Hypervirulent Klebsiella pneumoniae Endogenous Endophthalmitis—A Global Emerging Disease

The review aims to document the new emerging hypervirulent Klebsiella pneumoniae (Kp) endogenous endophthalmitis (EKE) in terms of incidence, microbiological characterization of the pathogenic agent, associated risk factors, management, and outcomes. Hypervirulent (hv) strains of KP (hvKp) induce invasive liver abscesses (LA) with specific clinical features. Up to 80–90% of cases have hepatic liver abscess as a primary focus of infection, followed by renal or lung hvKp infections. However, the incidence of EKE in patients with KPLA varied between 3.4% (19) and 12.6% (13), with a total of 95 cases of endophthalmitis in 1455 cases of KPLA (6.5%). Severe visual loss was encountered in 75% of cases, with 25% bilateral involvement. Intravitreal antibiotics are the mainstay therapeutic approach. Pars plana vitrectomy is a subject of controversy. HvKp strains present mostly natural “wild-type” antibiotic resistance profile suggestive for community-acquired infections, being highly susceptive to the third and fourth generation of cephalosporins and carbapenems. Antimicrobial resistance in hypervirulent strains was recently documented via plasmid transfer and may result in extremely difficult to treat cases. Global dissemination of these strains is a major epidemiologic shift that should be considered in the diagnostic and therapeutic management of patients with endogenous endophthalmitis. Ophthalmologic screening in patients with KPLA and other hvKp infections and a multidisciplinary therapeutic approach is extremely important for early diagnosis and preservation of the visual function.


Introduction
Klebsiella pneumoniae (Kp) is a Gram-negative opportunistic bacterium, from the Enterobacteriaceae family, which classically produces lobar pneumonia, particularly in immunocompromised patients, and it is known to cause hospital-acquired pneumonia, meningitis, bloodstream, and urinary tract infections [1,2].
In recent decades, new challenges regarding Kp have emerged. One concerns the growing evidence of multidrug resistance strains [3]. Therapeutic management is threatened by the complex mechanisms of multidrug resistance, mainly due to extended-spectrum  53] This review aims to document the endogenous hvKp endophthalmitis (EKE) in terms of epidemiology, risk factors, clinical features, therapeutic management, and outcomes. We performed a comprehensive review of literature on PubMed and additional databases (Science direct-Elsevier, Springer Nature, Web of Science), by the terms "hypervirulent Klebsiella pneumoniae" and "endogenous endophthalmitis". Case reports and clinical studies in the English language, reporting clinical data, and therapeutic management were included. The elements taken into account for further analysis were: type of article (case report/ clinical study), length of the follow-up period (if existed), number of patients with EKE included; comorbidities; bilateral ocular involvement; associated septic disseminations; hvKp strain, if documented; ophthalmic findings; general and local treatment; outcomes in terms of preserved visual acuity.
The reports and clinical studies included in this review were comparable in terms of patient selection, methodology, and documentation of the results. However, due to the relatively new emergence of this Klebsiella pneumoniae pathologic association, we encountered significant differences regarding the documentation of cases, therapeutic approach-both general and local, ophthalmic treatment, according to the development of knowledge and therapeutic protocols.

