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
Transcript
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
Wonderful talk. Very helpful for low resource settings. Thank you sir.
Really a fruitful talk, a perfect lesson
Beautiful talk. THANK YOU SO MUCH.
High standard lecture I have enjoyed
Thank you Dr Swapan