The invasive Klebsiella pneumoniae syndrome: Case series.

This case-series aims to report three cases of endogenous endophthalmitis due to invasive Klebsiella pneumoniae syndrome. Case 1: A 34-year-old lady who was admitted for pneumonia developed painful blurring of vision and redness in the right eye (RE) for one week. An examination of the RE revealed visual acuity (VA) of light perception (PL) with positive relative afferent pupillary defect (RAPD), proptosis, and restriction of extraocular movement with hypopyon. The patient was treated for RE panophthalmitis with a lung abscess and was started on systemic and topical antibiotics. The vitreous tap culture grew Klebsiella pneumoniae. Despite treatment, the patient's condition deteriorated, and evisceration was undertaken. Case 2: A 38-year-old lady presented with a acute onset of RE pain associated with blurred vision and redness for two days, and fever for one week. RE VA was hand movement with a positive RAPD and anterior chamber cells of 2+. A B-scan revealed a dome-shaped subretinal mass with exudative retinal detachment. The patient was treated for RE panophthalmitis complicated by a basal ganglia abscess. The urine and vitreous tap cultures grew Klebsiella pneumoniae. She responded to high-dose intravenous and intravitreal antibiotics. Unfortunately, her RE became phthisical. Case 3: A 70-year-old lady presented with painless blurring of vision over the RE. The blood and urine cultures grew Klebsiella pneumoniae. RE VA was PL, and she was treated for endogenous endophthalmitis. The vitreous culture grew Klebsiella pneumoniae. Unfortunately, the RE became phthisical.

Introduction

Klebsiella pneumoniae is a gram-negative, nonencapsulated, anaerobic bacterium that forms part of the normal nasopharyngeal and gut flora. It is a bacterium with a high rate of antibiotic resistance. Notably, Klebsiella pneumoniae has dominated the microbiological spectrum of endogenous endophthalmitis in East Asia. Often, endogenous endophthalmitis caused by Klebsiella pneumoniae leads to devastating outcomes due to its increased affinity for crossing the blood ocular barrier. Despite its increasing incidence, infection is commonly misdiagnosed and undertreated with a common group of antibiotics. The hypervirulent strain of Klebsiella pneumoniae is often associated with rapid dissemination; hence, a more potent antibiotic, such as ceftriaxone, should be initiated early. Detailed investigations are not routinely performed in isolated cases of endophthalmitis because we perceive that endophthalmitis is confined to the intraocular region only. Here, we highlight Klebsiella endophthalmitis as a secondary nidus of hypervirulent Klebsiella pneumoniae metastatic spread. Conversely, patients who are diagnosed with Klebsiella septicaemia may harbour infection in multiple organs. We aim to demonstrate the importance of prompt diagnosis and early treatment of metastatic Klebsiella endophthalmitis in patients presenting with painful red eye associated with fever.

Materials and Methods

Three retrospective case series were collected from Hospital Raja Permaisuri Bainun, Ipoh, Malaysia. Ethical approval by Ministry of Health, Malaysia and patients consent were obtained prior. Ethical approval number NMRR-21-402-59110.

Results

Case 1

A 34-year-old woman with poorly controlled diabetes mellitus presented with painful blurring of vision and redness in the right eye (RE) for one week. She was treated for pneumonia after presenting with fever and lethargy a week prior to the ocular symptoms that warranted admission. However, the patient refused and was discharged with oral erythromycin 800 mg twice daily (BD). Upon presentation to the eye clinic, the visual acuity (VA) was light perception (PL) RE and 6/9 left eye (LE). Examination of the RE showed positive RAPD, proptosis, swollen eyelid, injected conjunctiva, and chemosis. The cornea was oedematous with dilated pupil. There was fibrin and a streak of hypopyon in the anterior chamber. The intraocular pressure (IOP) of both eyes was normal. Extraocular movement of the RE was restricted. The view of the fundus was hazy. A B-scan ultrasound revealed dense loculations with thickened sclera. The LE was unremarkable. A systemic examination revealed crepitations over the lower zone of the right lung, with temperature spikes (See Figure 1, Figure 2).

Figure 1

Presence purulent discharge, subtotal hypopyon (red arrow) with scleral abscess (blue arrow).

Figure 2

PA view CXR showed ill-defined opacity at right middle lobe (red arrow) with the presence of air-fluid level within the transverse fissure (blue arrow).

Blood investigations showed a raised white cell count (19.5 × 10⁹/L), predominantly neutrophil, with a high C-reactive protein level (104.5 mg/L) and erythrocyte sedimentation rate (94 mm/Hr). The patient's random blood sugar level was 14.6 mmol/L. Diabetic ketoacidosis was ruled out. Computed-tomography (CT) brain and orbit showed features of right pre-septal cellulitis, with no intra-orbital pathology. She was diagnosed with RE endogenous endophthalmitis and proceeded with right intravitreal tap and antibiotics injection. IV ceftazidime (1 g daily) and hourly topical antibiotic eye drops were commenced. The patient was co-managed with the medical team and was started on subcutaneous insulin for blood sugar optimisation.

