This live webinar will widely cover Microbial Keratitis caused by different organisms, and answer the following questions. How can we clinically differentiate between bacterial and fungal keratitis? What are the classical clinical presentations of fungal, bacterial, pythium, nocardia, microsporidia and acanthamoeba infections from early to advanced disease? When to do scrapings and microbiological evaluation? What are specific antimicrobial regimes for each organism and when do we go in for a surgical intervention?

Lecturer: Dr. Madhu Uddaraju, Director, Srikiran Institute of Ophthalmology, Head of Cornea & Refractive Surgery Services, Kakinada, Andhra Pradesh, India


DR UDDARAJU: Hi. Welcome to everyone. I’m Dr. Madhu Uddaraju, from India. I hope all of you are doing well and keeping safe during this pandemic. It is my pleasure to interact with all of you in this prestigious learning platform, from Orbis Cybersight. In the next 30 to 40 minutes, I’ll be covering the topic of microbial keratitis, making it relevant, and also as an update for the general ophthalmologist in their day-to-day practice. As you can see here in the background of my first slide, I come from one of the rice bowls of India. That’s the Godavari Delta, where we have lush green fields and coconut fields around us. In these beautiful fields also there is lurking fungus that affects most of our patients during the reaping season. I have no financial disclosures in any of the topics that I’m going to speak on in this webinar. So the webinar — I will be covering it under the following headings. First of all, we’ll start off with a pretest, to test your existing knowledge that you have right now. And we’ll tell you the answers at the end of the sessions. Next I’ll discuss about the background, burden, and causes of microbial keratitis. Next we’ll discuss the clinical diagnosis, how you can clinically diagnose different forms of microbial keratitis and how you can differentiate it from other forms. And then we’ll touch upon the role of microbial evaluation and confocal microscopy. Then we’ll see the medical management, both empirical and specific therapies, we’ll briefly touch upon the landmark trials in microbial keratitis like MUTT and SCUT from the Aravind group, and we’ll see the role of intrastromal injections and crosslinking in infectious keratitis. Finally, we’ll see the surgical interventions, starting with tissue dehiscence, patch grafts, and therapeutic grafts, and then a take-home message and post test to see how much knowledge you’ve gained in this webinar. Without any delay, let’s start the pretest questions. I have five pretest questions for you. The first question is: Over-the-counter steroids are the most important cause for or the most common cause for… A, bacterial keratitis, B, allergic conjunctivitis, C, fungal keratitis, D, both B and C. Yeah. Let’s go to the next question. I’ll reveal the answers in the end of the session. Which bacterial organism causes rapid progression and corneal melting? A, staphylococcus, B, pseudomonas, C, streptococcus, D, nocardia. Thank you. Let’s go to the next question. When should we refer a case of microbial keratitis to our cornea colleagues for management? A, when the ulcer size is more than 3 millimeters. B, when the ulcers are in the central axis, obscuring the vision. C, one eyed patients and children. D, all of the above. Thank you. Fourth question. What is the indication for therapeutic keratoplasty? Or surgical intervention in microbial keratitis? A, impending corneal perforation. B, limbal involvement. C, deep stromal ulcers, not responding to maximal medical therapy. D, all of the above. Thank you. So let’s go to the last question. Steroids should be avoided in which form of viral keratitis? Non-necrotizing stromal keratitis. B, Disciform endotheliitis, C, epithelial disease, like dendrites, D, both options A and B. Thank you. So I think 50% to 60% of you have answered right to all the questions. So by the end of the session, I would like to see at least 90% of you answering the questions correctly. So let us go to the background of microbial keratitis. So every year, around the world, we see around 1.5 to 2 million new cases of microbial keratitis that come up. And they also amount nearly to 5% of the total blindness caused by trauma and its consequent infection. And the burden of this infection in the US alone is $175 million US dollars, as direct expenditure. And an additional 70 million US dollars on Medicaid or Medicaid per year. That is how problematic this disease can be. And when you go into final details, the fungal keratitis, the outcomes are poorer when you compare to other forms of keratitis. It has almost 5 times more — higher perforation rate, when you compare it with bacterial. And also the surgical intervention is nearly 30% in all the cases. And the treatment cost also is three times more, when you compare it with other forms of microbial keratitis. Throughout our network, we see 3 to 4 new cases every day. So with this experience, I will be sharing with you whatever we have seen in the past, and how you can easily differentiate clinically between different organisms, just by looking and having a meticulous slit lamp examination. And one more important thing that all of us should keep in mind, when you’re treating microbial keratitis, is the emergence of antibiotic resistance that is throwing a challenge for all of us in the management of this dreaded disease. So if you see the causative organisms, there is a whole list of organisms that can cause microbial keratitis, starting from fungus, from bacteria that can be Gram positive, Gram negative, or atypical mycobacteria. Then you have acanthamoeba, that’s a parasite, nocardia, that’s a filamentous bacteria, microsporidial, pythium, and a combination of these that is polymicrobial. Usually I don’t cover viral in my talks, but from the preregistered feedback that I got, I tried to cover HSV keratitis also in a brief way for the sake of the audience that have asked me yesterday. So coming to microbial keratitis, the two major forms we see in the developing world are fungal and bacterial keratitis. So if you’re able to differentiate between fungal and bacterial keratitis clinically, half your job is done. And as the classical teaching goes, the fungal lesions — they’re irregular, they have serrated margins, and they have a raised profile over the cornea. Whereas the bacterial lesions have more well defined margins and they have a flatter profile. And when it comes to color, the bacterial keratitis has a more whitish hue, whereas fungal keratitis has more of a yellowish tinge to it. And apart from this clinical aspect, you should always take the history into consideration. For example, you’re practicing in a rural area and the patient gives you a history of trauma, with vegetative matter, a history of steroid use, all of these things are more inclining towards fungal keratitis. Whereas if you’re practicing in a semi-urban but not a city area, it’s more likely that you’re going to see bacterial keratitis because of contact lens wear instead of trauma from vegetative matter. So this is how you can differentiate. If you see these pictures, wherever the borders are irregular, they are more raised, it’s more likely to be fungal. If it is flattened and has a whitish hue to it, it is more likely to be bacterial. So with this, let us go into fungal keratitis in detail. 