Infectious keratitis caused by Klebsiella spp.: predisposing factors, presentation, and management

To study predisposing factors, clinical presentation and management strategies for Klebsiella keratitis. A retrospective case review was performed on clinical records of culture-proven Klebsiella keratitis cases in a tertiary referral center over an 8-year period (from 2012 to 2020). Thirty eight episodes of culture-proven Klebsiella keratitis were identified in 37 patients. The mean age of the patients was 62.9 years (range, 24–101). Multiple predisposing factors were identified in 33 eyes including history of previous keratoplasty (n = 11) history of ocular trauma (n = 7), preexisting ocular surface disease (n = 7) and diabetes (n = 6). Corrected distance visual acuity (CDVA) at presentation was light perception (LP) in 16 patients, hand motion (HM) in 12, counting fingers (CF) at 50 cm in 5, CF at 1 m in 1, CF at 2 m in 2. One patient had a CDVA of 3/10. On initial examination Hypopyon was detected in 21 eyes. Descemet's membrane folds were present in 1 eye. Corneal thinning was identified in 20 eyes and perforation occurred in 4 patients. Corneal ulcer progressed to endophthalmitis in one patient. Microbiologic sensitivity testing showed that 89.5% isolates were sensitive to amikacin (34/38),88.9%sensitive to ceftazidime (32/36),94.4% were sensitive to gentamicin (34/36),97.2% sensitive to ciprofloxacin (35/36), and 100% to levofloxacin (26/26).Ultimately, one or more surgical procedures was needed in 21 patients. Previous keratoplasty, history of ocular trauma, ocular surface disease and systemic disease such as diabetes are major risk factors for Klebsiella keratitis. In most of the patients, surgical and tectonic procedures were necessary to control the infection.


Introduction
Infectious keratitis is a sight-threatening ocular emergency that can lead to visual impairment and blindness if not treated appropriately [1,2]. Bacterial keratitis is the most common type of infectious keratitis [3]. Common clinical sign and symptoms of infectious keratitis include acute ocular pain, decreased vision, conjunctival injection, corneal ulceration, and/or stromal infiltration [4]. Contact lens wear, trauma, ocular surface diseases, and previous corneal surgery are major predisposing factors leading to infectious keratitis [5]. Klebsiella spp. are gram-negative rods of Enterobacteriaceae family. They can cause urinary tract, lower

Abstract
Purpose To study predisposing factors, clinical presentation and management strategies for Klebsiella keratitis. Methods A retrospective case review was performed on clinical records of culture-proven Klebsiella keratitis cases in a tertiary referral center over an 8-year period (from 2012 to 2020). Results Thirty eight episodes of culture-proven Klebsiella keratitis were identified in 37 patients. The mean age of the patients was 62.9 years (range, 24-101). Multiple predisposing factors were identified in 33 eyes including history of previous keratoplasty (n = 11) history of ocular trauma (n = 7), preexisting ocular surface disease (n = 7) and diabetes (n = 6). Corrected distance visual acuity (CDVA) at presentation was light perception (LP) in 16 patients, hand motion (HM) in 12, counting fingers (CF) at 50 cm in 5, CF at 1 m in 1, CF at 2 m in 2. One patient had a CDVA of 3/10. On initial examination Hypopyon was detected in 21 eyes. Descemet's membrane folds were present in 1 eye. Corneal thinning was identified in 20 eyes and perforation occurred in 4 patients. Corneal ulcer progressed to endophthalmitis in one patient. Microbiologic sensitivity testing respiratory tract, and wound infections, as well as bacteremia and meningitis [6]. In Asian countries, Klebsiella spp. are a major cause for endogenous endophthalmitis [7]. However, Klebsiella spp. keratitis is rare and most of the related studies are case reports. This retrospective study aims to review epidemiology, predisposing factors, antibiotic sensitivity pattern, clinical profile and management strategies of culture-proven Klebsiella keratitis over an 8 year period in a tertiary eye center in Iran.

