vitreous contamination

(No.)

Ocular surface contamination after placing lid speculum

at beginning of surgery

at completion of surgery

Physiological saline (103 eyes)

6/103 (5.5%)*

1/103 (1.0%)**

2/103 (2.0%)***

CNS (4)

CNS (1)

CNS (2)

0/103 (0 %)**

0 /103 (0%)**

>0.9999**

0.4774***

Streptococcus (1) Staphylococcus aureus (1) 0.25% povidone-iodine (103 eyes)

7/103 (6.8%) * CNS (4) Streptococcus (1) Staphylococcus aureus (1) Propionibacterium acnes (1)

P

>0.9999*

CNS=coagulase-negative Staphylococcus sp. *, **, ***: Fisher exact probability test.

active against multidrug resistant bacteria and fungi is necessary for the prevention and treatment of endophthalmitis. 2.3. Ocular Surface Disinfection to Prevent Endophthalmitis For the prevention of postoperative endophthalmitis, rather than “reduction” of the normal flora present on the eye surface (disinfection), it is necessary to make greater efforts to achieve “elimination” of the normal flora (sterilization). According to a systematic

literature review and evidence rating of commonly used cataract surgery bacterial endophthalmitis prophylaxis techniques [22], no technique received the highest clinical recommendation (A). Preoperative povidone-iodine preparation received the intermediate clinical recommendation (B). All other reported prophylactic interventions, including postoperative subconjunctival antibiotic injection, preoperative lash trimming, preoperative saline irrigation, preoperative topical antibiotics, antibiotic-containing irrigating solutions, and the use of intraoperative heparin, received the lowest clinical


Table 3.


577

Antimicrobial spectra of antimicrobial agent and povidone-iodine. Contact time (seconds)

Bacteria Gram positive

Antibiotic resistant bacteria Gram negative

Fungus Virus Acanthamoeba

Antimicrobial agent

15-60 min

+

+

-

+

+

(fluoroquinolones) +

Povidone-Iodine (0.1 to 1.0%)

15 sec

(2.5 to 10%)

30-120 sec

+: effective, -: non-effective.

recommendation (C). Thus the literature strongly supports the use of preoperative povidone-iodine for endophthalmitis prophylaxis. In a 20-year retrospective analysis, endophthalmitis rate was significantly decreased with introduction of irrigation of the conjunctival sac with 10 mL of 1.0% povidone-iodine [23]. Povidone-iodine is used worldwide due to its wide-spectrum antimicrobial activities, absence of resistant bacteria, and low cost [24]. Furthermore, the effective and safe concentrations have been well established. 3. BASICS OF POVIDONE-IODINE 3.1. Antimicrobial Spectrum, Contact Time Povidone-iodine was developed in 1956, and is marketed as a 5% solution (Betadine; Alcon Laboratories, Fort Worth, Texas, USA) and a 10% solution (Meiji Seika, Tokyo, Japan). A 10% povidone-iodine solution contains 1% available iodine. Iodine oxidizes water to release ions that directly act on bacterial or viral membrane proteins to exhibit microbicidal effects [25]. Since iodine also acts directly on membrane proteins of normal cells, using an effective and nontoxic concentration for an appropriate contact time is important. Disinfectants are classified into three levels depending on the spectrum of microbicidal activity: high-level, intermediate-level, and low-level [26]. High-level disinfectants are capable of killing all types of microorganisms, but their use is limited to disinfecting instruments. Povidone-iodine is an intermediatelevel disinfectant and can be used for preoperative disinfection of skin. This compound exhibits potent bactericidal effect upon contact for 15-120 seconds and is microbicidal against multidrug resistant bacteria [27], Candida species [28], viruses [29] and Acanthamoeba [30] as well as capable of destroying biofilms [31] (Table 3). Additional merits of this agent include its availability worldwide, low cost, and absence of drug resistance bacteria to povidone-iodine [25]. Furthermore, the safe concentration range and oculotoxicity have been investigated in detail. On the other hand, chlorohexidine is a low-level disinfectant and has more limited microbicidal effect compared to povidone-iodine [32]. Antibiotic ophthalmic solutions in general use are active against common bacteria, but have no effect against resistant bacteria, fungi, viruses and Acanthamoeba. Moreover, antibiotic ophthalmic solutions require a contact time of 15 to 60 min to achieve antibacterial effect [33]. A study suggests that during intravitreal injection, ocular surface preparation using topical povidone-iodine alone without topical antibiotics does not promote bacterial resistance or remarkable change in conjunctival flora (Fig. 5) [34]. Further studies are required to investigate the use of topical povidone-iodine instillation alone without antibiotic eyedrop during cataract surgery and vitrectomy.

