Residency · Residency · Ophthalmology

Infectious Keratitis: Bacterial, Fungal, and Acanthamoeba

Overview

Corneal infection is a sight-threatening emergency that demands prompt diagnosis and treatment. The leading risk factor in developed countries is contact lens wear, while in developing countries trauma predominates. Other important risk factors include ocular surface disease, immunosuppression, and topical corticosteroid use. The annual incidence in the general population ranges from approximately 2 to 11 per 100,000, but is substantially higher among contact lens wearers.

Bacterial Keratitis

Common Organisms

Among gram-positive bacteria, Staphylococcus aureus is the most common cause of bacterial keratitis overall, followed by Streptococcus pneumoniae and coagulase-negative Staphylococci. On the gram-negative side, Pseudomonas aeruginosa is the dominant pathogen in contact lens-related infections, with Serratia marcescens and Moraxella also playing important roles. Polymicrobial infections are not uncommon, particularly in cases related to trauma.

Clinical Features

Patients typically present with acute onset pain, redness, photophobia, decreased vision, and mucopurulent discharge. On slit lamp examination, the hallmark finding is an epithelial defect overlying a dense, white stromal infiltrate. The clinical appearance varies by organism: Pseudomonas produces a rapidly progressive, suppurative ulcer that may form a ring infiltrate, with adherent mucopurulent discharge and a significant risk of corneal thinning and perforation. Streptococcal ulcers tend to be dense and expanding with sharp, well-defined margins, often accompanied by a hypopyon. Staphylococcal keratitis typically presents as a round, well-defined infiltrate with a less aggressive clinical course. Moraxella infections are characteristically indolent, producing an oval, paracentral ulcer, and are classically seen in debilitated or alcoholic patients.

Diagnostic Workup

The gold standard for diagnosis is corneal scraping for smears and cultures. The ulcer should be scraped with a sterile blade (such as a Kimura spatula or #15 Bard-Parker blade) from both the base and the leading edge of the infiltrate. Material is plated directly onto multiple culture media: blood agar for most bacteria, chocolate agar for fastidious organisms like Haemophilus and Neisseria, Sabouraud dextrose agar for fungi, non-nutrient agar with an E. coli overlay for Acanthamoeba, and thioglycolate broth for anaerobes and low-count organisms. Staining with Gram stain and Giemsa provides rapid preliminary identification, while KOH preparation and calcofluor white staining help detect fungal elements. In vivo confocal microscopy is an increasingly valuable adjunct that can identify Acanthamoeba cysts and fungal hyphae without the need for scraping.

When to Culture

Cultures should be obtained when the infiltrate is large (greater than 2 mm) or centrally located within the visual axis, when there is deep stromal involvement, when the infection is chronic or unresponsive to empiric therapy, when an atypical organism such as fungus or Acanthamoeba is suspected, when infiltrates are bilateral or multifocal, or when there is a history of trauma with organic matter. There remains some controversy regarding the necessity of culturing small peripheral infiltrates that are already responding to empiric fluoroquinolone therapy.

Organism Clinical Features Summary

Empiric Treatment

For small to moderate ulcers, fluoroquinolone monotherapy with moxifloxacin 0.5% or gatifloxacin 0.3% is appropriate. Severe ulcers require fortified antibiotics: a combination of fortified tobramycin (14 mg/mL) with either fortified cefazolin (50 mg/mL) or fortified vancomycin (25 mg/mL). In severe cases, drops should be instilled every 30-60 minutes around the clock initially, then tapered based on clinical response. The SCUT trial (Steroids for Corneal Ulcers Trial) found that adjunctive topical corticosteroids did not improve overall outcomes, though subgroup analysis suggested potential benefit for central ulcers and non-Nocardia bacterial infections. When corticosteroids are considered, they should not be initiated until at least 48 hours of effective antibiotic therapy have been administered.