Epidemiology of Endogenous hvKp Endophthalmitis (EKE)
Since the first case described in 1986, EKE has become currently the most frequent cause of endogenous endophthalmitis in Asian countries, with an incidence of up to 9%, and with an emergent trend in US, Australia, and European countries [22,54]. Epidemiological studies evidenced an incidence of 100 higher of metastatic spread in hvKp vs. other microorganisms. The incidence is higher in middle-aged adults, 50-60 years, with a slight male predominance and associated metabolic disorders, diabetes mellitus being a constant association.
Up to 80-90% of cases appear in the context of hepatic liver abscess. However, the incidence of EKE in patients with KPLA varied between 3.4% [17] and 12.6% [55], with a total of 95 cases of endophthalmitis in 1455 cases of KPLA (6.5%). One of the reasons for this wide variation may be the fact that the incidence was reported to all patients with a pyogenic liver abscess in some studies (19), while others analyzed only hypervirulent K1, K2 KPLA [56], as a different pathogenic entity. In a systematic review performed by  [30], and 84.2% of these patients developed irreversible catastrophic disabilities, including loss of vision, quadriplegia, paraparesis, and/or impairment of the higher cortical function [38,57]. This highlights the need for clinical awareness about the possibility of catastrophic septic ocular or CNS complications from KPLA in previously healthy individuals. Location in the right hepatic lobe, segment VII and VIII [27,[58][59][60][61][62], size larger than 5 cm and thrombosis of the suprahepatic vein are associated with a higher risk of metastatic spread.
Although hvKp commonly causes a hepatic abscess, and endophthalmitis may occur in this clinical setting, endophthalmitis can occur from hvKp in conjunction with non-hepatic sites of infection, such as the urinary tract (5.5-8%) or lung infections (4-11%) [63,64]. Only one study [30] found an equal incidence of 40% each for liver and lungs as the primary focus of EKE. Post-spider bite cellulitis [65,66], prostate abscess, endocarditis [30], and osteomyelitis were reported as unusual causes of hvKp endophthalmitis, The entry gate is considered to be the gastrointestinal tract [15], oropharyngeal [67], or recent urinary tract infections [62]. Oropharyngeal colonization could lead to infection with aspiration, but it is still unclear what the mechanism of entry is via the GI tract since many individuals subsequently infected have no apparent GI pathology. Entry through micro-breaks in the skin, similar to Staphylococcus aureus is also a theoretical possibility. However, the exact mechanism and necessary time lapsed between inoculation and the onset of the invasive systemic infection is not fully understood [41].
Chung et al. found a significant fecal carriage of K1 and K2 pathogenic stains in stools in a cohort of healthy South Korean residents [15]. Fujita et al. found a correlation with previous treatments with ampicillin or amoxicillin, leading to the hypothesis that these antibiotics may increase the risk for KPLA by selection pressure [67][68][69]. Diabetes, by impaired gastrointestinal permeability, may favor bacterial translocation into the portal bloodstream [68,69]. In a two-case report, Fujita et al. found KPLA and endophthalmitis appeared in patients previously incompletely treated with amoxicillin/clavulanic acid for sore throats and upper respiratory infections and postulated the possibility of systemic dissemination following incomplete eradication of the pathogen [67].

Risk Factors
This emerging epidemiological issue was initially attributed to the association with the Asian race and diabetes [10,27,36,59,60]. However, a significant number of published papers documented the presence of the infectious strain in young, previously healthy subjects, of all ethnic groups [18,19,22,25]. In recent years, cases from United States, Belgium, Spain, UK, Germany, Sweden, Romania, Saudi Arabia have been reported, indicating global dissemination of these strains causing invasive liver abscesses and endogenous endophthalmitis in both Asian and non-Asian patients, independent from their immunocompetent status or coexistence, or coexistence with diabetes [70].
Diabetes was frequent comorbidity [18,25,26,71] with an incidence between 35-92%, although it may appear in previously healthy adults (Tables 2 and 3). The role of poor glycemic control in the impaired phagocytosis of capsular serotypes K1 or K2 of Klebsiella pneumoniae was postulated for the pathogenesis of serious metastatic complications in diabetic patients [72], but the hypothesis was not supported by further experimental studies [73]. On the other hand, Coburn et al. demonstrate that a possible explanation of the frequent association of diabetes with EKE following KPLA may be the specific diabetic ocular environment, with increased retinal blood barrier permeability [74]. Another possible explanation may be the disturbing gastrointestinal defense mechanisms in diabetes, which may favor the bacterial translocation from the gastrointestinal lumen into the bloodstream [15].    Chung et al. found also an increased incidence of other metabolic disorders, such as hypertension and fatty liver [15], but it is not clear what specific mechanisms may favor the invasive infection in these cases.
Other associated pathologies were: thrombocytopenia [12], anti-interferon type 3 (anti-IFN3) autoantibodies [24], hypertension [26,55], and less frequent cirrhosis and Guillain Barre syndrome [17]. IFN-3 is considered to be involved in the neutrophil response, hepatic macrophage activity, and mucosal immunity. IFN-3 signifies type 3 interferon, which is considered to be involved in the neutrophil response, hepatic macrophage activity, and mucosal immunity. The identification of the anti-IFN3 in the case reported by Castle et al. may explain the poor outcome, with bilateral vision loss, in a previously healthy patient [24].