Fig. (5). Rates of detection of conjunctival bacterial flora before and after intravitreal injection when povidone-iodine alone is used for ocular surface preparation. When povidone-iodine alone is used, no bacteria including resistant bacteria are isolated from the conjunctiva sac. Bacteria (total and resistant) also do not increase after the procedure. (Authors’ unpublished data).

3.2. Effective Concentration The effective concentrations of povidone-iodine have been reported to range from 0.005 to 10% [35]. Previous basic research used a 5% povidone-iodine that contains other additives (Betadine; Alcon Laboratories). In a study on the effect of povidone-iodine on Staphylococcus aureus, marked bactericidal effect was observed at concentrations of 0.01% and above after bacteria were exposed to the solution for 15 seconds (Fig. 6). This data shows that the 0.25% povidone-iodine solution used for ocular surface washing will exhibit bactericidal effect even if the solution is diluted 25 to 50-fold in the operative field. Moreover, the 0.025% povidone-iodine solution used in intraocular irrigation is expected to exhibit bactericidal effect even if it is diluted 2.5 to 5-fold in the vitreous cavity. There is a common misunderstanding that higher concentrations of povidone-iodine, such as 5% and 10%, have higher bactericidal activity and require even shorter contact time. In actual fact, release of free iodine becomes more difficult as povidone-iodine concentration increases, and diluting the solution facilitates iodine release [24]. The concentration of free iodine is 5 ppm in a 10% povidoneiodine solution, 13 ppm in a 1% solution, 24 ppm in a 0.1% solution, and 13 ppm in a 0.01% solution (Fig. 7) [24]. For this reason, the time required for killing bacteria is shorter for 0.1 to 1.0% povidone-iodine (15 seconds) than for 2.5 to 10% povidone-iodine (30 to 120 seconds) [36]. Free iodine is inactivated upon reaction with bacteria and organic matters, and therefore has to be replenished.


Shimada et al.

(Table 4). Lower concentrations require a shorter contact time to exhibit microbial effect, but the duration of residual activity is also shorter. Therefore repeated replenishment of fresh solution is required for eye surface washing or vitreous irrigation during surgery.

Fig. (6). Effect of povidone-iodine concentration on bactericidal effect against Staphylococcus aureus. At povidone-iodine concentrations of 0.01 to 0.1%, marked bactericidal effect is observed after contact with the bacteria for 15 seconds. (Data extracted from [48]).

Fig. (7). Effect of povidone-iodine concentration on the concentration of free iodine. At 0.1% povidone-iodine, the available iodine concentration is 24 ppm showing the maximum antimicrobial effect. At 5-10% povidone-iodine, the available iodine concentration is 5-10 ppm. (Modified from [24]).

At 2.5 to 10% of povidone-iodine, the presence of abundant free iodine in the surrounding readily provides a source of replenishment. At 0.1 to 1.0% however, the bactericidal effect of povidoneiodine cannot be sustained, and repeated application is necessary to maintain the sterilization effect. While 2.5-10% povidone-iodine requires a longer time of contact for microbial killing, the duration of residual activity is also longer. For this reason, this concentration range is used in situations of a single application, such as eyelid or skin disinfection and instillation during intravitreal injection Table 4.