Fungal Keratitis

Epidemiology

Fungal keratitis is more prevalent in tropical and agricultural settings, and the classic risk factor is trauma with vegetable or other organic matter. Filamentous fungi such as Fusarium and Aspergillus predominate in tropical climates, while yeast forms -- particularly Candida -- are more common in immunocompromised patients, those with chronic ocular surface disease, or in temperate climates.

Clinical Features

Compared with bacterial keratitis, fungal infections typically follow a more indolent course. Filamentous fungal keratitis characteristically produces feathery, irregular borders with satellite lesions surrounding the main infiltrate. Candida keratitis presents differently, with a well-defined, white-yellow, collar-button-shaped infiltrate deep in the stroma. Additional findings may include an endothelial plaque and a hypopyon that can be thick and immobile. A ring infiltrate is sometimes present, and notably, the overlying epithelium may remain intact in the early stages of the infection.

Diagnosis

Corneal scraping with a KOH wet mount dissolves surrounding tissue and reveals fungal hyphae under light microscopy. Calcofluor white staining examined under fluorescence microscopy provides another sensitive method of detection. Cultures should be plated on Sabouraud dextrose agar and blood agar, incubated at 25-30 degrees Celsius; growth may take one to three weeks, so patience is required. In vivo confocal microscopy can identify hyphae in real time without the need for invasive sampling, and PCR-based methods are increasingly available for rapid organism identification.

Treatment

Natamycin 5% suspension is the first-line treatment for filamentary fungal keratitis, supported by the MUTT I trial which demonstrated its superiority over voriconazole for Fusarium infections. Topical voriconazole 1% is useful for Aspergillus and Candida and may serve as an adjunct or primary therapy for deep stromal infections. Topical amphotericin B (0.15-0.25%) is primarily reserved for yeast infections, particularly Candida. Systemic antifungals such as oral voriconazole are indicated when there is deep corneal or scleral involvement, and intrastromal voriconazole injection may be attempted in refractory cases. Treatment is necessarily prolonged, typically requiring a minimum of six to eight weeks, and clinical response is slow. Corticosteroids must not be used until the infection is clearly controlled and there is microbiologic confirmation that antifungal therapy is effective.

Acanthamoeba Keratitis

Epidemiology

Acanthamoeba keratitis is strongly associated with contact lens wear, particularly in the setting of poor lens hygiene, use of tap water for lens care, and exposure to swimming pools or hot tubs. Acanthamoeba is a free-living amoeba found ubiquitously in water and soil, existing in two forms: an active, motile trophozoite and a dormant cyst that is highly resistant to treatment.

Clinical Features

In the early stages, Acanthamoeba keratitis may present with a pseudodendrite that can easily be misdiagnosed as herpes simplex keratitis, along with punctate epitheliopathy and limbitis. The classic and nearly pathognomonic finding is radial perineuritis -- perineural infiltrates tracking along corneal nerves. As the disease progresses, a dense stromal ring infiltrate develops, accompanied by severe pain that is characteristically disproportionate to the clinical findings. Advanced disease may produce a non-healing ulcer with corneal thinning and secondary microbial superinfection.

Diagnosis

The organism is cultured from corneal scrapings plated onto non-nutrient agar with an E. coli overlay, exploiting the fact that the amoebae feed on bacteria. Calcofluor white staining reveals the characteristic double-walled cysts. In vivo confocal microscopy is highly sensitive for detecting cysts, which appear as bright, round, double-walled structures approximately 15-25 microns in diameter. PCR for Acanthamoeba DNA provides another diagnostic option.

Treatment

The mainstay of treatment is dual biguanide therapy with polyhexamethylene biguanide (PHMB) 0.02% combined with chlorhexidine 0.02%, supplemented by a diamidine agent such as propamidine isethionate 0.1% (Brolene) or hexamidine 0.1%. Treatment is initially administered hourly around the clock, including overnight, for the first 48-72 hours, then tapered very slowly over months. The total treatment duration is typically three to six months at minimum because the cyst form is extremely resistant to antimicrobial agents; the prolonged course is designed to eliminate cysts as they periodically convert to the more vulnerable trophozoite form. The role of corticosteroids is controversial: they may impair cyst elimination but can help control inflammation in the later stages of disease. Therapeutic keratoplasty is reserved for cases of corneal perforation or medically refractory infection.

