Ray, Manotosh M.D., F.R.C.S.; Nigel, Lim Chen Siang; Tan, Anna Marie M.R.C.S., M.Med.
Department of Ophthalmology (M.R., A.M.T.), National University Health System, Singapore, Singapore; and Yong Loo Lin School of Medicine (M.R., L.C.S.N., A.M.T.), National University of Singapore, National University Health System, Singapore, Singapore.
Address correspondence to Manotosh Ray, M.D., F.R.C.S., Department of Ophthalmology, National University Hospital, 1E, Kent Ridge Road, NUHS Tower Block, Level 7, Singapore, Singapore 119228; e-mail: email@example.com
The authors have no funding or conflicts of interest to disclose.
Accepted January 16, 2014
To analyze the demographics, risk factors, and clinical and microbiological characteristics of triple infection keratitis.
Retrospective case series.
Five patients (five eyes) with triple infection keratitis were identified.
Eyes with polymicrobial keratitis were identified from January 2002 to December 2010. Only culture-positive cases and eyes infected by three different organisms were included. Demographics, risk factors, clinical and microbiological characteristics, and treatment outcomes were analyzed.
Main Outcome Measures:
The size of the corneal infiltrate, presence of hypopyon, pre- and post-treatment best-corrected visual acuity, antibiotic regimen and sensitivity, types of isolated pathogens, duration of infection, and treatment outcomes.
The mean age was 39 years (SD, ±23.4; range, 21–74). Use of topical steroids was the commonest risk factor (80%). Multiple risk factors were identified in four eyes. The average size of corneal infiltrate was 23.5 mm2 (SD, ±35.2; range, 2.08–85.5), and all eyes developed hypopyon. A total of 15 organisms belonging to 10 species (bacteria=7, fungi=3) were isolated. Pseudomonas aeruginosa and Candida albicans were the most frequently isolated bacteria (n=3) and fungi (n=3), respectively. All patients had at least one type of fungal isolate. Infection resolved with medical treatment in four eyes and one eye had to be eviscerated as the patient developed panophthalmitis. The average time taken for infection to resolve was 30 days (SD, ±19.3; range, 13–61).
A high index of suspicion of polymicrobial keratitis should be made in patients with multiple and systemic risk factors. Use of topical steroid was the most common risk factor. Prolonged course of disease, relatively large infiltrate, and presence of hypopyon and fungal isolates are typical features of triple infection keratitis.
Polymicrobial keratitis is a sight-threatening ocular condition that poses a major diagnostic and therapeutic challenge. The severity of infection is enhanced because of microbial synergism,1 therefore prompt diagnosis and treatment is imperative in preventing further visual dysfunction. Triple infection keratitis is a rare type of polymicrobial keratitis in which three different types of pathogens are involved simultaneously. Despite the existence of sporadic case reports of triple infection keratitis after corneal cross-linking2 and in a patient with severe ocular surface disease,3 the literature remains scarce. Therefore, the aims of our study were to identify the demographics, risk factors, and clinical and microbiological characteristics of triple infection keratitis.
MATERIALS AND METHODS
In this retrospective case series, we identified all patients treated for polymicrobial keratitis at the National University Hospital, Singapore, a tertiary referral center, between January 1, 2002 and December 31, 2010. Only culture-positive cases involving three different types of pathogens were included. The study was approved by the institution's ethics committee (Domain Specific Review Boards, National Healthcare Group, Singapore).
Demographics, predisposing factors, and clinical and microbiological characteristics were reviewed from medical records. Clinical characteristics reviewed included the size and location of corneal infiltrate, presence of hypopyon, pre- and post-treatment best-corrected visual acuity, antibiotic regimen, duration of infection, and treatment outcomes. The size of infiltrate was measured in square millimeters at presentation, and the location was classified as central or peripheral. The central zone was defined as the central 3 mm in diameter, whereas peripheral zone refers to corneal infiltrate lying outside the central zone. Visual acuity was recorded using Snellen's visual acuity chart and converted into logMAR (logarithm of the minimum angle of resolution) acuity. All patients were initially treated empirically with topical cefazolin (50 mg/mL) and gentamicin (14 mg/mL), which were subsequently changed according to culture and sensitivity results if required. Topical antifungals were administered if fungal keratitis was suspected clinically or on microbiological investigations. Clinical outcome was considered “successful” when the patient developed a corneal scar and did not require any further medical treatment, or “failure” if further surgical intervention such as therapeutic keratoplasty or evisceration was necessitated. Microbiological characteristics reviewed included the types of isolated pathogens and their sensitivity to common antibiotics such as cefazolin, gentamicin, ciprofloxacin, and piperacillin. For statistical analysis, SPSS version 16.0 for MS Windows (SPSS Inc, Chicago, IL) software was used.
