CLINICAL UPDATE

New Gains With Fungal

ungal keratitis is notoriously 1 2 3 challenging to diagnose and Ftreat, and aggressive cases can perforate through the cornea and spread inside of the eye, making early diagnosis critical. “The keys to being able to successfully manage these cases are first having the suspicion of a fungal infection, then being able to confirm the diagnosis quickly,” said PROGRESSION. This patient’s ulcer was culture-positive for Fusarium. At enroll- Bennie H. Jeng, MD, at the University ment in MUTT I (Fig. 1), his VA was 20/25; after three weeks of topical voriconazole, of Maryland School of Medicine in his VA had declined to hand motions (Fig. 2). He experienced perforation and Baltimore. required a TPK, and at three months (Fig. 3), his VA was light perception. “Current management is still based on figuring out that it’s as diagnosis. And corneal cross-linking With a fungal infection of the cornea, quickly as possible and using tradition- (CXL) may improve treatment out- the corneal epithelium is often intact, al antifungal treatment, which includes comes. so the infection is harder to catch with topical ,” said Thomas M. traditional cultures. And, as fungus can Lietman, MD, at the University of Cali- Devastating Infections occur in a wound and penetrate deeper fornia, San Francisco (UCSF). But top- “These devastating fungal infections into the cornea, it’s less amenable to the ical natamycin penetrates poorly into are very difficult to treat,” said Jennifer scraping techniques used for bacteria. the corneal stroma, making deep ulcers Rose-Nussbaumer, MD, also at UCSF. Moreover, the rate of culture-positive hard to treat,1 and a new “wonder “In one of our studies, we gave patients scraping is low, even in academic settings. drug” for fungal keratitis remains elu- everything we had: eyedrops, oral med- “I am at a tertiary center, and we sive, Dr. Leitman said. In the Mycotic ications, and surgery—and about 50% sometimes only see the infection once Ulcer Treatment Trials (MUTT) I and still needed therapeutic penetrating it has resulted in a corneal melt,” said II, even the newest drug, voriconazole, keratoplasty [TPK].” Zaina N. Al-Mohtaseb, MD, at Baylor failed to show significant benefit, either Diagnostic challenge. A key issue College of Medicine in Houston. “Many in outperforming topical natamycin (in with fungal keratitis is the time lag to referral physicians don’t have the capa- MUTT I) or as an adjuvant oral thera- an accurate diagnosis. “We always jump bilities we have at academic institutions py to antifungal topicals (in MUTT II), to thinking about the best way to treat [e.g., a good microbiology lab and con- he said. fungal keratitis,” Dr. Lietman said, “but focal microscopy]. But even with these, Fortunately, there are some bright if patients are not coming in for two or the sensitivity and specificity of these lights on the horizon: Metagenomic three weeks and the damage is already tests for fungal keratitis is low.” . 2017;124(11):1678-1689. deep sequencing (MDS) and repeat done, then early diagnosis is where Treatment attempts. Furthermore, cultures raise the promise of an earlier we’re going to make a big leap forward.” attempted treatment can backfire. “Giv- en the difficulty with diagnosis, some

Ophthalmology of the patients sent to our practice are BY REBECCA TAYLOR, INTERVIEWING ZAINA N. AL-MOHTASEB, MD, on multiple therapies, such as antibac- BENNIE H. JENG, MD, THOMAS M. LIETMAN, MD, AND JENNIFER ROSE- terials, antivirals, and steroids,” said Dr.