3.3. Safe and Effective Concentration of Povidone-Iodine for Eye Surface Washing Many basic studies on povidone-iodine have been conducted (Fig. 8) [15]. Povidone-iodine is an acidic solution with pH 4.5. Tissue toxicity of povidone-iodine has been reported to be unrelated to pH but depends on concentration [24]. A study in rabbit eye observed toxicity to corneal epithelium upon conjunctival sac instillation of 0.5 ml or more of 2.5% povidone-iodine, as well as toxicity to endothelial cells with 0.05 ml or more of 1.5% povidone-iodine, and reported that 1.0% or lower concentration is safe to use [37]. An investigation of retinal toxicity in rabbit eyes found no retinal damage when 0.1 ml of 0.4% povidone-iodine was injected intravitreally [38]. In another study, no adverse changes were observed in 9 of 10 eyes given intravitreal injection of 0.1 ml of 0.5% povidone-iodine, while the remaining eye showed temporary mild iritis and mild suppression on electroretinogram [39]. Furthermore, temporary hypotony and iridocyclitis occurred after injection of 0.1 ml of 5% povidone-iodine [39]. From the above findings, the concentration range of 0.05 to 0.5% has been reported to exhibit potent antimicrobial effect and at the same time nontoxic to ocular tissues [38]. The authors used 0.25% povidone-iodine, the median value of 0.05-0.5%, for ocular surface washing during surgeries. Even if 0.25% povidone-iodine is diluted 2.5-fold on the ocular surface, the resulting concentration of 0.1% has the highest bactericidal effect. Many institutions in European and American countries use instillation of 5% povidone-iodine on the ocular surface during intravitreal injection [40-42]. Some of the evidence of using 5% povidone-iodine is as follows. Preoperative skin disinfection with 10% povidone-iodine and conjunctival disinfection with 5% povidone-iodine has been shown to significantly reduce the relative risk of postoperative endophthalmitis after cataract surgery [40]. An in vitro study demonstrated that exposure to 5% povidone-iodine for 15 minutes or 10% povidone-iodine for 5 minutes was effective in preventing the growth of most post-cataract surgery endophthalmitis bacterial isolates [41]. A prospective randomized study reported that 5% povidone-iodine was more effective than 1% povidoneiodine in decreasing the human conjunctival bacterial flora, particularly in the presence of heavier initial bacterial load [42]. The European Society of Cataract & Refractive Surgeons recommends to apply povidone-iodine 5-10% to the cornea, conjunctival sac and periocular skin for a minimum of three minutes prior to surgery [43]. The American Academy of Ophthalmology states that “nonrandomized controlled trials and a prospective trial with the unoperated eye as the control have provided evidence that using topical 5% povidone iodine in the conjunctival cul de sac reduced the bacterial load and the incidence of postoperative infection“ [44].

Properties and uses of different concentrations of povidone-iodine.

Povidone-iodine concentration

2.5-10%

0.25%

0.025%

Free iodine concentration (ppm)

5‒10

20

15

Contact time (seconds)

30‒120

15

15

Sterilization duration

Long-lasting

Short-lasting

Short-lasting

Use site

Skin cleansing

Ocular surface washing

Intravitreal irrigation

How to use

Single application

Repeated washing every 20-30 seconds

Continuous irrigation

ppm: parts per million.



579

Fig. (8). The effective and safe concentration of povidone-iodine when used for washing ocular surface. The diagram shows the safe concentrations for corneal epithelium, corneal endothelial cells, and retinal when povidone-iodine is used for washing the ocular surface. The concentration of 0.25% is the median value for the effective and safe range of 0.05 to 0.5%. (Modified from [15]).