Materials and methods
This is a retrospective observational case series. We reviewed clinical records and antibiotic sensitivity profile of all culture-proven cases of Klebsiella keratitis who presented to Farabi Eye Hospital from May 2012 to September 2020. This study was approved by the institutional review board of Tehran University of Medical Sciences and adhered to the tenets of the Declaration of Helsinki. After slit-lamp examination, all ulcers were scraped by a surgical blade for Gram staining smear and plating on blood agar, chocolate agar and Sabouraud's dextrose agar. Samples were incubated at 35 °C in carbon dioxide. Cultures were considered positive for Klebsiella spp. if there were discrete colonies of Klebsiella on two solid media or confluent growth of micro-organism was observed along with the site of inoculation. Antibiotic susceptibility was determined according to the disk diffusion method. Data collected from clinical records of identified cases were the following: age, sex, local and systemic predisposing factors, presenting signs and symptoms including the size of corneal infiltration, presence of corneal thinning and hypopyon, antibiotic sensitivity, and treatment method.
The patient was admitted based on the severity of infection including: infiltrates extending to the middle of cornea or across a large area (> 2 mm), presence of corneal thinning and perforation and inability to instill drops intensively. The initial antibiotic instillation protocol was 1 drop/hour for 48 h and then modified according to clinical response and bacterial susceptibility. An experienced cornea specialist determined indication of the adjunctive procedures (cyanoacrylate glue application or therapeutic penetrating keratoplasty (PKP)).

Results
In this study, 38 episodes of Klebsiella keratitis were reported in 37 patients.
The study included 25 males and 12 females. In 20 cases the right eye and in 17 cases the left eye was involved)both eyes were involved in one case). The age of patients ranged from 24 to 101 years with a mean age of 62.9 years.
At least one risk factor was identified in 33 patients. History of previous keratoplasty (n = 11) including PKP (n = 10) and descemet stripping automated endothelial keratoplasty (DSAEK) (n = 1) was the most common risk factor. Klebsiella keratitis occurred 15.3 ± 9.8 months (range: 6-34 months) after corneal transplantation. Seven patients had a history of ocular trauma including 2 cases of penetrating injury, 2 patients with corneal foreign body, one patient with a history of vegetative trauma, one case of chemical burn and one case of thermal burn. Preexisting ocular surface disease was found in 7 patients; five with a history of herpes simplex virus keratitis and neurotropic keratopathy was present in 2 patients. Six patients had diabetes mellitus. Four patients were under treatment with topical steroids, and 3 cases used systemic steroids or immunosuppressive drugs. History of contact lens use was present in 3 patients. Corrected distance visual acuity (CDVA) on presentation ranged from LP to 3/10.light perception (LP) in 16 patients, hand motion (HM) in 12 patients, 5 patients with counting fingers (CF) at 50 cm, 1 patient with counting fingers (CF) at 1 m, 2 patients with counting fingers (CF) at 2 m and one patient with vision of 3/10 infiltration size varied from 3 to 45 mm 2 with a mean size of 14.29 mm 2 . On initial slit-lamp examination hypopyon was detected in 21 eyes. Descemet's membrane folds were present in 1 eye. Corneal thinning in the area of infiltration was identified in 20 eyes and perforation occurred in 4 patients.
Corneal ulcer progressed to endophthalmitis in one patient who was a 59 year-old diabetic man with a history of previous keratoplasty and systemic immunosuppressive state.
Initial therapy with fortified antibiotic drops containing amikacin (20 mg/ml) combined with topical cefazoline (50 mg/ml) was started until antibiogram sensitivity testing was prepared. 68.4 and 47.4% of patients were treated with oral doxycycline and vitamin c, respectively.
Ultimately, one or more surgical procedures was needed in 21 patients (56.8%). Eight patients underwent therapeutic PK (TPK). Follow-up data were available in seven patients who underwent TPK. Three eyes developed pthisis bulbi (42.8%), 3 eyes demonstrated graft failure (42.8%), and only one graft (14.3%) remained clear in the last follow-up exam. Cyanoacrylate glue was applied in 7 patients due to corneal melt and thinning. Five patients underwent a patch graft. Amniotic membrane transplantation (AMT) was used to treat persistent epithelial defect in three patients.

