• Cornea/External Disease

    In March, 2006, the Centers for Disease Control and Prevention (CDC) issued an alert warning of an increase in fungal keratitis eye infections nationwide that appeared to be linked to the use of Bausch & Lomb’s ReNu with MoistureLoc contact lens solution. As the CDC and other agencies continue the investigation, case studies from nationwide corneal disease centers may support the initial findings. To date, of the 130 cases of confirmed Fusarium keratitis, 125 have involved contact lens wearers. In addition, 75 of 118 individuals reported using only Bausch & Lomb's Renu with MoistureLoc, and 14 of 118 reported using MoistureLoc in combination with another product during the month before the onset of infection. The CDC has since disclosed that the use of Bausch & Lomb's ReNu with MoistureLoc during the month before the onset of keratitis was independently associated with corneal infection, and that this association was statistically significant (Morbidity and Mortality Weekly Report. May 19, 2006 / 55 (Dispatch);1-2). This article explores the experience of 1 laboratory center that managed a handful of suspicious keratitis cases during the outbreak and discusses the consequences of these findings.

    The Problematic Fusarium Fungus

    Fusarium sp. is an ubiquitous, filamentary fungus that gathers its nourishment from decaying organic matter, and in nature causes disease in plants. In the past decades there has been an emergence of infection by this microorganism in critically ill and immunocompromised individuals (J Med Microbiol. 2006;55(Pt 7):809-818). Fusarium sp has been an infrequent causative agent of keratitis, when compared with bacterial agents, because corneal infections with this microorganism have typically been associated with vegetable or organic matter that causes trauma to the eye. With the widespread use of contact lenses in the modern population, another mechanism of trauma to the corneal epithelium may have been inadvertently introduced. Even though fungal keratitis has historically been more prevalent in warm and tropical climates, in the past few years the southern states have seen an increase in its incidence (Am J Ophthalmol. 2006;142(1):154-155). Also, in temperate climates there has been an increase in filamentary fungal keratitis. In 2000 a report from Wills Eye Hospital revealed a series of 24 cases of fungal keratitis, in which 6 out of 24 isolates were Fusarium sp. This was second only to Candida sp. Of these 6 patients, 5 were identified as contact lens users (Cornea. 2000;19(3):307-312).

    Clinically, the ophthalmologist should be aware of the characteristic appearance of fungal keratitis. Typically, the edges of the corneal ulcer are diffuse and feathery, and there may be multiple ulcers and even a ring infiltrate. In patients who have been receiving topical steroids, the full clinical picture may be masked, possibly due to a decrease in the local inflammatory reaction. These patients need to be observed very closely once the steroids are stopped.

    Fusarium tends to infiltrate deep into the cornea early in the disease. There is some evidence that there is lack of a full inflammatory response in the cornea initially, which allows the fungus to penetrate deep into the tissue (Ophthalmology. 2002;109(8):1538-1546). One of the most feared complications of Fusarium keratitis is its penetration into the anterior chamber, where it can invade the lens and iris and form a “fungus ball” that mechanically occludes the pupillary area by creating a “keratomycotic malignant glaucoma” (Indian J Ophthalmol. 1991;39(3):118-121).

    The Pittsburgh Experience

    Between 1993 and August, 2005, a total of only 1 positive Fusarium culture had ever turned up on the contact lenses of patients at the University of Pittsburgh Medical Center (UPMC) Eye Center. Then between September 18, 2005, and April 19, 2006, 12 cultures that tested positive for Fusarium sp. were isolated from contact lens wearers who presented with clinically suspicious keratitis at this facility.

    The best way to establish a diagnosis of Fusarium infection is through bacterial culture. Fusarium is not a fastidious grower and will appear as fuzzy colonies from 1 to 7 days after media inoculation at 30 degrees centigrade (C) or 37 degrees C incubation. Fusarium will also isolate on commonly used media such as Sabouraud agar, sheep blood agar, and thioglycolate broth. Antibacterial antibiotics such as gentamicin, chloramphenicol, or a penicillin-streptomycin combination can be added to the Sabouraud medium to prevent bacterial growth. A culture from both the cornea and the contact lens should be taken in order to maximize the chances of isolating the fungus. Direct examination of corneal smears may also be advantageous, because the results of a culture may take several days.