The above studies and recommendations refer to a single application on the skin with a heavy bacterial load or single installation to the conjunctiva. Under these conditions, 5 or 10% povidoneiodine that contains large quantities of available iodine provides longer bactericidal duration and hence more potent sterilizing effect than 1% povidone-iodine that contains small quantity of iodine. However, instilling 5% povidone-iodine to the conjunctiva and waiting for 15 minutes is not a practical method of disinfection. The reason is that 5% povidone-iodine instilled into the conjunctival sac as preoperative antisepsis may induce edema of corneal epithelium, which is frequently observed in clinical practice [37]. 3.4. Safe and Effective Concentration for Intraocular Irrigation When povidone-iodine is diluted in irrigation solution and used for intraocular irrigation, more careful research is necessary. In an in vitro study using bovine corneal endothelial cell cultures, endothelial cytotoxicity was observed at povidone-iodine concentrations of 0.1% and above, but not at 0.05% and below [45]. In in vivo studies of injecting povidone-iodine into the vitreous of rabbit eyes (volume of vitreous cavity, 1.5 ml), retinal damage was not observed at vitreal povidone-iodine concentrations of 0.0033% [44] and 0.027% [38], while retinal damage was found in 1 of 10 eyes

with a vitreal povidone-iodine concentration of 0.033% [44]. An in vitro study using cultured human corneal endothelial cells reported no cytotoxicity at povidone-iodine concentrations lower than 0.125% [46]. Having established that the highest non-oculotoxic concentration of povidone-iodine in the vitreous is 0.027%, the lowest vitreous concentration that is active against endophthalmitis has to be decided. In a rabbit model of endophthalmitis caused by Staphylococcus epidermidis, endophthalmitis was not improved at a vitreal povidone-iodine concentration of 0.007% (intravitreal injection of 0.1 ml of 0.1% povidone-iodine), but was improved at a concentration of 0.013% (intravitreal injection of 0.1 ml of 0.2% povidoneiodine) [47]. These results indicate that when povidone-iodine is added to irrigation fluid, the concentration range that is safe and effective against endophthalmitis is 0.013%-0.027% (Fig. 9). 3.5. Color, Diluting Solution, Room Temperature Storage The brown color of povidone-iodine reflects the amount of available iodine that has bactericidal activity. A 0.25% povidoneiodine solution is pale brown, while a 0.025% solution is pale yellowish brown. During cataract surgery, washing the ocular surface with 0.25% povidone-iodine once every 20 to 30 seconds does not

Fig. (9). The effective and safe concentration of povidone-iodine when used for intraocular irrigation. The diagram shows the safe concentrations for corneal epithelium, corneal endothelial cells, and retinal when povidone-iodine is used for intraocular irrigation. The concentration of 0.025% is within the effective and safe concentration range of 0.013 to 0.027%. (Modified from [48]).


interfere with the surgery. During vitrectomy, irrigation with 0.025% povidone-iodine in Balanced Salt Solution PLUS (BSS PLUS; Alcon Laboratories) does not affect the procedure. Regarding the diluent, 0.25% and 0.025% povidone-iodine diluted in physiological saline retains the bactericidal effect even after storage at room temperature for 1 day or longer (own data). If the solutions are in sealed bottle and stored in the refrigerator, the bactericidal effect is maintained for one month or longer (own data). A 0.025% povidone-iodine solution diluted in BSS PLUS starts to lose color upon storage at room temperature for 15 minutes, and becomes remarkably decolorized after 30 minutes (Fig. 10) [48]. When a 0.025% povidone-iodine solution is prepared in BSS, the bactericidal effect does not decrease even after storage at room temperature for 60 min. On the other hand, when 0.025% povidone-iodine is diluted in BSS PLUS, the bactericidal effect is reduced after 30 minutes (Fig. 11). A possible reason is that in a dilute povidone-iodine solution, ion formation during oxidation of water may be suppressed by oxiglutathione, an ingredient in BSS PLUS. By maintaining ATPase activities in the retina [49] and suppressing oxidative stress [50], oxiglutathione is anticipated to protect the cornea, inhibit breakdown of the blood-aqueous barrier, maintain lens transparency, and preserve retinal functions [51]. After exhibiting antibacterial effect in the ocular cavity, the effect of povidone-iodine is attenuated, then oxiglutathione may act to suppress oxidative changes of intraocular tissues due to endophthalmitis.