Discussion
Klebsiella genus belongs to the family of Enterobacteriaceae. It consists of different species. K. pneumoniae and K. oxytoca are the main species causing human infections. Klebsiella spp. are found in nose, mouth, and intestines of humans and animals and are common microorganisms in the environment (soil and water) [6].
The most common predisposing risk factor for Klebsiella keratitis in this case series was previous keratoplasty (29%) (PKP in 10 patients and DSAEK in one patient). It was consistent with case reports of Klebsiella keratitis following previous keratoplasty [8,9]. Epithelial defects, compromised immunity of the ocular surface, suture related problems and graft failure are major predisposing factors that can contribute to graft infection [10]. Klebsiella keratitis developed 15.3 ± 9.8 months after corneal transplantation; therefore, donor contamination does not seem to play a role here. Further studies are warranted to determine if the prevalence of Klebsiella keratitis is higher in patients with a history of keratoplasty.
Previous ocular trauma serves as another predisposing factor in 7 of 37 patients (18%). Occupational exposure to foreign bodies and history of penetrating injury, which was frequently compounded by the lack of eye protection were the most common type (57%) of ocular trauma in this study. Based on reported studies about infectious keratitis in the literature, farmers (54-70%) and manual labour workers (11-17%) constituted the main occupations in Asia with occupational exposures to vegetative matter, organic and non-organic materials and animal products [2].
Ocular surface disorders encompassing history of herpes simplex keratitis and neurotrophic ulcer were found in 7 of 37 patients (18%). Ocular surface disease plays a major role as a predisposing factor for infectious keratitis in both the developing and developed countries [2,11].
Diabetes as a systemic risk factor was found in 6 of 37 (16%) patients. Diabetic keratopathy can predispose the cornea to keratitis with several mechanisms including persistent corneal epithelial erosion, superficial punctate keratopathy, delayed epithelial regeneration, and decreased corneal sensitivity [12].
Only 3 of 37(8.1%) patients had a history of contact lens wearing. However, contact lens wearing have been identified as the most common risk factor for developing infectious keratitis in developed countries [2,13,14].
Progression to endophthalmitis occurred in one eye (2%) and none of the eyes underwent enucleation. The incidence of progression from infectious keratitis to endophthalmitis is reported to be 0.29% [15]. In a study by Henry and colleagues topical corticosteroids, fungal keratitis, corneal perforation, and infectious keratitis developing adjacent to a previous surgical wound were identified as risk factors of progression to endophthalmitis [16]. This patient had several risk factors that predisposed him to develop endophthalmitis, including diabetes, previous keratoplasty and immunosuppressive state (Table 1).
In this series, 89.5% of isolates were sensitive to amikacin (34/38), 94.4% were sensitive to gentamicin(34/36), 88.9%to ceftazidime (32/36) 97.2% to ciprofloxacin (35/36), and 100% to levofloxacin (26/26) which is consistent with results of a metaanalysis conducted by Zhang and colleagues in which antibiotic susceptibility of Gram-negative bacilli has been reported to be 96% to cephalosporins, 96% to fluoroquinolones, followed by 92% to aminoglycosides [3]. Some of Klebsiella spp. that caused infectious keratitis are reported to be nosocomial, multi drug resistant and extended spectrum beta-lactamase producing [17][18][19]. In this series only one patient had klebsiella keratitis resistant to aminoglycosides, cephalosporins and fluoroquinolones. She was a 24 year old female with multiple risk factors including history of chemical burn, neurotrophic keratopathy and PKP.
The necessity for surgical procedures was 56% in this series which was higher than rates reported for other gram-negative bacilli keratitis such as Haemophilus and Moraxella keratitis [20][21][22]. This shows more severe presentation of Klebsiella keratitis and its poorer visual outcome. Moreover, our hospital is a tertiary eye care center and many of the patients are referred to our center by clinicians who work in outpatient settings. This explains the high rate of patients who presented with severe infectious keratitis and had multiple risk factors including history of corneal surgery.
The limitations of this study were the absence of data about follow-up examinations and its retrospective nature. However, to the best of our knowledge, this is the largest case series about Klebsiella spp. keratitis, its risk factors, clinical presentation and antibiotic sensitivity profile.
In conclusion, Klebsiella spp. is a rare cause of infectious keratitis. Ocular and systemic predisposing factors including previous keratoplasty, history of ocular trauma, ocular surface disease and systemic disease such as diabetes predispose the patients to this corneal infection. In most of the patients, surgical and tectonic procedures were necessary to control and resolve the infection.