Commentary: Current concepts, recent updates, and future treatment options for Pythium insidiosum keratitis

Pythium insidiosum is an oomycete classified under phylum Straminipila, class Oomycetes, order Pythiales, and family Pythiaceae. Pythium closely mimics mycotic keratitis and results in rapidly progressive vision-threatening keratitis.[1] The past decade has seen a massive upsurge in Pythium insidiosum keratitis (PIK) cases. It recently gained importance because of its rare presentation, rapid progression, high virulence, difficulty in diagnosis by routine microbiological modalities, and poor response to conventional antifungal agents. However, with growing interest and continued research, clinical and microbiological diagnoses have improved, and treatment protocols have evolved.[2] Although there are no guidelines for the medical and surgical management of PIK, based on a detailed literature review, most clinicians favor antibacterials over antifungals. The current study by the authors is a comprehensive article where PIK has been treated on a similar protocol. Based on my experience managing PIK, we will enlist the medical and surgical management options and protocols in PIK.[3]

Role of antifungals

Approximately a decade ago, antifungals were considered the drug of choice for PIK as Pythium was grouped as a fungal species. Commonly used antifungals such as 5% natamycin, 1% voriconazole, 1% itraconazole, and 0.3% fluconazole were considered first-line drugs. Antifungals such as polyenes (amphotericin B), azoles (miconazole, ketoconazole, fluconazole, itraconazole, posaconazole, and voriconazole), allylamines (terbinafine), and echinocandins (caspofungin, anidulafungin, and micafungin) have been used for managing PIK.[4] As per the literature review, antibacterials have scored more over antifungals, and antifungals have shown limited success. Antifungals still play a crucial role in treatment in resource-limited laboratories and facilities where culture facilities are inaccessible. Since Pythium mimics fungus clinically, morphologically, and microbiologically, it is difficult to distinguish the two species based on smear characteristics alone. Before culture results are available, antifungals can be given in case of a diagnostic dilemma as fungal keratitis is far more common than PIK in India. Hence, we cannot completely eliminate them from the treatment armamentarium of a clinician. In large vision-threatening ulcers, combined therapy of antifungals and antipythium drugs can be initiated till a definitive diagnosis is available. Despite the evidence that antifungals have anti-Pythium activity, it has been challenging to achieve consistent results.[5]

Role of antibiotics

In vivo antimicrobial susceptibility testing by Bagga et al.[6] and in vivo rabbit models utilizing antibiotics have proven that antibiotics currently have better efficacy in microbiologically confirmed cases of PIK. The antibiotics of choice are topical 0.2% linezolid and 1% azithromycin. Linezolid is prepared from IV formulation, and azithromycin is used as topical drops and ointment formulation. Topical 0.2% linezolid and 1% azithromycin are started on an hourly regimen for at least 48 hours, and the further dose is modified based on the response. Azithromycin ointment is given twice a day. Oral Azithromycin 500 mg is given daily for 1–2 weeks. In cases with an ulcer size less than 4 × 4 mm and not involving visual axis, we preferred monotherapy of linezolid or azithromycin based on availability. We preferred combination therapy in vision-threatening ulcers greater than 4 × 4 mm affecting mid-stroma and beyond. Earlier reports from Thailand and China have documented surgical treatment (therapeutic keratoplasty, evisceration, and enucleation) as the only treatment option for PIK, but currently available antibiotics have revolutionized the management as nearly 50% of the cases can be managed conservatively now. Antibiotics have changed the management protocol in PIK.[7]

Concept of therapeutic keratoplasty

Rapidly progressive ulcers, ulcers infiltrating the limbus, non-resolving endoexudates, corneal melt, scleral abscess, descemetocele, and corneal perforation patients should be subjected to early and aggressive TPK. TPK should be planned along with medical treatment. The differences from a conventional TPK are host trephination with approximately 1–1.5 mm margin (conventional is 0.5 mm) and early keratoplasty within 10–14 days. Most large-scale studies previously reported recurrence as a concerning issue in PIK; hence, TPK remains the mainstay of treatment.[5]

Optical penetrating keratoplasty

Optical penetrating keratoplasty is recommended at least after 6 months of quiescence once the cornea has scarred or after a failed therapeutic keratoplasty.[8] In few cases after a failed optical penetrating keratoplasty, Descemet stripping endothelial keratoplasty (DSEK) has also been performed after an endothelial graft rejection.

Newer drugs and future treatment options

Many treatment options have shown efficacy in human Pythiosis and can become potential future treatment options for PIK. Varied drug combination, multi-drug therapy, natural plant extracts, natural compounds, bacterial isolates, biogenic silver particles, copper acetate, and miltefosine (a drug used for Leishmaniasis) have shown efficacy in PIK, but clinical trials are needed to prove their efficacy. The tried and tested antibacterial therapies in PIK are tetracyclines (tigecycline and minocycline), lincosamides (clindamycin), streptogramins (quinupristin-dalfopristin), phenicols (chloramphenicol), aminoglycosides (neomycin, streptomycin), macrolides (azithromycin, clarithromycin), and oxazolidinones (linezolid). The other class to which PIK is sensitive is glycylcyclines. Immunotherapy has also shown promising results where in vitro cultured PI antigens are injected into the patient. Nitrofurantoin, the drug of choice for urinary tract infection, was found to inhibit mycelial growth when in vitro susceptibility test was used. Mupirocin has also been shown to inhibit PI isolated at an MIC of lower than 4 ug/ml. Xanthyletin, a natural coumarin derivative from the green plant, has also been found to have an anti-Pythium effect by altering the protein composition of the cell wall. Streptomyces species have been used as a biocontrol agent against Pythium. Photodynamic therapy is also being explored as a future treatment option for PIK. Amorolfine hydrochloride (antifungal) inhibits ergosterol synthesis, alters membrane permeability, and has been shown to have in vitro inhibitory activity against PIK. Disulfiram, a drug used to treat alcohol dependence, was shown to have anti-Pythium activity in the MIC range of 8–32 mg/liters. Additionally, nitric oxide-containing antibiotics are being explored as a therapeutic option in human pythiosis. Pseudomonas stutzeri and Klebsiella pneumoniae metabolites have also been found to have anti-Pythium activity.[4]

The current study by the authors[9] is an evidence-based documentation of 50 Pythium keratitis subjects and adds value to the existing literature. The authors have followed the correct treatment protocol for PIK and have detailed the results holistically. The authors used antibiotic therapy for 2 weeks before taking up the patient for TPK, which sets this study distinct compared to others, and the globe salvage was nearly 100%. PIK still remains an active area of research as 70–80% of patients still need TPK despite the availability of a number of medical management options. Large-scale randomized clinical trials and meta-analysis will enlighten us more regarding this devastating vision-threatening keratitis.