50% of the keratitis we see is fungal keratitis, so I would like to stress it, especially in developing countries. There are two dangers aspects of fungal keratitis. One, most of our population are dependent on agriculture, and work day in and day out in the fields, where they are prone to trauma with vegetative matter. Once this trauma occurs, the second bad thing is that they go to a medical shop, where unfortunately over-the-counter steroids are freely available, or sometimes they even take the steroid drops that we give postoperatively for cataract to them or family members. For any redness or itching or irritation in the eye, they go to these postoperative drops we give them and use it throughout the family. And this combination of vegetative matter trauma and use of steroids gives rise to a very fulminant use of fungal keratitis that you can see in the picture here, that almost will not heal to medical therapy, and obviously you have to go in for a large therapeutic graft, and the outcomes, as you know, are very poor. And also, the ulcers we see have a seasonal variation to them over here. So whenever there is the reaping of patty, we tend to see more trauma, and then we have this crop of ulcers also coming along with it. So it depends also where you are practicing. For example, in India, in the southern part of India, fusarium is more common. Whereas in the North and eastern part, aspergillus is more common. Candida, infection with yeast, we see more rarely in our country. It is usually seen in immunocompromised individuals. So let us see the earliest signs of fungal keratitis. If the patient is lucky enough, he may present to you with this kind of a picture. So if you see the first two pictures, they can easily mimic a dendritic ulcer. So you have to be very careful in examining these ulcers. So how do you differentiate between a dendritic ulcer and early fungal keratitis? You have to look for the end bulbs and the central ulceration. Typically in an HSV keratitic dendrite, it will not be hazy. The surrounding stroma will be clear. If you see the surrounding stromal haze, it is likely of a fungal origin. And when you elicit the history properly, you will get the trauma with vegetative matter, which you should always have in fungal keratitis. Sometimes the patient can present to you in a healing phase. In this phase, it can mimic a geographic ulcer of viral keratitis again. You have to look for signs of inflammation. Obviously when it is a healing ulcer, you don’t see any congestion as in this picture. With a viral geographic ulcer, you’ll definitely see a lot of conditions that are there and the lid matter that accompanies it. So in early forms of fungal keratitis, always try to differentiate it from the dendrite of HSV. And there is no harm in debriding both the lesions. If it is HSV, debridement is known to be a useful tool. The same way if it is a fungal keratitis, with your debridement, you’re taking off the load of the fungal organisms from the cornea. So next is the classical picture that usually presents to us after the patient undergoes treatment with a local medical shop or someone who is practicing near his village. Here you can see a textbook appearance, like feathery margins you see in the picture here, then you have satellite lesions that you can see in the picture down here. Sometimes you can see the superficial plaque, pigmented kind of thing. This is pathognomonic of a fungal infection with dematiaceous fungi. Whenever you see this pigmented lesion that is spread like a carpet over the cornea, always try to scrape it out with a 15 number blade once, and you can just catch the edge with a fine toothed forceps and you can nicely peel off this entire plaque. Believe me, when you peel off this entire plaque, the cornea almost clears up. And until and unless you do this plaque removal of therapeutic debridement, the drug won’t penetrate, and the ulcer will just be over the surface, and it will start spreading like a carpet. So whenever you see these pigmented lesions, carpet-like lesions, try to lift one edge with the help of a blade, and gently pull it out with the help of a fine toothed forceps. Next, coming to anterior stromal infections in fungal keratitis — can mostly be caused by fusarium, and when they’re deeper, they’re more likely to be caused by aspergillus. So these are the things you have to remember, when you see a classical picture. Anterior stromal, more likely to be from fusarium. Dematiaceous fungi, therapeutic debridement is more important. Otherwise your drugs will not work. Aspergillus, these are more deeper infections that will require a modification in the treatment, that we’ll discuss in the treatment part. This is an advanced stage of fungal keratitis. If you see this advanced stage of fungal keratitis, you can see deep endothelial plaques, abscess formation, and in the second picture, you can clearly see the limbal involvement, and the picture over here, it is a frank corneal perforation with the PCIOL that is extruding through it. These are all the advanced cases that will probably require a therapeutic graft. Coming to the microbiological diagnosis, if you have access to them, a simple KOH mount will show the fungal filaments over there. And this is what the fungal growth will look like on potato dextrose, and this is what the filaments look like on confocal microscopy. If you don’t have access to it, don’t worry. With the help of the clinical signs I have told you, look for the signs and start the treatment. What is the role of confocal microscopy in fungal keratitis? Wherever the lesions are scrapable, they’re in the anterior stroma, and you can scrape these lesions, there is no role for in vivo confocal microscopy. These are lesions that are not scrapable. Mostly deeper lesions in the deeper stroma. For example, you can see the corneal slit is clear, but from the lip of the tunnel, this growth is extending into the anterior chamber. And in the anterior chamber, if you see, those are the fungal filaments you can beautifully appreciate. So you can see the depth at which this confocal scan was taken was 834 microns. As all of you know, at 500 to 550, the