Due to persistent dense loculations and vitreous abscess, she underwent right anterior chamber washout and vitrectomy. The vitreous sample grew Klebsiella pneumoniae, which was sensitive to amoxicillin/clavulanic acid, ceftazidime, cefuroxime, ciprofloxacin, trimethoprim/sulfamethoxazole, and gentamicin.

Repeated chest X-rays showed the development of a left lung abscess with consolidation seen over the right middle lobe. Other investigations, such as echocardiogram, ultrasound liver, urine, and blood cultures, were unremarkable. Subsequently, the patient developed RE panophthalmitis and eventually proceeded with evisceration. She completed IV ceftriaxone 2 g once daily (OD) for two weeks and continued with oral ampicillin/sulbactam 750 mg twice daily (BD). The eviscerated eye culture was sterile. Repeated chest X-rays showed improvement in lung opacity.

Case 2

A 38-year-old lady with no comorbidity presented with fever for one week and a sudden, painful RE associated with blurred vision and redness for two days. VA was hand movement (HM) RE and 6/9 LE with positive RAPD. An initial eye examination showed features of panuveitis, with the presence of cells 2+ in the anterior chamber, and vitritis. There was a raised lesion involving the entire posterior pole with optic disc swelling and numerous intraretinal haemorrhages, with Roth's spots at the periphery. The LE was unremarkable. The IOP of both eyes was normal. An initial B-scan of the RE revealed a subretinal mass involving the posterior pole with vitreous opacity. The patient was worked up for causes of panuveitis. Her condition deteriorated with RE proptosis, severe conjunctival chemosis, and hypopyon. There was formation of a fibrin membrane adhered on the anterior lens capsule with early seclusio pupillae. Extraocular movements were restricted, with elevated IOP over the RE. The fundus was no longer visible. Repeated B-scans revealed a worsening of the subretinal mass, vitreous opacity, and retinal detachment involving the superior and inferior quadrants with thickened sclera (See Figure 3, Figure 4, Figure 5, Figure 6, Figure 7, Figure 8, Figure 9, Figure 10).

Figure 3

Area of multiple Roth spots (red arrow) with vasculitis (blue arrow) seen on the right fundus.

Figure 4

Severe lower lid chemosis with injected conjunctiva over the right eye.

Figure 5

Presence of injected conjunctiva with fibrin plaque around the pupillary axis (red arrow) and a streak of hypopyon (blue arrow) over the right eye.

Figure 6

B-scan over the right eye (A) On day 1 showing subretinal dome-shaped mass involving the posterior pole. (B) On day 4 showing worsening of loculations with exudative retinal detachment.

Figure 7

Presence of scleral abscess at the intravitreal injection site over the right eye.

Figure 8

Anterior segment on week three of antibiotics showed improving inflammatory signs with peripheral synechiae 360O and tuft of iris vessels formation at the pupillary region on the right eye.

Figure 9

Pointed arrow area is hypoechoic lesion at the mid pole of left kidney measuring 2.2 × 2.2 cm.

Figure 10

Axial cut of CT brain showed early rim enhancing lesion at right external capsule suggestive of abscess.

Blood parameters showed an increasing white cell count from 12.3 × 10⁹/L to 18.2 × 10⁹/L and a raised C-reactive protein level of 178.1 mg/L. Urine full examination and microscopic examination (FEME) had leucocytes and pus cells >2250 cells/μl. Urine culture and sensitivity reported Klebsiella pneumoniae to be sensitive to cefuroxime, trimethoprim/sulfamethoxazole, amoxycillin/clavulanic acid, and ampicillin/sulbactam. CT brain and orbit showed features of pre-septal cellulitis and vitreous chamber hyper density. The abdominal ultrasound reported hypoechoic lesion at the mid pole of the left kidney measuring 2 × 2 cm. The patient was diagnosed with RE panophthalmitis secondary to a left renal abscess. She was co-managed with the infectious disease team and started on IV ceftriaxone 2 g daily for two weeks and topical moxifloxacin and ceftazidime hourly. Intravitreal injection was deferred in the initial phase due to the risk of retinal detachment.

Repeated CT brain and orbit revealed a small rim-enhancing lesion in the brain at the right lentiform nucleus, suggestive of early abscess and orbital cellulitis features. We proceeded with the first right intravitreal tap and antibiotic injection (vancomycin 2 mg/0.1 ml, ceftazidime 2 mg/0.1 ml) and repeated the second course after 48 hours. The patient refused a third intravitreal antibiotic injection. The first vitreous tap demonstrated pus aspirate that yielded Klebsiella pneumoniae sensitive to cefuroxime, trimethoprim/sulfamethoxazole, amoxycillin/clavulanic acid, and ampicillin/sulbactam, while the latter had no growth. At this point, with the development of a brain abscess due to Klebsiella pneumoniae, IV ceftriaxone was increased to 2 g thrice daily for six weeks. Repeated ultrasound of the kidney, ureter, and bladder reported no evidence of residual renal abscess. The repeated urine FEME and urine culture and sensitivity were also unremarkable.