Diagnostic of Endogenous hvKp Endophthalmitis
The distinctive clinical course of irreversible ocular injury caused by hvKp strains is still not complete elucidated. However, experimental animal studies showed a significant decrease in electric activity of the infected retina within 18 h from the onset [34].
In 25.8% (5-50%) of cases, the septic involvement was bilateral, resulting in permanent vision loss. Bilaterality was encountered in 5-50% of cases in the reviewed studies, in association with multiple septic determinations, such as lungs [38], meninges and CNS, coagulopathy, thrombocytopenia, urinary sepsis (Tables 2 and 3). There were a total of 78 bilateral cases in a total of 302 patients with EKE and KPLA (25.8%). In all cases with ocular determination, the localization of liver abscess was in the right hepatic lobe (Figures 1 and 2) Life 2021, 11, x FOR PEER REVIEW 10 of 17 In 25.8% (5-50%) of cases, the septic involvement was bilateral, resulting in permanent vision loss. Bilaterality was encountered in 5-50% of cases in the reviewed studies, in association with multiple septic determinations, such as lungs [38], meninges and CNS, coagulopathy, thrombocytopenia, urinary sepsis (Tables 2,3). There were a total of 78 bilateral cases in a total of 302 patients with EKE and KPLA (25.8%). In all cases with ocular determination, the localization of liver abscess was in the right hepatic lobe (Figures 1 and  2) (a) (b)

Clinical Evaluation. Prognostic Factors
Various reports found that the ophthalmologic findings, with decreased vision and painful eye, may precede the signs related to the initial focus of infection [10,55,56,62,67]. The most common presentation was blurred vision and ocular pain. In the study of Park et al., ocular symptoms developed prior to the diagnosis of liver abscesses in 66.7% of cases [15]. These findings were confirmed by other case reports [26,67]. General signs are suggestive of an infectious syndrome, although the fever may not be present at admission.

Clinical Evaluation. Prognostic Factors
Various reports found that the ophthalmologic findings, with decreased vision and painful eye, may precede the signs related to the initial focus of infection [10,55,56,62,67]. The most common presentation was blurred vision and ocular pain. In the study of Park et al., ocular symptoms developed prior to the diagnosis of liver abscesses in 66.7% of Ocular findings included chemosis, red painful eye, haze cornea, and vitreous. Decreased visual acuity at presentation of hand movement or less and hypopyon were associated with poor prognosis [15,68,72,[75][76][77]. Patients with unilocular involvement were found to be a risk factor for evisceration, in comparison with bilateral infection, one possible explanation being the delay in presentation in cases in which only one eye was affected [16]. In a study by Ang et al [16], early onset of the ocular symptoms was also a factor of poor prognosis, in correlation with the virulence of the pathogen and bacterial load.
Hypopion may be present in 30-40% of cases and is considered a factor for adverse outcomes [15]. EKE is the result of the metastatic septic emboli in the choroid, with subsequent development of the infection through a blood-retina barrier, into the retina and vitreous body. Passage of the germs, leukocytes, and inflammatory products into the anterior segment of the eye may occur at the level of zonular fibers. The increased number of cellularity and fibrin at the level of the anterior chamber is an expression of intense inflammation in the posterior segment [15].
According to the focal or diffuse aspect, as well as the extension of the septic process, various clinical forms were described: subretinal abscess, posterior diffuse involvement, anophthalmia, scleral abscess with spontaneous perforation, orbital cellulitis.

Imagistic and Laboratory Tests
Ocular imagistic investigations (ultrasonography) CT and an IRM exam may indicate the increased density of vitreous body +/− subretinal abscess, as well as the extension of the septic process with eyeball disorganization and infiltration of the orbital soft tissue. Documenting the initial focus of infection and the possible septic associations requires hepatic, renal pulmonary, and CNS imaging, or other locations suggested by clinical findings.
Aqueous humor and vitreous taps may identify the pathogen at the eye level in 30-40% of cases. Additionally, K. pneumoniae was isolated from the blood culture in most cases. A string test is an inexpensive tool, which can strongly suggest the involvement of a hypervirulent strain of Klebsiella pneumoniae. However, physicians should be aware that a negative string test does not exclude the presence of hvKp in cases with the clinically documented invasive syndrome. Extensive documentation of the serotype and virulence gene by genomic sequences and PCR was performed in recent studies and reports, revealing a high incidence of K1 serotype and magA gene [5,21,29].