    The data from the 12 aforementioned cases (Table 1) were reported to the CDC as part of an ongoing, multi-state investigation. Of the 12 total Fusarium isolates, 6 were found to be growing from patient corneas, and the lab returned negative cultures from the contact lenses of 2 of these patients. The remaining 6 patients were found to have Fusarium sp. growing in their contact lenses or lens cases. Four of these latter 6 patients tested negative for corneal fungi.  

    Courtesy University of Pittsburgh Medical Center (UPMC) Eye Center.
    Table 1. Clinical Data of Patients with Positive Cultures for Fusarium sp.

    Interestingly, 7 patients (Table 1 case #1, 4, 5, 7, 8, 10, and 12) who were started on a topical fourth generation fluoroquinolone before culture results were available (5 received Vigamox, 1 received Vigamox and fortified cefazolin (50mg/ml), and 1 received Zymar) improved remarkably and needed no other medication added to their regimen. By the time their culture results became available 2-3 days later, their Fusarium infections had completely resolved. Since fourth generation fluoroquinolones have been noted to have some antifungal activity (Invest Ophthalmol Vis Sci. 2005;46:e2766), this may have allowed the patients’ immune systems to overcome the infection before any further invasion into the cornea.

    An Intriguing Finding

    Of the 12 cases that tested positive for Fusarium sp., one was considered to be particularly relevant due to its clinical impact and ability to provide insight into the recent outbreak of fungal keratitis in users of ReNu MoistureLoc solution. A 25-year-old male, contact lens wearer presented toward the end of February, 2006, with a clinical picture of keratitis in the left eye. At the time, he was started on gatifloxacin ophthalmic solution (Zymar). On follow-up, the patient was found to have improved symptomatically, but he had developed an atypical pattern of corneal infiltrates (Figure 1).

     

    Courtesy University of Pittsburgh Medical Center (UPMC) Eye Center.
    Figure 1. Slitlamp photograph.

     

    Physicians decided to send this individual’s contact lenses and contact lens solution (ReNu MoistureLoc) to the ophthalmic microbiology lab for staining (Giemsa and Gram) and cultures (trypticase soy agar supplemented with 5% sheep blood, chocolate agar, and Sabouraud dextrose supplemented with gentamicin).

    In the laboratory setting Fusarium generally appears as branching, septated hyphae between epithelial and inflammatory cells. Gram stain has a sensitivity of 45% to 70%, and Giemsa has a sensitivity of 55% to 85%. More specific stains like KOH and calcoflour white have a higher sensitivity of 75% to 90%.7,8 The advantage of using a stain is that a presumptive pathogen can be identified in a matter of minutes, and treatment initiated immediately.

    For the patient mentioned above, microscopic examination of separate samples taken from his contact lenses and directly from his bottle of Renu contact lens solution displayed filamentary fungal elements when stained with Giemsa and Gram (Figure 2). Topical ophthalmic amphotericin B 0.15% and natamycin 5% applied every hour were started. Oral fluconazole was also started with a loading dose of 200mg twice the first day followed by 200mg daily. Cultures from this individual’s contact lenses and contact lens solution tested positive for Fusarium sp. in 2 days.

    Courtesy University of Pittsburgh Medical Center (UPMC) Eye Center.
    Figure 2. Fusarium sp. microphotograph.

     

    Treatment strategies for fungal keratitis include the combined use of 5% natamycin and 0.15% to 0.30% Amphotericin B. The first is commercially available, and the second can be obtained from compounding pharmacies. An oral agent like fluconazole or other azoles have good intraocular penetration, but they have been noted to have poor activity against filamentous fungal organisms (Eye. 2003;17(8):852-862). Recently, topical and systemic voriconazole has shown promising results in the treatment of Fusarium keratitis that do not respond to the usual drugs (Clin Infect Dis. 2005;40(12):e110-112). However, more research needs to be done with this medication.

    After 4 continuous weeks of antifungal therapy, the patient’s keratitis resolved, leaving small corneal opacities (scar tissue) that did not interfere with vision. The patient continues to be asymptomatic as of the date of the writing of this article.