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4. CLINICAL APPLICATIONS OF POVIDONE-IODINE 4.1. Prevention of Postoperative Endophthalmitis A 0.25% povidone-iodine solution is prepared in the operating room by adding 10% povidone-iodine into a 250-ml bottle of physiological saline (Fig. 12). Attaching a washing needle to the cap of the bottle facilitates washing of ocular surface. The diluted solution is prepared once in the morning and once in the afternoon. The 0.25% povidone-iodine solution is dispensed from the bottle into a cup on the surgical tray, and is drawn into a syringe for use. By this method, the same solution can used in successive surgeries conducted in the same morning or afternoon.

Fig. (12). Preparation and use of 0.25% povidone-iodine solution. A: Appropriate amount of 10% povidone-iodine is added to a 250-ml physiological saline bottle to prepare a 0.25% solution, and a washing needle is inserted into the cap. B: The 0.25% povidone-iodine solution is dispensed from the bottle into a cup on the surgical tray, and a syringe is filled with the solution for washing. (Authors’ unpublished images).

Fig. (10). Attenuation of bactericidal activity of 0.025% povidone-iodine in BSS PLUS upon storage at room temperature. Bactericidal activity is maintained when 0.025% povidone-iodine in BSS PLUS is stored at room temperature for 0 to 15 minutes, but the activity is attenuated after 30 minutes. (Data extracted from [48]).

Fig. (11). Decoloration of 0.025% povidone-iodine BSS PLUS upon storage at room temperature. A: 0.025% povidone-iodine in BSS PLUS at 0 minute. B: The color becomes paler after 15 minutes. C: Marked loss of color is observed after 30 minutes. D: BBS PLUS containing no povidone-iodine. The color of povidone-iodine solution correlates with the bactericidal activity. (Authors’ unpublished images).

4.1.1. Preoperative Disinfection of Eyelid Skin The eyelid skin is scrubbed with a sponge soaked in 5% or 10% povidone-iodine [52]. Attention should be paid when using cotton balls, because cotton fibers (lint) attached to instruments may be introduced into the intraocular compartment. Since a concentration of 5% or 10% povidone-iodine is within the range that may cause corneal injury, the solution should not be allowed to get inside the eyelid. A 5% or 10% povidone-iodine stains the skin yellow, which is an advantage because it indicates the area of application. To disinfect the eyelid skin, a sponge soaked in povidone-iodine is applied three to four times and moved outward in concentric circular motion (Fig. 13). The area of scrubbing should extend superiorly until slightly above the eyebrow, medially until slightly passing the bridge of the nose, laterally until midway between the outer corner of the eye and the ear, and inferiorly until around the wing of the nose. There is a misconception that 5% or 10% povidone-iodine only exhibits bactericidal effects when it is dried. The truth is that adequate bactericidal effect can only be obtained after 2 to 3

Fig. (13). Preoperative disinfection of the eyelid skin. A: The skin is disinfected with 10% povidone-iodine. B: The conjunctival sac is washed with 0.25% povidone-iodine. C: The 10% povidone-iodine on the eyelid is wiped off, but the color in the surrounding skin is left on for identifying the eye being operated. To benefit from the antibacterial effect, do not rinse out the 10% povidone-iodine or 0.25% povidone-iodine with physiological saline. (Authors’ unpublished images).