General Antibiotic Therapy and Assesment of the Primary Focus
The antibiotic regimen should be chosen considering the penetration of the available antibiotics in different tissues, like the eye and CNS, when the metastatic spread is encountered. In particular, third-generation cephalosporin is recommended due to its good penetration in the vitreous cavity and cerebral spinal fluid. Peak vitreous concentrations of at least 2 mg/l can be achieved [56]. The clinical management was based on 2-3 weeks intravenous antibiotic therapy with the 3rd or 4th generations of cephalosporins, which are considered to be superior to the first generation of cephalosporin in septic metastasis and recurrence prevention [15,16,18,19,37,68]. In some papers, metronidazole or piperacillin/tazobactam was added for anaerobic pathogens [20,23]. The use of aminoglycosides is debatable, due to the relatively low penetrance of the abscess capsule. However, they may be useful upon pathogens in the bloodstream, thus preventing septic dissemination [10,12,50,68]. After 2-3 weeks, if the criteria for favorable evolution are met, the patients were switched to oral fluoroquinolones, for 1-2 months, with periodic follow-up to identify possible recurrence early [10,23,26].
ESBL strains were identified in up to 10-13% of cases [40,57,58,61]. In a recent study on 110 patients with KPLA, with a mean follow-up period of 3.65 years, Wang et al. [76] found that ESBL was encountered significantly more frequently in the patients who experienced recurrence (30.0% vs. 8.89%). This finding supports the idea that ESBL should be considered an independent risk factor for the recurrence of KPLA [76]. and in these cases, cephalosporins should be replaced with imipenem or meropenem therapy [21]. In the absence of ESBL, such use of reserve antibiotics should be avoided, to preserve as long as possible the natural "wild-type" phenotype of hypervirulent KP strains.
In non-responding cases, percutaneous or surgical drainage of the primary infection focus should be performed to mitigate the hematogenous spread. Percutaneous drainage of the liver abscess, ultrasound or preferable CT guided, may be performed either needle assisted or by continuous catheter drainage with negative pressure. The indications for drainage include febrile patient after more than 48-72 h of adequate intravenous antibiotherapy, abscess of more than 6 cm in diameter, or impending perforation [50,78,79]. Multiple location and multiloculated abscesses are relative contraindications due to increased chances of failure. High locations may not be suited for guided drainage due to the increased risk of pneumoperitoneum. When a catheter is used, one must take into account the specific high viscosity of the KP strains, thus larger size and frequent flushing should be used to prevent blockage [68]. The catheter was usually maintained for 1-2 weeks and removed when drainage is sterile, less than 5 mL daily, and fever does not reappear when the tube is clamped [57].
Surgical drainage should be considered if a patient fails to improve at a satisfactory rate with percutaneous drainage and intravenous antibiotics, in cases of impossible percutaneous evacuation due to thick pus, multiloculated or multiple liver abscesses, located in the left hepatic lobe. Surgery is mandatory in cases of spontaneous rupture or if other biliary pathology should be addressed. Abscess spontaneous rupture is a serious complication, requiring immediate surgery. It is favored by: dimensions of more than 5 cm, thinned walls, intracavitary gas formation, and hyperglycemic dysregulation in diabetic patients [68].

Ocular Management and Visual Outcomes
Early case reports and clinical studies using topical antibiotics, corticoids, and mydriatics reported a poor outcome resulting in most cases in blindness and anophthalmia due to spontaneous eye perforation that required evisceration or enucleation [18,20,60,61].

Intravitreal Antibiotics
Today, the mainstay of ocular management is intravitreal antibiotics based on a combination of 3rd-generation cephalosporins +/− vancomycin +/− aminoglycoside. The role of intravitreal antibiotics is supported by evidence that vitreous samples are Intravitreal drugs used were: ceftazidime 2.25 mg/0.1 mL +/− vancomycin 1-2 mg/ 0.1 mL+/− amikacin 0.4 mg/0.1 mL [13,15,16,18,29,55]. There are no current guidelines regarding the number and frequency of intravitreal antibiotics administration, the therapeutical decision is based on the clinical response. The median number of administrations in the reviewed studies was 3-5 [12,58,67,77]. However, Martel successfully treated a Kp subretinal abscess with intensive intravitreal ceftazidime and vancomycin, daily for one week, then at 48 h, with a total of 13 administrations [80].

Intravitreal Steroids
There is no consensus regarding the utility of intravitreal triamcinolone in EKE. Intravitreal corticoids administration was found to be associated with vision gain of more than 6/60 [22,55] and may be performed after 2-3 intravitreal antibiotic injections. However, in the reviewed studies, corticoids were administrated in only 20-50% of cases.