Austin A. et al. Austin NUSSBAUMER, MD. Al-Mohtaseb. “Unfortunately, these can

EYENET MAGAZINE • 29 worsen the infection—especially the good for pathogen discovery.” ity to using repeat cultures in future topical steroids.” As a result, she said Not FDA approved. However, it clinical trials.” that she has had to re-culture some should be noted that MDS is neither patients. “Others have needed a corneal approved nor in mainstream use. Once New Use of CXL? biopsy for diagnosis, and, at times— it is, the hope is that any ophthalmolo- Although CXL has been well studied although this is rare—the diagnosis gist will be able to take a swab, preserve for ectasia, “it hasn’t been very well occurs after a TPK.” it in nucleic acid–stabilizing media, studied as a useful adjuvant for people Dr. Jeng also pointed out that “dif- and ship it off to a lab. The sample will with infections and corneal ulcers,” said ferent fungi may respond differently be sequenced, and the treating clini- Dr. Rose-Nussbaumer. to the various antifungal medications. cian will get the results faster than the After the MUTT II trial, Dr. Rose- Personally, my go-to antifungal for cultures could grow. Nussbaumer said, she went back to Candida is amphotericin B, which Repeat cultures. Another new diag­ look at patients’ charts, and many needs to be extemporaneously com- nostic—and prognostic—tool is the needed multiple surgeries. “The fungal pounded.” use of repeat cultures after initiating infection came back, or they had a ret- Dr. Mohtaseb added, “Cases that treatment. inal detachment; it looked like almost result in corneal perforation or fail to “A really interesting subfinding all those eyes were lost. That’s why we progress despite maximal appropriate of MUTT I and II came from repeat started looking at cross-linking as a antifungal therapy might require TPK cultures at six days,” said Dr. Rose- potential therapy for fungal keratitis: to prevent scleral involvement and Nussbaumer. “If patients were positive We’ve run out of medical therapies, and and to preserve the on that repeat culture, they had a much intrastromal injection of antifungals .” With regard to therapeutic higher risk of going on to need surgery, doesn’t really work.” grafts, she said, “the risk of recurrence having worse three-month visual acuity, CLAIR trial. Dr. Rose-Nussbaumer’s is as high as 50%2—so, again, early and having a larger scar size. It correlat- current trial, Cross-Linking–Assisted diagnosis and treatment is of utmost ed with every single negative outcome.” Infection Reduction (CLAIR), is now importance.” Identifying TPK need. Repeat cul- in its follow-up phase. “We randomized tures identified patients who would patients to medical therapy alone ver- Improving Diagnosis ultimately need TPK, said Dr. Rose- sus medical therapy and adjuvant CXL,” Metagenomic deep seqencing. MDS Nussbaumer. “In MUTT II, we found she said. “We enrolled 111 patients with is at the cutting edge of new diagnostic that the vast majority of patients who moderate fungal keratitis, and our pri- technology for fungal corneal ulcers. met certain criteria, such as large ulcers mary outcome measure will be culture With a targeted test like polymerase that were deep and culture positive, positivity after CXL.” The researchers chain reaction (PCR), clinicians must needed TPK. Repeat cultures are a very will also look at clinical measures such know what they’re looking for. In con­ useful tool for prognosis and helping as visual acuity, scar size, the need for trast, MDS is considered unbiased, identify patient populations, such as TPK, and other complications. as it will identify any organism in the those who might benefit from a TPK CXL caveats. There are still un- clinical sample. early on when the chances of eliminat- knowns in using CXL to treat corneal “With next-generation sequencing, ing the infection are higher.” infections. It’s possible, for instance, the gain is in quicker, more accurate Adapting treatment. When six-day that CXL “has an antiseptic quality diagnosis because we don’t have to wait repeat cultures are positive, clinicians that treats the infection but also causes for the fungus to grow,” said Dr. Liet- can increase the drug dosage, add a a lot of abnormalities in the shape of man. “MDS can tell us whether it’s a different topical antifungal, try an oral the cornea that could negatively affect bacteria, a fungus, a parasite like Acan- antifungal, and more closely monitor vision,” Dr. Rose-Nussbaumer hypoth- thamoeba, or another organism. This patients who are at higher risk of cor- esized. “For patients with , should allow for very rapid diagnosis.” neal perforation or may need TPK to for instance, we counsel that they may Clinical benefit. “Sequencing tech- excise the infection.3 lose a line of best-corrected vision after nology is being used more and more to Use of repeat cultures also helps CXL, because some opacity could form help clinicians make diagnoses, and determine which antimicrobials are in the cornea that might be a result of in the setting of fungal infections, this working.4 “If we only use healing time cross-linking.” technology has huge potential in mak- or vision as outcomes, we don’t have ing a positive clinical impact,” said Dr. much hope of distinguishing different Evolving Epidemiology Jeng. antimicrobial agents,” Dr. Lietman said. In the United States, fungal keratitis Scientific benefit. “The technol-­ In contrast, he said, “repeat cultures is most often seen in warm, humid ogy is also scientifically interesting are an excellent way to distinguish new regions. “Some of the most devastating for us because there are new organisms antimicrobials, because we’re directly infections that I saw in Miami and now we didn’t know that cause keratitis,” testing how well we killed the fungus. see in Texas are due to fungal keratitis,” Dr. Lietman said. As a result, he And the fact that six-day culture cor- Dr. Al-Mohtaseb said. said, “next-generation sequencing is relates with vision gives more credibil- There is some speculation that cli-

30 • JANUARY 2019 mate change may be driving an increase in fungal ulcers, as they tend to occur in patients who live in tropical areas. “In these areas, filamentous fungi such as Fusarium predominate,” said Dr. Jeng. However, he added, “Even in temperate areas of the world, fungal keratitis is still seen, and it needs to be suspected in certain cases.” In temper- ate climates, he noted, “yeasts such as Candida are most frequently seen. In either case, successful treatment of fungal keratitis still depends on accu- rate and timely diagnosis.” Find Training What about bacterial keratitis? “Bac- terial ulcers seem to be becoming less Opportunities common because people can quickly access antibiotic drops anywhere in the world,” Dr. Lietman said. Given the prevalence of antibiotics, by the time a patient comes to the doctor’s office, the bacteria may already be dead. “That may be why, from the ophthalmolo- gists’ perspective, the ulcers they see— particularly in tertiary settings—are often not bacterial; they’re now often The Academy’s Global Directory of fungal or Acanthamoeba infections.” Training Opportunities is the most comprehensive list of observership 1 Austin A et al. . 2017;124(11): and fellowship opportunities. It is 1678-1689. 2 Sharma N et al. Curr Opinion Ophthalmol. easy to find an opportunity for you: 2010;21(4):293-300. 3 Ray KJ et al, for the Mycotic Ulcer Treatment 1. Go to Trial Group. Am J Ophthalmol. 2017;178:157-162. aao.org/training-opportunities. 4 Ray KJ et al, for the Mycotic Ulcer Treatment 2. Narrow your results by Trial Group. Am J Ophthalmol. 2018;189:41-46. subspecialty and/or region. Dr. Al-Mohtaseb is assistant professor of ophthal- 3. Browse the listings. mology and associate director of the Residency 4. Contact the programs that Program at Baylor College of Medicine in Hous- interest you. ton. Relevant financial disclosures: None. Dr. Jeng is professor of ophthalmology and chair of the Department of Ophthalmology & Visual Questions? Email [email protected] Sciences at the University of Maryland School of Medicine in Baltimore. Relevant financial disclosures: None. Dr. Lietman is director of the Francis I. Proctor Foundation for Research in Ophthalmology and professor of ophthalmology, epidemiology, and biostatistics at UCSF. Relevant financial disclo- sures: None. Dr. Rose-Nussbaumer is a cornea and exter- nal disease specialist and assistant professor of ophthalmology at UCSF. Relevant financial disclosures: NEI: S. See the disclosure key, page 10. For full disclo- sures, find this article at aao.org/eyenet.

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