corneal endothelium ends, and now the scan that we’re taking is in the AC, and without doing any microbiology, if you have access to Confoscan, you can easily identify these organisms with the help of this wonderful equipment. So going a step ahead, if you have access to confocal microscopy, and the lesions are not scrapable, you can also try to speciate the fungus. For example, if the fungus is having branches at right angles, it is more likely that it is fusarium. And if the fungus has dichotomous branching, with branching at 45 degrees, it is more likely to be aspergillus. You can see the comparison here. Aspergillus is more dichotomous in its branching. Whereas in fusarium, the branching is more right angular. This is how you can differentiate in confocal microscopy. This will not hold when you’re looking at broken filaments, because you won’t know which kind of fungus you’re looking at. Especially when you’re looking at healing ulcers, you might not get a good idea. But when you’re looking at a deep active lesion with exudate, you can get a cue most times of which kind of fungus you’re looking at also. The treatment for fungal keratitis will follow the modified TST protocol. That is the topical, systemic, and targeted therapy that was recommended, that we have modified to our needs. So we start off with natamycin, 5% eye drops one hourly during waking time. If it is aspergillus, we add voriconazole. One important take-home message from our MUTT studies: Never use voriconazole as a monotherapy. Always use it in combination with the natamycin or any other antifungal. Because in the study, they have found out that the group in which they have used voriconazole as a monotherapy, the perforation rate was higher. For the nighttime cover, we give itraconazole ointment, and for symptomatic relief, we treat with antiglaucoma medicine. We have done a randomized controlled trial to see the role of oral doxycycline for its activity in prevention of perforation and surgical intervention in fungal keratitis. And our results have been that in the group which we used oral doxycycline, the results were better and statistically significant lesser perforations and therapeutic grafts were done in that group. We’re shortly going to publish this study. It’s in the process of publication. So systemic ketoconazole we usually add in case of deeper ulcers. Usually ketoconazole, 200 milligrams, twice a day, and keep monitoring the liver function tests, as we’re continuing the dose systemically. But candida, as I have told you, is the drug of choice. Along with that, you can add voriconazole or natamycin. Usually seen in immunocompromised individuals. Intrastromal or intracameral injections — I’ll show you a short video. This is limited. But however the group from our centers — it is also good with these injections. Our own colleague, Dr. Krishna, has done a study in which he has found that instead of waiting for a longer time and letting the ulcer to worsen, if you can do an early TPK using optical tissue, the results are far better, and once things are under control, you can even start steroids postoperatively, with caution, and slowly salvage the same TPK graft into an optical graft. And one more important thing is: Crosslinking should never be done for fungal keratitis. I was one of the investigators during my fellowship period at Aravind. So we found that crosslinking did not have any beneficial role in advanced fungal keratitis. Actually, the perforation rate was higher in the group in which we were doing fungal keratitis. What we found out later was probably because of crosslinking, we are making the stroma compact, so the antifungals are not reaching the disease. And after that, they have done one more study in Aravind that is the CLAIR study, that tells that even as a primary therapy also in fungal keratitis, crosslinking does not have any role. One thing we can look for in future is the role of tacrolimus for its antiinflammatory properties. In animal studies, it has been shown to have beneficial role, and it acts synergistically with voriconazole and natamycin in the treatment of fungal keratitis. So with this protocol, we are able to achieve healing in 75% of our cases. So you may be wondering why we are achieving these results. There are two reasons for these results. One is: When you are giving specific therapy, instead of empirical therapy for fungal ulcers, you have better drug compliance. You are not diluting your drugs with antibiotics. Second, the commensal bacteria that are there within the conjunctiva and lid margins, they actually act against the fungus. When you are giving antibiotics indiscriminately, you are taking away this beneficial role from your body. So this is the reason, when we give very specific antifungal therapy, the healing almost is there in 75% of our cases. So let’s see the intrastromal injection. In this intrastromal injection, if you can see — so there is the abscess that is there in the graft-host junction. Again, scraping showed aspergillus fungus. And culture showed aspergillus. So whenever there is an abscess, never try to give an intrastromal injection directly. It will not be of any use. First you have to drain the abscess. That is what we’re trying to do in this video, with the help of a fine needle. So as you can see, the pus is very thick. We’re unable to drain it with the needle. So what we have done is now we have removed the needle and with the help of the tuberculin syringe, we have aspirated the entire abscess. Now that the abscess is cleared, you can gently go into the stroma, 365 degrees, and start injecting your voriconazole in the lesion. There is some infiltrate that is still there. So I’m giving it just into that area, so that the drug will work better. So the most important thing with intrastromal injections is: A single injection in most of the time may not suffice. You may need to give multiple injections, and after multiple injections, these organisms will start responding. And always try to give 360 degrees in the lesion, and never use it as a monotherapy. Use it as an adjuvant therapy to your topical therapy. So next let us see the next case… Where suppose the grafts are — the perforation is not in the center. Then we can do patch grafts that are 4 to 5 millimeters. And you do this patch graft. You have to make sure that you clear the angle. If you see that angle, you can see the endo exudates that are adherent to the iris. You have to make sure that you release all those adhesions, and you clean that angle before you close it up. So this later can be taken up for an optical graft. But when you do this, you are saving a lot of endothelium, instead of doing a large graft. Here again you can see a full thickness thing. That is again in the periphery. Again, it is involving the