Pars Plana Vitrectomy (PPV) and Subretinal Abscess Drainage
The benefits of early pars plana vitrectomy are still a subject of debate in the clinical management of EKE. The timing and indications for PPV are a challenging issue, with contradictory results. Some authors recommend early vitrectomy, considering as beneficial results the decrease of intraocular bacterial load and increased penetration of the antibiotics into the eye, preventing irremediable damage of the eye structures. Connel et al. reported a 0% evisceration and enucleation rate in eyes treated by PPV and intravitreal antibiotics when compared to 50% in eyes treated with intravitreal antibiotics only [79]. However, Ang et al. found that early vitrectomy is not associated with a better visual outcome [16]. Martel et al. raised concern about the efficacy and results of PPV on an inflamed necrotic retina [80]. A vitrectomy could result in supplementary damage of the retina, especially if the vitreous body is not detached due to vitreoretinal tractions. Another aspect to be taken into account is that removing the vitreous body will reduce the time of contact with the antibiotic with the infected retina. An absolute contraindication for PPV is the presence of life-threatening septic dissemination, such as meningitis or CNS abscess. Early removal of vitreous abscess can favor rapid evacuation of the pathogen load and mediators of inflammations. A more conservative approach would indicate PPV only in eyes with VA severely decreasing a worsening grade of relative afferent pupillary defect with no response to intravitreal antibiotics for 48 h [18,80]. Choosing the surgical timing should take into account the general status of the patient, hemodynamics, and coagulation parameters, which can be affected during Klebsiella infection.
In cases with abscesses larger than four disks areas, retinotomy and abscess drainage may be an option, but the risk for post-operative retinal detachment and vitreoretinal proliferation is higher due to active inflammation, laser photocoagulation is difficult on a fragile retina. Venkatesh used a conservative approach, by combining PPV with 41G needle abscess drainage, which has the advantage of an easily self-sealing retinal hole [81].
PPV alone may be also beneficial even in large-size retinal abscesses according to Xu et al. [29], by removal of the toxins and inflammatory products.

Lensectomy
Phacoemulsification of the lens was employed by some authors, but with limited results in vision improvement and the risk of corneal melting and spontaneous perforation [38].

Evisceration and Enucleation
Evisceration or enucleation was performed in cases non-responsive to other therapeutical options, with spontaneous perforation and total vision loss. Despite immediate management, the visual outcome in patients with EKE is poor [82,83]. It ranges from hand motion visual acuity to evisceration or enucleation of the eye in more than 75% of cases [74,82]. In a study of Ang et al., on 71 eyes of 61 patients with EKE, the severe visual loss was encountered in 76% of cases, despite adequate treatment. with a high likelihood of bilateral blindness [16]. However, early intervention in the first 48 h from the onset, with intravenous 3rd or 4th generations of cephalosporins, intravitreal antibiotics +/− corticosteroids and, in severe, non-responsive cases, pars plana vitrectomy, may preserve a vision of more than 6/60 in 13.6% of cases [13]. Several reports showed that early treatment before severely decreased vision appears, based on systemic and intravitreal antibiotics may preserve vision in variable degrees [13,16,45]. The introduction of an ophthalmological screening program for patients with KPLA was useful in early diagnosis and reducing the risk of progression to enucleation of eyes due to earlier diagnosis and more aggressive treatment [16,72,75,84].

Conclusions
Global dissemination of hvKp is a major epidemiologic shift that should be considered in the diagnostic and therapeutic management of patients with endogenous endophthalmitis. There is a concern regarding the possibility of abelon further combination of virulence and resistance, causing severe, untreatable infections in healthy individuals, which would be extremely difficult to manage [34,73]. Ophthalmologic screening in patients with KPLA or other suspected primary hvKp infections is extremely important for early diagnosis that could preserve visual function. Once vision is severely decreased, the outcome of hvKP endophthalmitis is extremely severe, despite aggressive ophthalmological treatment. The dramatic evolution of the ocular damage, with loss of vision in most cases and anophthalmia in 25-50% of cases, requires awareness of this new pathological association and the need to follow up these patients in multidisciplinary teams and to initiate aggressive ophthalmic treatment early concomitantly with antibiotic treatment as this is essential for saving vision.

Conflicts of Interest:
The authors declare no conflict of interest.