minutes, roughly the time taken for the applied solution to dry [52]. After application, povidone-iodine should be left on the skin to sterilize it and not be rinsed with physiological saline. The yellow color around the eye stained by 5% or 10% povidone-iodine serves to identify the eye to be operated, after the drape is placed. 4.1.2. Cataract Surgery, Vitrectomy, Intravitreal Injection, Scleral Buckling, and Fluid Catch Bag Even washing the operative field with 0.25% povidone-iodine does not reduce the passage of bacteria into the intraocular compartment to 0%. In cataract surgery and vitrectomy, adequate irrigation of the anterior chamber and vitreous excision are important. In cataract surgery, the operative field should be irrigated with 0.25% povidone-iodine thoroughly at the beginning of surgery, before inserting the intraocular lens, and at the end of surgery [15] (Fig. 14). In microincision vitrectomy, the operative field should be irrigated thoroughly at the beginning of surgery, when creating scleral tunnels using trocars, when inserting instruments into the eye, and at the end of surgery [16]. In intravitreal injection, bacteria that are introduced into the vitreous via the needle tip cannot be washed out. Moreover, most antibiotic ophthalmic solutions do not penetrate into the vitreous, and hence cannot be expected to reduce the bacteria that have entered the vitreous [53]. Therefore, to prevent bacteria from gaining access into the intraocular compartment, the operative field should be washed at the beginning, during intravitreal injection, and at the end of the procedure [54]. In scleral buckling, the buckle and suture are the sources of acute scleral buckle infection [55]. The operative field should be irrigated during suture of the buckle and after suture [56]. For scleral buckling and non-vitrectomizing surgery conducted using a chandelier fiber probe, insertion of instruments into the intraocular cavity should be done under povidone-iodine. For cataract surgery and vitrectomy, the washing fluid of the ocular surface is collected into a fluid catch bag. Bacteria are isolated from the fluid catch bag fluid in 23.1% (12/52) of the cases [57] (Table 5). Therefore, care has to be taken not to drop any instrument used during surgery into the fluid catch bag. When surgery is conducted using 0.25% povidone-iodine for washing and irrigation, the bacteria detection rate in the fluid catch bag is significantly reduced to 3.8% (2/52) [57].


581

Fig. (14). Washing of ocular surface with 0.25% povidone-iodine during various ophthalmic surgeries. The ocular surface should be washed with 0.25% povidone-iodine during the following procedures: (A) cataract surgery, before insertion of foldable intraocular lens; (B) 25-gauge vitrectomy, before insertion of trocar; (C) 30gauge intravitreal injection, before insertion of needle; and (D) scleral buckling, during buckle placement. (Authors’ unpublished images).

4.1.3. Effectiveness, Intraocular Passage, Ocular Complications In 200 eyes undergoing cataract surgery in which the eye surface was washed with infusion fluid during surgery, the bacteria detection rate in the anterior chamber at the end of surgery was 5% (10/200 eyes) [15] (Table 1). On the other hand, in 200 eyes undergoing cataract surgery in which the eye surface was washed with 0.25% povidone-iodine, the bacteria detection rate in the anterior chamber at the end of surgery was reduced significantly to 0% (0/200 eyes) (P=0.0017) [15]. The corneal endothelial cell densities before and on day 7 after surgery were not different between two groups. When vitrectomy was conducted while washing the eye surface with infusion fluid, the bacteria detection rate was 1.0% (1/103 eyes)at the beginning and 2% (2/103 eyes) at the end of surgery [16] (Table 2). Washing the eye surface with 0.25% povidone-iodine during vitrectomy reduced the bacteria detection rate to

Table 5. Bacterial contamination rates of ocular surface wash fluid and inside fluid catch bag when 0.25% povidone-iodine was used to repeatedly irrigate the ocular surface during cataract surgery. Solution used in ocular surface irrigation (no. of eyes)

Ocular surface fluid contamination rate at beginning of surgery (%)

Fluid catch bag contamination rate at completion of surgery (%)

Infusion fluid

3/52(5.8%) *

12/52 (23.1%) **

(52 eyes)

CNS (2)

CNS (7)


Staphylococcus aureus (2) Micrococcus sp. (1) Corinebacterium sp.(1) Enterococcus faecalis (1)

0.25% povidone-iodine

4/52 (7.7%) *

2/52 (3.8%) **

(52 eyes)

CNS (3)

CNS (2)

Micrococcus sp. (1) P CNS = coagulase-negative Staphylococcus sp. *, **: Chi-square test for independent variable. Data extracted from [57].

0.6955 *

0.0041 **


Shimada et al.

Table 6. Bacterial contamination rate when 0.25% povidone-iodine was used to repeatedly irrigate the ocular surface during scleral buckling. Ocular surface fluid bacterial contamination rate

Solution used in ocular surface irrigation (no. of eyes)

After placing lid speculum

After placing scleral buckle

Infusion fluid

2/37 eyes (5.4%) *

7/37 eyes (18.9%)+

(37 eyes)

CNS (2)

CNS (5) Staphylococcus aureus (1) Corynebacterium sp.(1)

0.25% povidone-iodine

3/37 eyes (8.1%) *

(37 eyes)

CNS (2)

0/37 eyes (0%)+

Micrococcus sp. (1) P

0.6433 *

0.0114+

CNS: coagulase-negative Staphylococcus sp. *: Chi-square test for independent variable. + : Fisher exact probability test. Data extracted from [56].