limbus in the periphery. So this is a perforation again in the periphery, with active lesion, inferiorly. So again, here, you just take that part. You don’t go for the entire cornea. And then later plan for an optical graft. And tunnel infiltrates also… You can plan for this kind of a technique. So now let us see a total corneal graft. If you see a total corneal graft, with something like this… There is nothing that you need to trephine here. It’s more like a free hand dissection. So gently remove the ulcer. It’s almost full thickness thing. And the entire limbus is involved. You can see the cornea. Now you can see the plaques that are there in the anterior chamber. The use of saline, you remove the plaques, and then place the corneal button. And these large buttons can develop glaucoma and will require a glaucoma drainage device. You should be using 9-0 sutures instead of 10-0 here. Or it becomes difficult. But always give it a chance. Never lose hope. Because sometimes these grafts will survive, and with secondary procedures, you can turn them into vision saving things. So now that we have finished fungal keratitis, let us go to a disease that mimics this fungal keratitis closely. That is pythium keratitis. So if you see in this pythium, there are two things that will differentiate pythium from fungal keratitis. One is this tentacle-like projections that come out from the main lesion. And the peripheral gutter, just like PUK, that you can see in these cases. So these are, again, a series of cases produced from our work at Aravind, where you can easily see a history — you’ll have a history of water exposure, and usually in rainy seasons, you tend to see this pythium more. So two lesions that you should remember are: Tentacle-like projections and a peripheral gutter. When you see these lesions, have a high suspicion for pythium keratitis. And most of the time, when you mistake these as fungal keratitis, and you are giving treatment and you see it is not responding to it, that is the time when you have to reassess again, go back and do the scraping again, and look for pythium in particular. So this is how a pythium will look like, in Gram stain. If you see it is more ribbon-like, it will not have septa, like you have seen in the fungal hyphae. And its walls are also relatively thicker. And when you see in blood cultures, you have these zoospores that are there. This is how you differentiate between a fungus and pythium. Pythium management has not been standardized. But there is a group that has recommended the use of topical linezolid hourly, and oral azithromycin. We also add antifungals such as itraconazole, voriconazole, or econazole. And also topical azithromycin. But only 30% to 40% heal from medical therapy, and most have very poor prognosis, especially if it is pythium. It is a very invasive disease. We have a case from our center where it has gone for cranial involvement, and even death has occurred. So in these cases, you should be prepared for a therapeutic graft, evisceration, or enucleation. However, we need more data to have a standardized protocol for this particular disease. So next, let us go to bacterial keratitis. So in bacterial, first we’ll cover Gram positive. So Gram positive are usually because of your staph aureus or staph epididymis, or streptococcus that are there in your ocular adnexa. These lesions are usually well defined and superficial, however large they may be. They’re usually well defined. They usually heal well to antibiotics. And when it’s Gram negative, especially pseudomonas, it worsens within hours. If you see this picture here, it’s almost like within one day that it has turned from this into this. And your suspicion should always be high for pseudomonas, if it is turning worse overnight, and if the patient is a contact lens wearer, and here the inflammatory component is more than the infectious component. That is where you see this pathognomonic worsening, rapid worsening, and corneal melting, that is very, very classical of pseudomonas. So these are the — if you see GPC pairs, they’re more likely to be streptococcus. Then you have GNB that are there in the background. That’s pseudomonas. GPC in groups is staph aureus. And GPB, this is atypical mycobacteria. So we’ll discuss about this in the coming slides. Always remember, Gram negative organisms are difficult to identify in Gram stain, because they’re lost in the background. Unlike Gram positive, which stand out. So whenever you have a smear negative thing, go back and look for Gram negative organisms. Especially if there is a rapid course of worsening in the case that you’re seeing. So coming to the bacterial management for Gram positive cocci, we prefer to use moxifloxacin or gatifloxacin, along with the fortified antibiotic of our choice — cefazolin. We can also add levofloxacin that has recently come into the market. Oral antibiotics, again, like antifungals, we give them only in case of deeper ulcers, endoexudates, limbal involvement, or such cases only. Gatifloxacin ointment in the night cover we give, along with symptomatic treatment that we have already discussed. For Gram negative organisms, the drug of choice is tobramycin or gentamicin that is fortified. And here the role of steroids was studied in the SCUT study done by the Aravind group, again. Here they have found it doesn’t have any beneficial role in the final scarring or vision recovery. However, if you look into the details, there is a particular subtype of pseudomonas that is very aggressive, that will have a beneficial role with the addition of steroids. However, I will not profess the use of steroids until and unless you are sure of it microbiologically. But just to keep you updated, if you know for sure it is pseudomonas, definitely steroids will have a role. Because the inflammatory component here is more than the infectious component. Again, crosslinking, our own student has done a thesis on this, and she found that crosslinking has a beneficial role in bacterial keratitis. However, most of them will not require it. As I’ve told you, most of the Gram positives recover with antimicrobial therapy alone. If you need it, you can use it, but it may not be required in most of our cases. Next let us go to this very menacing organism that is atypical mycobacteria. This has been an emerging infection, especially specifically post-LASIK. This is so relevant in post-LASIK infections,