    Fusarium and Renu MoistureLoc

    The preceding case appears to be the first instance of Fusarium sp. isolated directly from ReNu MoistureLoc solution. The correlation between Fusarium keratitis and ReNu MoistureLoc solution, however, remains a mystery. Alexidine, a preservative in this solution, may have played a role in the 130 cases of confirmed fungal infections that occurred recently, for this compound was never used in contact lens solution manufacturing before. While Bausch & Lomb has acknowledged that “ some aspect of the MoistureLoc formula may be increasing the relative risk of Fusarium infection in unusual circumstances,” the American Academy of Ophthalmology (AAO) believes that evaporation may have caused an increase in the concentration of polymers in the ReNu MoistureLoc formula, making the solution “more likely to be contaminated with Fusarium in the environment.”

    Meanwhile, federal investigators have found no evidence of product contamination at the facility in South Carolina where Bausch & Lomb manufactures the MoistureLoc solution. This finding increases the possibility that Fusarium contamination occurred after the bottles were opened by end users. It also means that contact lens wearers may be at a higher risk of developing fungal keratitis under regular contact lens wear.

    Recommendation and Summary

    Although Bausch and Lomb voluntarily recalled MoistureLoc worldwide, some contact lens wearers have continued to use the solution. Ophthalmologists should, therefore, advise their patients to stop using any residual ReNu MoistureLoc solution still in their possession and to discard any contact lenses or contact lens cases that have come into contact with the solution. Physicians and medical personnel should also continue to watch for patients who may be at risk of developing this condition. As the ophthalmic community continues to innovate and discover new ways to enhance patient vision with the use of contact lenses or by other means such as surgery, it must remember that each new technology may alter the fine interaction between ourselves and the microscopic organisms that surround us.

    References

    1.Centers for Disease Control and Prevention (CDC). Update Fusarium Keratitis --- United States, 2005-2006.Morb Mortal Wkly Rep (MMWR). 2006;55:563-564.
    2.Enoch DA, Ludlam HA, Brown NM. Invasive fungal infections: a review of epidemiology and management options.J Med Microbiol. 2006;55(Pt 7):809-818.
    3.Alfonso EC, Miller D, Cantu-Dibildox J, O'brien TP, Schein OD. Fungal keratitis associated with non-therapeutic soft contact lenses.Am J Ophthalmol. 2006;142(1):154-155.
    4.Tanure MA , Cohen EJ, Sudesh S, Rapuano CJ, Laibson PR. Spectrum of fungal keratitis at Wills Eye Hospital, Philadelphia, Pennsylvania.Cornea. 2000;19(3):307-312.
    5.Vemuganti GK, Garg P, Gopinathan U, et al. Evaluation of agent and host factors in progression of mycotic keratitis: A histologic and microbiologic study of 167 corneal buttons.Ophthalmology. 2002;109(8):1538-1546.
    6.Kuriakose T, Thomas PA. Keratomycotic malignant glaucoma.Indian J Ophthalmol. 1991;39(3):118-121.
    7.Thomas PA. Current perspectives on ophthalmic mycoses.Clin Microbiol Rev. 2003;16(4):730-797.
    8.Thomas PA. Fungal infections of the cornea.Eye. 2003;17(8):852-862.
    9.Klont RR, Eggink CA, Rijs AJ, Wesseling P, Verweij PE. Successful treatment of Fusarium keratitis with cornea transplantation and topical and systemic voriconazole.Clin Infect Dis. 2005;40(12):e110-112.
    10.Bausch & Lomb voluntarily recalls MoistureLoc ® worldwide; customer safety is our top priority, says CEO [press release]. Rochester, NY: Bausch & Lomb, Inc.; May 15, 2006.
    11.ReNu with MoistureLoc identified as likely cause of increased infection risk [press release]. San Francisco, CA: American Academy of Ophthalmology (AAO); May 22, 2006.
    12.Alfonso E, Miller D. Impact of 4th generation fluoroquinolones on growth rate and detection time of fungal pathogens.Inves t Ophthalmol Vis Sci. 2005;46:e2766. Poster presented at: ARVO; May 3, 2005; Fort Lauderdale, FL.

    Author Disclosure

    Mr. Kowalski states that he receives consulting fees from Alcon Labs, Inc. and Allergan, Inc. Dr. Mah is a consultant for and receives research support from Alcon Labs, Inc. and Allergan, Inc. None of the authors have any proprietary interest in any of the procedures or products discussed in this article.