From January 1, 2002 through December 31, 2010, a total of 430 cases of infective keratitis were seen. There were 21 patients (21 eyes) with culture-proven polymicrobial keratitis and 5 patients (5 eyes) with triple infection keratitis. The prevalence of polymicrobial and triple infection keratitis was therefore 4.88% and 1.16%, respectively.
Demographics and clinical and microbiological characteristics are summarized in Table 1. The mean age of triple infection keratitis patients was 39 years (SD, ±23.4; range, 21–74). There were 3 males (60%) and 2 females (40%). Most of the patients were Chinese (80%). The most common predisposing factor was the use of topical steroids (4 patients), followed by contact lens use, trauma, and diabetes mellitus (2 patients each). Multiple risk factors were identified in 4 patients (80%).
The mean size of corneal infiltrate was 23.5 mm2 (SD, ±35.2; range, 2.08–85.5). Infiltrates were located centrally in 3 eyes and peripherally in 2 eyes. Hypopyon was present in all eyes. Visual acuity at presentation ranged from 6/60 to positive perception of light, with the mean being 1.51 (SD, ±0.47). All patients were initially treated empirically with the standard protocol of topical cefazolin and gentamicin. Two patients were administered natamycin 5% simultaneously because of clinical suspicion of fungal keratitis. All patients eventually received antifungal eye drops (natamycin 5%) in addition after culture and sensitivity reports were reviewed. Two patients were given a second antifungal (amphotericin B 0.15%) because of poor treatment response. Resolvement of infection with corneal scarring was noted in 4 patients after medical treatment, all of whom experienced improvement in the visual acuity. The last patient developed panophthalmitis, and his affected eye had to be eviscerated. All patients were treated inpatient, and the average time taken for the infection to resolve was 30 days (SD, ±19.3; range, 13–61).
A total of 15 organisms belonging to 10 species (7 bacteria and 3 fungi) were isolated (Table 2). Pseudomonas aeruginosa (n=3) and Candida albicans (n=3) were the most frequently isolated bacteria and fungi, respectively. Most of the isolated bacteria were gram-negative bacilli (88.9%). All patients with triple infection keratitis were infected by at least one type of fungi. The most common pathogenic combination was one fungus and two gram-negative bacilli. Gram stain and potassium hydroxide (KOH) stain were positive in one and two patients, respectively.
All the isolated bacteria were tested against 4 antibiotics, and sensitivity results are shown in Table 3. P. aeruginosa was isolated in 3 eyes and was 100% sensitive to cefazolin, gentamicin, ciprofloxacin, and piperacillin, respectively. Gram-negative bacteria were isolated in 9 eyes and were most sensitive to cefazolin and ciprofloxacin (88.9%, respectively), followed by gentamicin (77.8%) and piperacillin (55.6%).
Triple infection keratitis is a rare type of polymicrobial keratitis, which accounts for 1.16% of all infective keratitis cases seen at our institution from 2002 to 2010. As it is relatively uncommon in clinical practice, only a few case reports on triple infection keratitis exist. To the best of our knowledge, our case series is the largest one reported in the literature to date.
In previous case reports, risk factors such as HIV infection4 and corneal cross-linking2 were noted in patients with polymicrobial keratitis. In developing countries, where agriculture is a main occupation, polymicrobial keratitis after vegetative matter injury is a common occurrence.5 In contrast, topical steroid usage was the commonest risk factor in our study. This is not surprising, because inappropriate administration of topical steroids by general practitioners (GPs) before presentation at the ophthalmology clinic has become a common phenomenon in Singapore.6 Topical steroids may cause ocular immunosuppression, thus predisposing to infection by multiple organisms simultaneously. It may also encourage stromal penetration, which results in larger ulcers.6 Close interaction between the GP and ophthalmologist is therefore essential in the treatment of infective keratitis, and GPs should refrain from prescribing steroids in contact lens users who present with a red eye.