50% of post-LASIK infections are caused by mycobacteria. They can be seen in immunocompromised patients otherwise. It is both a diagnostic and therapeutic challenge for all of us. And the typical appearance — what you see is this cracked windshield appearance that you can see with the atypical mycobacteria. The problem is, it mimics both fungal and viral keratitis, as you can see here. So most of the time, when we don’t know what we are looking at, and we miss out on the microbiology, we treat it as viral, we treat it as fungal. That is how it takes a longer time to heal. Why is it a diagnostic challenge? If you carefully look at this picture on your left, you can see these white lesions that are there in the center. This phenomenon is called as negative stain. So this atypical mycobacteria is known for negative staining. It does not take any stain. Because of the large amount of lipids that are in the cell walls. So if you use special stains, they will stand out like this in the background. So this is again like Gram negative bacilli. It is very, very easy to miss on a smear. So if you see here, and just go through it, you will not be seeing anything. You have to look specifically for negative staining features in atypical mycobacteria. That is very, very common after LASIK infections. And the treatment for mycobacteria is topical amikacin. Either you can use 2%, if it is not responding, you can fortify it to 4%, along with it, you can give a fluoroquinolone. Azithromycin orally on day one you can do 500 milligrams, followed by 250 for 5 days. You should wait at least one month for this medical therapy to heal. I’ve told you this is a very menacing organism. It will take some time to heal. If it doesn’t heal with medical therapy for one month, you have no choice but to go ahead with the LASIK flap amputation. And if it doesn’t get healed with that, you have to go in for a therapeutic graft. So that finishes the atypical mycobacteria. Next we have acanthamoeba keratitis. This is a typical ring infiltrate that you can see, and these are the enlarged corneal nerves. Pathognomonic of perineuritis, that causes intense pain in the patient. And also in chronic cases, like in the third picture, you can see this chronic corneal melting. So intense pain, ring infiltrate, and corneal melting in longstanding cases are pathognomonic features of acanthamoeba keratitis. Usually contact lens users are also at risk of developing this disease. So this is how acanthamoeba cysts will look like in a KOH wet mount, and these are acanthamoeba cysts in in vivo confocal microscopy. And the treatment is PHMB or chlorhexidine 0.02% drops, one hourly. The problem is that PHMB is nothing but a swimming pool disinfectant. Usually we get it from the US whenever we go, and that solution comes for almost 2 years. In India, we have the solution in LV Prasad and Aravind, so whenever surgeons ask, we send the solution to them, and they titrate it with help of a micropipette and reconstitute and give to the patient. Here the pain management is not easy. It won’t be — the pain here will not be amenable to regular analgesics. You have to give amitriptyline 25 milligrams BID or TID to control the pain. You have to give antimicrobials like PHMB or chlorhexidine at least for two weeks. Some people add voriconazole to it, and acanthamoeba, there are certain conditions in which you have to start steroids. Those conditions are when you see vascularization, when there is melting, when there is scleritis, lid edema, and the patient is very symptomatic. These are the five things, when you have to start giving steroids to the patient after initiating the antimicrobial therapy. In these cases, they are known to take a longer time to heal. Usually they take 2 to 3 months. If they’re not healing, you can try a therapeutic DALK or TPK here. It is a chronic disease, so be careful. The chronic surface toxicity should not cover and mimic the disease that is below it. Then we have nocardia keratitis. So nocardia, again, as I told you, is a filamentous bacteria. Here you can see this typical wreath shaped pattern, and in our experience, we see them in the tunnel infiltrates that can lead to endophthalmitis. So if you see this ring infiltrate, this is acanthamoeba. More or less a continuous ring. Whereas in nocardia, it’s a discontinuous wreath shaped pattern that you have to differentiate clinically to know it is nocardia. And nocardia usually will be superficial. It does not go deep. It will spread more in the superficial plane than going into the deeper plane. So nocardia, as I have told you again, it’s a filamentous bacteria. Here you can see the slender filamentous bacteria in Gram stain, dot-like filaments. You should never confuse them with fungal filaments that you see here. They’re broader, they have septa. Here you see the dot-like connections that you see and it’s a filamentous bacteria. You should not confuse it with pythium, which is broader with lesser septa. This is how you can differentiate them on microbiology. So treatment is amikacin, like atypical mycobacteria, along with the fourth generation fluoroquinolone. Systemically, we tend to give amikacin injection also if the lesions are more limbal. Or tunnel infiltrates. And orally, we can give sulfamethoxazole, trimethoprim combination in these cases. And most of the cases… 70% of the cases heal well with medical management. And some of them may require more surgical intervention. Finally, microsporidial keratitis. You can see this microsporidial keratitis, a coarse stuck on appearance that are typical. And the stromal form, you see rarely, and the stromal form is associated mostly with immunocompromised individuals. Whereas microsporidial keratitis you see with healthy individuals. They usually give you a history of having a bath in the pond or getting exposed in the rain water or something like that. So microsporidia, again, they’re grain-like lesions which you can appreciate with Gram stain or fluorescein microscopy. You can see this grain-like lesion. As seen here. Here you can see this beautiful picture taken by one of our fellows, and these are all the microsporidial lesions. The typical stuck on appearance. So with the help of a moist cotton tip, you place some topical anesthesia, and you can see how beautifully immediately after he has removed all those lesions, how clear the cornea looks. So here again, the organism is more towards fungus. So we prefer to give fluconazole or voriconazole drops. And in the night cover, you can give itraconazole eye ointment or gatifloxacin eye ointment. Stromal keratitis is very difficult to treat. It will not heal on medical therapy. It is mostly seen in immunocompromised patients and will require a therapeutic graft that again has a higher chance of recurrence and poorer prognosis. Finally let us wrap it off with HSV epithelial keratitis. HSV epithelial keratitis is the epithelial lesion — it’s the active replicating virus, and it is the infectious phase. So when you see these lesions, slowly they coalesce to form a geographic ulcer. When this happens, you have to differentiate it with other forms of dendrites. One is the early fungal thing that we have discussed