0% (0/103 eyes) both at the beginning and at the end of surgery [16]. When intravitreal injection was given 30 seconds after washing the ocular surface with 0.25% povidone-iodine, no endophthalmitis occurred in 15,144 injections [54]. When scleral buckling was performed while washing the eye surface with physiological saline, bacteria were detected during buckle placement in 18.9% (7/37 eyes) of the cases [56] (Table 6). Washing with 0.25% povidone-iodine reduced the bacteria detection significantly to 0% (0/37 eyes) [56]. With a small molecular weight of 253, iodine penetrates the cornea easily. When cataract surgery was conducted while washing the eye surface with 0.25% povidone-iodine, iodide ion was detected in the anterior chamber fluid at a concentration of 0.008% [15]. Since the effective concentration of povidone-iodine is 0.005 or above, the bactericidal effect probably also covers the intraocular tissues in the anterior chamber. When vitrectomy was conducted while washing the eye surface with 0.25% povidone-iodine, iodide ion in the vitreous was below the detection limit (lower than 0.001%) [16]. Therefore, povidone-iodine probably hardly infiltrates into the vitreous via the cornea and cannula. Regarding surgical complications of washing the eye surface with 0.25% povidone-iodine during surgery, no intraocular adverse events were observed one day after surgery in more than 10,000 cataract surgeries, more than 5,000 vitrectomies, and more than 30,000 intravitreal injections (own data). Corneal endothelial cell density did not differ significantly between 200 eyes using physiological saline and 200 eyes using 0.25% povidone-iodine to wash the ocular surface during cataract surgery [15]. In cataract surgery, even though 0.25% povidone-iodine enters the anterior chamber, it is diluted by the irrigation fluid to very low concentration (0.008%) [15]. When 0.25% povidone-iodine is used to wash the ocular surface, approximately 1% of the concentration passes into corneal tissues [58]. Therefore, even washing the eye surface every 20 seconds is not likely to cause corneal endothelial damage. However, using an automatic dispenser to deliver the drop to the same site of the cornea may cause endothelial damage. The reason is that the safe povidone-iodine concentration for cultured corneal endothelial cells is lower than 0.125% [46]. 4.2. Treatment of Endophthalmitis Regarding the treatment of endophthalmitis, results of the Endophthalmitis Vitrectomy Study supported the use of vitrectomy in

patients presenting with light perception, and the use of vitreous tap and intraocular antibiotic injection in patients presenting with visual acuity better than light perception [59]. A national prospective survey in France on patients with acute onset endophthalmitis after cataract surgery reported use of antibiotic injections in 95.1% of the patients and immediate vitrectomy in 14.0% [60]. A database survey on endophthalmitis after cataract surgery in China reported that treatment included antibiotic injection in 54.1% of eyes and immediate vitrectomy in 40.2%. During the last 15 years, the use of vitrectomy increased significantly (P < .05) [61]. The authors’ group has examined a novel approach of treatment for postoperative endophthalmitis using povidone-iodine. Initial treatment involves intravitreal injection of 0.1 ml of a 1.25% povidone-iodine solution. The 1.25% povidone-iodine solution is prepared by filling a 1-ml syringe with 0.1 ml of 10% povidone-iodine and 0.7 ml of physiological saline. Assuming a vitreous volume of 5 ml, the vitreous concentration will be 0.025%. This method of initial treatment is simple. For use in vitrectomy, BSS PLUS containing 0.025% povidone-iodine is used as irrigation solution. The solution is prepared just before starting vitrectomy by adding 1.25 of 10% povidone-iodine to 500 ml of BSS PLUS. 4.2.1. Initial Treatment Bacteria that gain access into the intraocular compartment proliferate rapidly within a short time [62]. Endophthalmitis-related symptoms may progress very fast. Intravitreal injection of vancomycin 1 mg/0.1 ml and amikacin 0.4 mg/0.1 ml is the recommended initial treatment for endophthalmitis [17]. This recommendation is based on the relatively low frequencies of resistance to these antibiotics. However, these antibiotics are not effective if the causative microorganisms are resistant bacteria or fungi. In rabbits, injection of 0.1 ml of 0.3% povidone-iodine into the vitreous (vitreous concentration, 0.02%) on alternate three days has been reported to be effective for endophthalmitis with no retinal damage on electroretinography [63]. This result supports the usefulness and safety of intravitreal injection of 0.025% povidoneiodine as initial treatment for endophthalmitis. 4.2.2. Vitrectomy The authors’ group treated 4 eyes with endophthalmitis by conducting vitrectomy using 0.025% povidone-iodine in BSS PLUS for vitreous irrigation [48] (Table 7). Visual acuity was light perception to hand motion before surgery, and was improved to 20/200 120/200 after vitrectomy. The intraocular lens was conserved in all


