Citrobacter sp. belongs to the family Enterobacteriaceae and consists of 13 currently recognized species. Citrobacter freundi and Citrobacter koseri are mostly associated with human infections 5. These organisms can be isolated from the intestinal tract of humans. Citrobacter sp is often considered an opportunistic pathogen and it causes a broad spectrum of infections related to the urinary tract, respiratory tract, and bloodstream 5. Citrobacter sp. are rare causes for ocular infections 3, 6, and is rarely isolated in patients with bacterial keratitis 2, 7, 8.
Contact lens wear is the most common risk factor for bacterial keratitis in developed countries 9–11, however, none of the patients in this series were contact lens wearers. A high proportion (44.4%) of patients diagnosed with Citrobacter keratitis suffered from the ocular surface disease. This is comparable to an epidemiologic study of bacterial keratitis from Vancouver, Canada 12, but is much higher compared to the reports of infectious keratitis from northern California (17.7%) 10, and southern Texas (17.6%) 11. The ocular surface disease impairs the defense mechanisms of the external eye and cornea, moreover, the decreased integrity of the corneal epithelium, persistent epithelial defects, and associated corneal inflammation can contribute to the increased risk of infectious keratitis in these patients13, 14.
Diabetes mellitus was the most common systemic risk factor in this series. The hyperglycemic state in the diabetic cornea impairs the immunologic defenses of the ocular surface. Moreover, delayed corneal re-epithelialization, and decreased corneal sensation that may progress to neurotrophic corneal ulcers further predisposes the eye to infectious keratitis 15.
It is noteworthy that 6 of 18 patients in our series had a history of corneal transplantation. Epithelial defects, compromised immunity of the ocular surface, suture related problems and graft failure can all contribute to increased risk of graft infection 16. The most common causative pathogens in infectious keratitis after PKP are gram-positive bacteria, with coagulase-negative staphylococci most commonly isolated. Pseudomonas aeruginosa is the most common inciting gram-negative bacterium in post-PKP infectious keratitis 17. There is no report of Citrobacter keratitis after PKP in the literature to the best of our knowledge.
None of the eyes in this series were enucleated, however, progression to endophthalmitis necessitated pars plana vitrectomy through a temporary keratoprosthesis in one eye. The incidence of infectious keratitis associated with endophthalmitis is reported to be 0.29% 18. Malihi et al. found that poor visual acuity, history of ocular surgeries, corneal perforation, topical corticosteroid use, and systemic immunocompromise increases the risk of endophthalmitis in a patient with infectious keratitis 19. As stated earlier many of these predisposing factors were present in the patient who progressed to endophthalmitis.
Antibiotic resistance is an emerging problem in Citrobacter sp., as in many other bacterial species, and limits the clinician's armamentarium. In vitro susceptibility testing shows that Citrobacter-caused keratitis may respond well to aminoglycosides. The rate of resistance to levofloxacin (14.7%) and ciprofloxacin (12.5%) was alarmingly higher compared to other reports about antibiotic sensitivity in gram-negative rods 7, 8, 20. Injudicious use of topical fluoroquinolones primarily for prophylaxis in cataract and refractive surgery might be responsible for this finding. Enhanced efflux of antibiotics and mutations in DNA gyrase subunit B is thought to be responsible for C.freundi resistance to fluoroquinolones 21.
The requirement for surgical procedures was 38.9% in this series, which is higher than reports about Haemophilus influenza 22 and Moraxella keratitis 23, 24. This implies the more severe presentation of infectious keratitis due to Citrobacter spp. and poorer visual outcomes.
As a tertiary eye care center, many of the patients seeking care in our unit are referred by clinicians who work in an outpatient setting. This may explain the high rate of patients with severe keratitis and who had a history of previous ocular surgeries. The clinicians may have a lower threshold for referral of patients who have undergone corneal surgeries.
The limitations of this study include its retrospective nature and small sample size. The absence of data about follow-up examinations further limits the results of this study. Nevertheless, to the best of our knowledge, this is the largest case series about infectious keratitis due to Citrobacter spp., elucidating the clinical features and risk factors for this devastating infection.
In summary, Citrobacter spp. is a rare cause of bacterial keratitis. It comprises 0.7% of all admitted keratitis cases. This study shows that ocular and systemic predisposing factors play an important role in the development of Citrobacter- caused keratitis. Previous keratoplasty and ocular surface problems are important risk factors. Surgical tectonic intervention is required in many cases to resolve the corneal infection.