earlier. This is the HZV dendrite. Very rarely do you see this. It occurs in isolation with no skin involvement — that’s called a zoster sine herpete. It is more epithelial and will not have a central ulcer or terminal bulb. Here there are terminal bulbs and central ulceration. In HZV, there is none of that. This is just a stuck on appearance like you see in microsporidia. So here scraping and debridement will do. There is no role for antivirals. In HSV keratitis, the treatment is: If you leave it also, if it is a single dendrite, it will usually heal spontaneously. But whenever it is multiple, make sure that the patient is not immunocompromised or diabetic, and treat it aggressively. So the treatment of choice for this is ganciclovir eye ointment 5 times a day for two weeks, and after two weeks also, if it is not healing, then we have to make sure that we are not treating the wrong condition. It could be HZV or could be some other acanthamoeba or fungal keratitis that is mimicking it. So whenever you’re giving ganciclovir eye ointment five times a day for two weeks, and the dendrite is not healing, 90% of the time, you’re not looking at HSV epithelial keratitis. Go back and look at the lesion again, and try to look for differential diagnosis. So more than two weeks, we don’t profess the use of ganciclovir eye ointment. However, you can give oral acyclovir, 400 milligram BID, or antivirals, topical antivirals, once in the night. Debridement also is a good thing. The most important thing is: Never use steroids in HSV epithelial keratitis. Next let us go to HSV stromal keratitis. It has two forms. Necrotizing and non-necrotizing. In necrotizing, there is an overlaying epithelial defect with associated stromal melting. The immune mediated destruction is there, so the antivirals have a role. Here it is primarily an immune disease and only steroids will help you. In the endothelial form, you have two forms. The disciform keratitis and the diffuse form. In both these things, topical steroids and antivirals have a role. Endotheliitis can be associated with folliculitis. So when you see dendritic keratitis and geographic ulcers, only antiviral or debridement. When you see stromal keratitis without ulceration, topical steroid and oral antiviral as prophylaxis. When you see stromal keratitis with ulceration, you give oral antiviral in therapeutic dose and topical steroid also. In endothelial keratitis, again, oral antiviral in therapeutic dose and topical steroids. So this is what therapeutic dose of acyclovir — 400 milligrams, three to four times a day. And in children, it becomes divided. And prophylactic dose is only twice a day. Therapeutic dose is 400 milligram, five times. Prophylaxis is 400 milligrams BID. Ganciclovir ointment is five times a day. We prefer to give, instead of prophylactic dose, nighttime application also. This can be used alternately. So when is HSV reactivated? This is an important thing. Whenever you see HSV reactivation, some of the features can be elicited with a good history. The patient might have undergone stress, or there is prolonged exposure to sun, there could be fever, trauma to body, such as injury or surgery, or during menstruation, or certain medications, and even crosslinking can cause reactivation of HSV keratitis. So HSV and HZV differentiation we have already seen. There will be obviously skin lesions that will be there in HZV, and the epithelial disease — it’s very easy to differentiate, as I have shown you in the previous pictures. And stromal and endothelial diseases are however difficult. But however — luckily, the treatment is the same. Whenever in doubt, you use the 800 milligrams acyclovir and give the treatment for HZV instead of HSV. The polymicrobial we rarely see. If you see the growth, this is the fungal growth and this is the bacterial growth seen on blood agar. This is truly polymicrobial. It’s not contamination. Usually it will be fungal first, followed by the superinfection from bacteria. It can be a combination of any organism, but we see polymicrobials in less than 5% of all of our cases. So just to sum it up: So if it is fungus, fusarium, feathery margins, the lesions are anterior stromal, branching at 90 degrees, and the treatment of choice is natamycin. If it is aspergillus, the lesions are deeper with endo exudates, and branching is dichotomous at 45 degrees, here you can add voriconazole, and also systemic antifungals. If it is dematiaceous fungus, it is superficial, pigmented, and carpet-like, the growth is also pigmented, and the treatment of choice is therapeutic debridement with antifungals. Next, coming to bacteria, Gram positive are usually well defined and superficial. They’re usually GPC, seen in pairs, chains, or groups. The treatment of choice is cefazolin, levofloxacin, moxifloxacin, or gatifloxacin of higher strength. Gram negative, there is rapid course and corneal melting. You have to identify carefully in the background. The treatment of choice is tobra and genta. Once it is confirmed, there will be a role of topical steroids. Atypical, the appearance is cracked windshield. There is negative staining, which is more important than microbiology, and the drug of choice is amikacin with oral azithromycin. Whereas acanthamoeba, it is ring infiltrate with perineuritis, and pain management is important. You can see it on KOH wet mount, and the treatment of choice is PHMB with chlorhexidine and proper pain management. Nocardia is a wreath shaped infiltrate, filamentous bacteria, treatment of choice is amikacin, microsporidial is stuck on appearance, SPKs, coarse, grain-like structures, treatment is debridement and fluconazole. Now let us go to the posttest and see how much knowledge you have gained through this course. The first question again. Over-the-counter steroids are the most common cause for… Bacterial keratitis, allergic conjunctivitis, fungal keratitis, both B and C. That’s excellent. Almost 75% of you have answered it right. So that’s a 15% improvement from your pretest. The second question. Which bacterial organism causes rapid progression and corneal melting? Staphylococcus. Pseudomonas. Streptococcus. Nocardia. Excellent. 91% of you have answered it right. Congratulations. Let’s go to the next question. When should we refer a case to our corneal colleague for referral, in case of microbial keratitis? When the ulcer size is more than 3, when the ulcers are central in the visual axis, one eyed patients and children, all of the above. Excellent. 92% of you have answered the question right. That’s good. Now let us go to the fourth question. What is the indication for therapeutic keratoplasty? Impending corneal perforation. Limbal involvement. Deep stromal ulcers. Not responding to maximal medical therapy. All of the above. Excellent. 