Table 7. Case


583

Patient characteristics. Age

Primary Disease

Primary Treatment

Visual Acuity

Gender

Before surgery

After surgery

1

80, F

Myopic CNV

Intravitreal anti-VEGF injection

HM

6/20

2

75, F

BRVO

Intravitreal TA injection

LP

4/20

3

52, M

PDR

vitrectomy

HM

6/20

4

34, F

RD

vitrectomy

LP

2/20

CNV; choroidal neovascularization, BRVO; branch retinal vein occlusion, PDR; proliferative diabetic retinopathy, RD; retinal detachment, VEGF; vascular endothelial growth factor, TA; triamcinolone acetonide, HM; hand movements: LP, light perception. Data extracted from [48].

four eyes [48]. A characteristic of using 0.025% povidone-iodine in vitrectomy was that inflammation early after vitrectomy was milder than that observed in cases treated with conventional vitrectomy (Fig. 15).

ACKNOWLEDGEMENTS Declared none. REFERENCES [1]

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[3] Fig. (15). Endophthalmitis after intravitreal injection. A: An 80 year-old women (pre-procedural visual acuity 8/20) underwent intravitreal injection of bevacizumab for myopic choroidal neovascularization. Endophthalmitis developed on day 6 after intravitreal injection. Visual acuity was hand motion. B: Day 1 after vitrectomy with irrigation using 0.025% povidone-iodine in BSS PLUS. Inflammation of the anterior segment improved and there was little corneal damage. Inflammation was milder than that observed in endophthalmitis cases treated with conventional vitrectomy. After 6 months, visual acuity improved to 12/20. (Authors’ unpublished images).

[4]

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In a separate study conducted by the same group, 4 eyes with endophthalmitis were treated initially with intravitreal injection of 0.1 ml of 1.25% povidone-iodine followed by vitrectomy using 0.025% povidone-iodine in BSS PLUS for vitreous irrigation (unpublished data). Visual acuity was 2/200 - 200/200 before surgery, and improved further to 60/200 - 200/200 after vitrectomy. Again, the intraocular lens was saved in all 4 eyes. Corneal endothelial cell density measurement, visual field test, and electroretinographic examination revealed no adverse events attributed to povidone-iodine (unpublished data). CONCLUSION Repeated washing of the ocular surface with 0.25% povidoneiodine during eye surgeries is useful for the prevention of endophthalmitis. This method of antisepsis should be used in every type of intraocular surgery, as it is simple, safe for the cornea, ffective and inexpensive. A small case series suggested the usefulness of 0.025% povidone-iodine for the treatment of endophthalmitis both as initial intravitreal injection and as irrigation solution in vitrectomy, but this treatment method remains to be established. Further studies on large series including resistant bacteria and fungi are required to confirm the usefulness of povidone-iodine for the treatment of endophthalmitis. CONFLICT OF INTEREST The authors confirm that this article content has no conflict of interest.

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