Complications of Infectious Keratitis

Regardless of the causative organism, infectious keratitis can lead to several serious complications. Corneal scarring with irregular astigmatism is common and may permanently reduce visual acuity even after the infection resolves. Corneal perforation may require emergency intervention with cyanoacrylate glue, amniotic membrane grafting, or emergent keratoplasty. Descemetocele formation indicates severe stromal thinning with only Descemet membrane remaining. Secondary endophthalmitis is rare but devastating. Chronic non-healing epithelial defects may develop, particularly after severe infections that damage the corneal nerves and limbal stem cells.

<image>Composite slit lamp photograph illustration showing four types of infectious keratitis side by side. Panel A: Pseudomonas bacterial keratitis with a large central suppurative ulcer, mucopurulent discharge, and corneal thinning. Panel B: Fusarium fungal keratitis with a feathery-bordered infiltrate and satellite lesions. Panel C: Acanthamoeba keratitis showing a ring infiltrate with radial perineuritis (perineural infiltrates highlighted). Panel D: Staphylococcal keratitis with a well-defined round white infiltrate and mild hypopyon. Each panel labeled with the organism name and key distinguishing features.</image>

<image>Flowchart diagram for the diagnostic workup of suspected microbial keratitis. Starting point: clinical examination and risk factor assessment. Decision node: small peripheral infiltrate versus large/central/severe ulcer. Small peripheral: empiric fluoroquinolone monotherapy with close follow-up. Large/central/severe: corneal scraping (technique illustrated), plating onto multiple media (blood agar, chocolate agar, Sabouraud, non-nutrient agar, thioglycolate), staining (Gram, Giemsa, KOH/calcofluor white), and empiric fortified antibiotics. Additional branch for suspected fungal or Acanthamoeba with confocal microscopy and PCR.</image>

<image>Microscopy panel showing diagnostic findings. Top left: Gram stain with gram-positive cocci in clusters (Staphylococcus). Top right: KOH preparation showing branching septate hyphae (Fusarium). Bottom left: Calcofluor white stain under UV light showing bright double-walled Acanthamoeba cysts. Bottom right: In vivo confocal microscopy image of Acanthamoeba cysts appearing as bright, round bodies approximately 15-25 microns in diameter. Label all findings.</image>

Key Clinical Pearls

Pain out of proportion to clinical findings in a contact lens wearer should raise immediate suspicion for Acanthamoeba keratitis until proven otherwise. Corticosteroids must never be initiated in a suspected fungal or Acanthamoeba ulcer until the infection is definitively controlled. Natamycin remains the first-line treatment for filamentary fungal keratitis, as established by the MUTT trial. A ring infiltrate has a broad differential diagnosis that includes Acanthamoeba, fungal infection, Pseudomonas, and autoimmune causes such as a Wessely ring. The general rule is to culture before treating whenever the ulcer is central, large, deep, or failing to respond to empiric therapy. Satellite lesions surrounding an infiltrate are highly suggestive of fungal etiology. Pseudomonas keratitis can progress to corneal perforation within 24-48 hours and demands aggressive treatment from the outset. Radial perineuritis, when present, is nearly pathognomonic for Acanthamoeba keratitis.

References

• AAO BCSC Section 8: External Disease and Cornea. 2023-2024.
• Prajna NV, et al. The Mycotic Ulcer Treatment Trial (MUTT): a randomized trial comparing natamycin vs voriconazole. JAMA Ophthalmol. 2013;131(4):422-429.
• Srinivasan M, et al. Steroids for Corneal Ulcers Trial (SCUT). Arch Ophthalmol. 2012;130(2):143-150.
• Dart JK, et al. Acanthamoeba keratitis: diagnosis and treatment update. Am J Ophthalmol. 2009;148(4):487-499.
• Austin A, et al. Update on the management of infectious keratitis. Ophthalmology. 2017;124(11):1678-1689.

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