88% of you have answered this correct. That’s a good improvement from the pretest. Let’s go to the final question. Steroids should be avoided in which form of viral keratitis? Non-necrotizing stromal. Disciform endotheliitis. Epithelial disease. A and B. Excellent. 82% of you have answered the question right. That’s a considerable improvement from the pretest. Thank you for your attention. So the take-home message from my lecture today is: Microbial keratitis, if you examine carefully, 60% can be diagnosed by meticulous clinical examination. That is classical features and history. Try empirical therapy for not more than five days or one week. If it is not responding, try to go back and look at the ulcer or refer it to a center where they have microbiological backup. If there are no signs of resolution, as I have already told you, and the ulcer is central, more than 2 millimeter, or if the patient is a child or one eyed patient, never hesitate to refer them to a corneal surgeon. The most important thing is: All of you start these antibiotics and antifungals very promptly. The problem comes with dosing. You only give them four times or five times or six times. No. You have to give them half hourly or one hourly. If possible, a loading dose in your clinic. You always put the first drop of antibiotic or antifungal in the clinic itself, so that the drug will start acting. You can do a loading dose thing and then make it to half an hour, one hour, and continue it at one hour in the waking period, and nighttime, you can give a cover. Next is maximal medical therapy, when you do it for two to three weeks. Don’t delay it further. You go for the surgical intervention. If you delay and go into corneal perforation or limbal involvement, the outcomes of therapeutic graft in such scenarios will be worse, as I have told you with our colleague Dr. Krishna’s study. Next, invest in a good microscope. All of you are investing in slit lamps, microscopes. The clinical… (audio drop) Thank you so much for your time this evening. And I am greatly indebted to my teachers for helping me gain this knowledge with their experience. And I’m also grateful to my dad and my mentor, for making me what I am today. It is all because of the great platform he has given me in the Institute of Ophthalmology. I also thank my cornea team. If you have any interesting or difficult cases, please feel free to share them at [email protected] Our team would be happy to look at the clinical photos and look at the history and give our opinion with our collective experience that we are having in this area. Thank you once again for your kind attention. Last but not least, thank you, Lawrence, for taking care of the wonderful coordination, and making this webinar a beautiful thing. So before we go into the questions by panelists, these are some of the questions asked by preregistered delegates. Let us finish them off before we go to the questions. The common questions they were asking were: When do you use steroids in infectious keratitis? So in bacterial keratitis, as I have told you, if you have a microbiological confirmation, in pseudomonas, it definitely has a role, but as a general ophthalmologist, I would not advise you to start steroids until and unless you are having a microbiological evidence of it. Next, in acanthamoeba, as I have told you, when there is vascularization, scleritis, pain, lid edema, congestion, there is definitely a role of topical steroids. Some people also tend to give systemic steroids in these cases. In viral cases, non-necrotizing stromal keratitis, nummular keratitis, and endotheliitis are the cases in which we can safely use steroids. Never, never use steroids in fungal, nocardial, viral epithelial, or in cases where you don’t have a microbiological evidence of what the organism is. And nowadays, we are having some alternative to steroids also. Like tacrolimus and cyclosporine. These can be used for its antiinflammatory properties in all the antimicrobial — along with all the antimicrobial agents in ulcers. Next, how do you differentiate between viral SPKs and microsporidial SPKs? So as I’ve told you, if you see the picture, above is microsporidial SPK, the picture below is viral SPK. Here the lesions are more pinpoint. And if you see closely there is some amount of underlying stromal haze. And they are also less in number when compared to this stuck on appearance, coarser SPKs, and when you put the high magnification slit lamp, these will be raised over the surface, microsporidial SPKs. Viral SPKs will almost be in the plane of the surface. So that is how you can differentiate with history, also, as I have told you. There will be history of water contamination in microsporidial, and conjunctivitis is more common in viral SPKs. Next they have asked me about contact lens induced keratitis. Contact lens induced keratitis is again commonly caused by pseudomonas and staphylococcus. Because in all the contact lens users, the innate defense mechanism of cornea is lost, and they are more prone to corneal infections than normal individuals. Rarely acanthamoeba and fungal can cause. Usually the source of infection is contamination of solution or the container or improper hygiene. So always along with the cultures, when you send for these organisms, send the contact lens and solution also for microbiological evaluation. And discontinue contact lens in cases where you have seen such kind of infection. So that you don’t want to put the patient into further risk. Finally, it is marginal keratitis, though it is not a form of infectious keratitis. Most of the attendees have asked me to explain about this. So this is — as I have told you, it is non-infectious. It is an inflammatory or immune response to staphylococcal antigen. This usually has an underlying cause in meibomitis and blepharitis. The treatment is steroids, mainstay of management, and unless you treat the underlying cause, this will not heal totally. The next is conjunctival hooding and Gundersen’s flap. This is again a great savior, especially in these COVID times. Lots of eyes were saved in this procedure. It’s purely a tectonic procedure. The problem with this procedure is — the future optical graft, if you really want to do, it will really have a high risk of rejection, because of the vascularization that is present. KPRO can be a viable option for visual restoration in these cases. However, all of us should be knowing this simple technique that saves eyes when the tissues are not available. I think now we’ll take questions from the attendees. So the first question is: Clinically suspect a fungal, load antibacterial first or load antifungal only in combination? If it’s looking like a fungal ulcer, it’s better to give antifungals and look for response within 24 hours. If it is responding to antifungals alone, go