Another common risk factor found was diabetes mellitus. Patients with diabetes may be predisposed to polymicrobial keratitis because of the following reasons: (1) neurotrophic keratopathy secondary to corneal hypoesthesia,7 (2) poor ocular surface secondary to decreased basal tear production,7 and (3) localized and systemic immunosuppression causing increased susceptibility to infections. Ophthalmologists should therefore have a high index of suspicion of polymicrobial keratitis in patients with multiple and systemic risk factors such as diabetes. Furthermore, one patient with diabetes in our study had to undergo evisceration as his eye developed panophthalmitis, and we believe that his poorly controlled diabetes may have been a contributing factor. Therefore, tight glycemic control is also important in preventing further ocular complications in triple infection keratitis.
Contact lens usage was another common predisposing factor. A high prevalence of myopia in Singapore8 has resulted in an increase in the number of contact lens wearers. The risk of keratitis is estimated to be 10 to 20 times higher9 because of induced hypoxia and hypercapnia of the cornea. Also, all contact lens users in our study were below the age of 30. This is in accordance with other studies, which have reported increasing contact lens usage in pediatric and adolescent populations,10 as well as younger age groups in contact lens–related keratitis patients.11 Therefore, more effort should be made in educating young contact lens users on contact lens hygiene, as well as recognizing the signs and symptoms of keratitis.
When compared with a previous local study on polymicrobial keratitis,12 our study on triple infection keratitis had a larger infiltrate size, longer duration of hospitalization, and greater incidence of hypopyon. The mean size of corneal infiltrate in our study was 23.5 mm2 (SD, ±35.2; range, 2.08–85.5), which was much larger than the reported sizes in previous studies on monomicrobial keratitis.11,13 This could be attributed to the synergistic effect of multiple organisms, coupled with ocular immunosuppression secondary to topical steroids or poorly controlled diabetes. Furthermore, all patients were infected by at least one type of fungi (Candida or Fusarium). These fungi may form a biofilm that prevents antibiotic penetration, thus allowing bacteria to adhere and survive.14
Prolonged course of disease (mean, 30 days; range, 13–61) was another feature of triple infection keratitis. This could be due to delayed diagnosis, poor response to initial antibiotic therapy and failure to isolate all causative pathogens. A longer duration of hospital stay may not only have financial implications on both the patient and Singapore's public health care sector but also predisposes the patient to hospital-acquired infections. Therefore, this emphasizes the importance of early diagnosis, accurate isolation of all causative pathogens, and prompt administration of medical therapy according to culture and sensitivity reports. Other notable features were the presence of hypopyon and poor visual acuity at presentation. All physicians should therefore adopt a high index of suspicion of polymicrobial keratitis in patients with the above clinical features.
P. aeruginosa was the most frequently isolated bacteria in triple infection keratitis. This is not surprising, because it is the most common organism worldwide in contact lens–related keratitis15 and is the most common bacteria found in corneal ulcers among Singaporean patients.16C. albicans was the most common fungal isolate (3 eyes), followed by Fusarium (2 eyes). The incidence of fungal keratitis is generally low, with only 29 cases reported in a 5-year period locally.17 Fungal infection among contact lens wearers is also rare.18 However, in our study, at least one type of fungus was isolated in each patient, including the two contact lens users. Polymicrobial keratitis with at least one fungal element should therefore be suspected in patients with multiple risk factors and poor response to initial antibiotic therapy. Prompt diagnosis and treatment is essential in preventing the need for penetrating keratoplasty, which has been reported to be approximately 5.86 times higher in fungal keratitis.19
Interestingly, Chryseobacterium meningosepticum was isolated in 1 patient, who was a 27-year-old woman with risk factors such as contact lens overwear and minor ocular trauma. Only a few cases of keratitis were previously reported in the literature with this rare opportunistic pathogen.20 It has been known to have a wide range of antibiotic resistance including aminoglycosides,20 but it is generally sensitive to quinolones as in this case.
The limitations of our study include its retrospective design and small sample size. Nevertheless, our study is the largest case series reported in the literature and highlights the demographics, risk factors, and clinical features of triple infection keratitis fairly well.
In conclusion, triple infection keratitis is a rare but clinically important disease with devastating visual complications if left untreated. A high index of suspicion should be made in patients with multiple and systemic risk factors that weaken the ocular immune system. Inappropriate use of topical steroids is the most common risk factor. Triple infection keratitis is frequently associated with the presence of fungal isolates, thus antifungal therapy should be administered promptly. Multiple risk factors, relatively large infiltrates, presence of hypopyon, and prolonged course of disease are typical features of triple infection keratitis.
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