ahead. If it is not responding, add antibiotic. Look at the classical presentation. If it is well defined, give only antibiotic. If you cannot differentiate, then only give both. If you are able to clinically differentiate, give that specific therapy. Next question. How can we increase the Gram stain and culture when we take a sample? That’s a very relevant question. When we do the scrapings, most of us — especially fellows or postgraduate students, only scrape the surface. When you scrape the surface, you’ll only get the slough. Slough will only have pus cells, but you’ll not have any organisms. So what you have to do is you remove the slough. Then go to the ulcer proper. And when you do the ulcer proper scraping, the yield will be more. You take it both from the center, and the margins. So next question. Do you still give steroids to patient who underwent therapeutic corneal transplant for uncontrolled fungal keratitis? Yes, sir. Actually in fungal keratitis, if it is a regular therapeutic graft, we do not give steroids. But if you intervene in this case, as I have told you with our colleague Dr. Krishna’s study, when the ulcer is small and we do a 7.58 millimeter graft, and use a good quality tissue, under close observation, you can definitely start steroids or tacrolimus or cyclosporine, and retain this graft as an optical graft. Next is: Can I do debridement by cotton tip? Cotton tip will not be of much use. You should use a spatula or 15 number blade. How to manage resolved fungal keratitis with 4mm pterygium and central corneal scarring? Will pterygium excision be beneficial? Yes, you can always remove the pterygium. It doesn’t affect the fungal thing. Not a problem. Do you fortify antibiotics? Details, please. I’ll send you the details in the chat box. Important sign for atypical microbial bacteria? Atypical mycobacteria — the thing I have told you — 50% of the time, it’s associated with LASIK infections. Otherwise, any longstanding infection. You are treating that disease. For more than three weeks, four weeks, you are treating it. And the ulcer is not responding. Then you have to go back and look for atypical mycobacteria. Repeat the scraping and look for negative staining phenomena that I have told you. Then you can identify this organism. Can Betadine be used for debridement? Yes, Betadine can definitely be used, and it’s also very useful. What is the preferable choice in bacterial? Regular paracetamol works in bacterial keratitis. Only in cases of acanthamoeba we need to give higher analgesics, like amitriptyline that I have told you. How long prophylactic treatment in herpes? Herpes, we usually continue… There are two doses. One is the therapeutic dose and prophylactic dose. Prophylactic dose you can continue for almost three to six months. If it is going for a graft, you can continue therapeutic dosage lifelong. Especially if you’re going for a corneal graft. Gabapentin also you can use instead of amitriptyline, definitely it works well. Yeah. Limbal involvement, indication for graft? Yes, definitely when there is a limbal involvement, you have to do a patch kind of graft that I’ve shown you in the videos. Indications for topicals versus oral antivirals in HSV? So if it is a frank infection, it is always better to give epithelial disease. We prefer topical, but if it is a prophylactic dosage, you can go for two choices. One is either acyclovir, 400 milligram BID dosage, or topical ganciclovir, in the night. The choice is yours. You can use both. How to recognize SPK from microsporidial SPK? The microsporidial SPK will be more coarse, the stuck on appearance will be there, and no underlying stromal haze, whereas in viral SPK, it’s more pinpointed, some amount of underlying stromal haze and lesser in number when you compare to microsporidial SPKs. How do you do loading in the clinic? Any of the antimicrobials — give it for every five minutes, for half an hour or one hour. That is the loading time, when the drug will reach its MIC activity. From there, you can give it half an hourly or one hourly. Lid hygiene in corneal ulcers. Lid hygiene — it plays a role sometimes if the origin is because of that. Otherwise, as I have told you, the normal bacteria in the lid will act against fungus. It is going to heal, but you have to be careful in marginal keratitis, where the lid hygiene is more important. Where you see meibomitis and blepharitis. There the lid hygiene plays a role more. Antiglaucoma should be given in all the cases that I already told you. Povidone-iodine drops for resistant cases? We have used a few, but the results are not very gratifying. Antifungal in aspergillus? Sometimes we have to give as long as 6 or 8 weeks, sir. For diagnosis, do you depend on clinical examination? Yes, most of the time, clinical examination. VZV, you can use steroids if it is a stromal or endothelial disease. Despite natamycin and voriconazole… Probably you are looking at pythium. If you go back, sometimes the diagnosis may be wrong. But even with best medical therapy sometimes they can perforate. You cannot have a reason for it. Next time you can try adding doxycycline to prevent perforations, which works well in our experience. So my friend from Bangladesh has asked a question. If there’s a huge exudate, do you feel that you should remove this exudate? Sir, actually, it’s very tempting. When you see these large exudates and hypopyons, it is very tempting for us to go inside and evacuate it, but in our experience, what we have seen is: At least in 70% of the cases, it comes back with a bang. You’ll have more endoexudate, more reaction, so in these cases, I think especially when it is large endo exudates, you can better go in for therapeutic graft itself, sir. Fungal keratitis, causing fungal endophthalmitis is very rare. Usually if the cause is postendophthalmitis… Contaminating thing is fungal only. You get fungal endophthalmitis, and fungal endophthalmitis, the visual outcomes are very, very poor. Viral SPKs, can you use steroids? Usually they’re self-limited. If they transition into nummular keratitis, then you can start using steroids. My father asked me a question, whether it’s acyclovir or ganciclovir. I prefer ganciclovir, because it’s in gel form and less toxic, compared to acyclovir, topical form. Yeah. I think we have answered most of the questions. If I’ve left any of the questions, I’ll definitely answer in the box, and you can have a look at them. >> Thank you.

DR UDDARAJU: We overshot by ten minutes. Sorry for the overshoot in time. >> Thank you very much, doctor. I will send you the questions via email. Thank you for your time today.

DR UDDARAJU: Thank you so much. It was a pleasure.

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December 11, 2020


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