The patient's condition improved with subsiding external signs of ocular inflammation and resolved scleral abscess, with improvement in blood parameters. Serial CT brain and orbit reported an improving RE condition with complete resolution of the brain abscess. She was discharged home with 625 mg oral amoxicillin/clavulanic acid twice daily for two weeks, after completing six weeks of IV antibiotics, with follow-up in two weeks. The RE eventually became phthisical.

Case 3

A 70-year-old lady with a history of adenocarcinoma of the colon presented with fever associated with vomiting and lethargy for two weeks. The patient was treated for community-acquired pneumonia. On Day two of admission, she had a sudden onset of painless blurring of vision with floaters on the RE. VA was PL (RE) and 6/18 (LE) with positive RAPD over the RE. The right conjunctiva was mildly injected with a clear cornea. Hypopyon was seen measuring 1.6 mm in height, with fibrin masking the pupil aperture. The left anterior segment was unremarkable. The IOP of both eyes was 18 mmHg. The RE fundus was not viewable, while the LE fundus was unremarkable (See Figure 11, Figure 12).

Figure 11

Anterior segment showed injected conjunctiva with the presence of fibrin plaque (red arrow) around the pupillary margin and hypopyon (yellow arrow).

Figure 12

B-Scan over the right eye (A) Initial B-scan upon presentation presence of loculations with vitreous opacity. (B) Finding after intravitreal antibiotic injection showed absence of loculations with thickened sclera.

An initial B-scan of the RE revealed dense loculations and vitritis. A systemic examination revealed coarse crepitations at the lower zones of the bilateral lungs and fever. She was diagnosed with RE endogenous endophthalmitis secondary to community-acquired pneumonia. An intravitreal tap for culture and sensitivity was done, and an antibiotic injection (vancomycin 2 mg/0.1 ml, ceftazidime 2 mg/0.1 ml) given and repeated after 48 hours.

The blood parameters showed a raised white cell count (21.1 × 10⁹/L), predominantly neutrophils. A urine FEME showed leucocytes 2+. All the cultures from the blood, urine, and intravitreal tap were positive for Klebsiella pneumoniae and were sensitive to cephalosporin (ceftazidime, cefuroxime, and ceftriaxone), ciprofloxacin, gentamicin, and amoxicillin/clavulanic acid. Radio imaging to rule out a possible nidus of infective metastasis of Klebsiella infection was unremarkable. The diagnosis was revised to RE endogenous endophthalmitis secondary to Klebsiella pneumoniae sepsis. The patient was managed with the medical team and was started on IV amoxicillin/clavulanic acid 1.2 g thrice daily for two weeks, with hourly topical moxifloxacin and dexamethasone.

Her condition improved following two intravitreal antibiotic injections; however, vision deteriorated to no PL on the RE. She completed two weeks of intravenous antibiotics and was discharged well, with follow-up at one month. Eventually, the patient's eye became phthisical.

Discussion

Endogenous endophthalmitis is part of the invasive Klebsiella syndrome characterised by multifocal metastatic infections. Klebsiella pneumoniae is the causative microbe for 90% of endogenous endophthalmitis in East Asia. Wong et al. reported that Klebsiella pneumoniae was the commonest pathogen isolated among endogenous endophthalmitis cases in Singapore. This is also evident in a few local studies.3, 4, 5

Clinical presentation

The Klebsiella pneumoniae strains gained increased notoriety due to their propensity to acquire antimicrobial resistance determinants. Commonly, Klebsiella pneumoniae causes liver abscess via its entry into the portal circulation. Other organs of metastasis are the lungs, brain, prostate, and kidney. Steven et al. reported that half of the patients who were treated for Klebsiella liver abscess developed endophthalmitis because of extrahepatic metastasis. Some studies have established the association of endogenous endophthalmitis concerning the hypervirulent Klebsiella pneumoniae strain with K1 and K2 serovars, which have exemplified a hypermucoviscous property.,, Wu et al. described that the hypervirulent Klebsiella pneumoniae strain produced more biofilm than the classic Klebsiella pneumoniae strain; thus, there was increased virulence in this strain. Hypervirulent Klebsiella pneumonia presents numerous capsule polysaccharides (CPS) on its surface to escape a host's immune system. They evade opsonisation and phagocytosis by macrophages, dendritic cells, epithelial cells, and neutrophils by preventing binding of the cells on its surface. CPS also prevent dendritic cell maturation, thus allowing the bacteria to avoid a host's defence and multiply effectively. In addition, hypervirulent Klebsiella pneumoniae secretes many siderophores for its survival, as it relies on iron uptake for bacterial growth. For instance, enterobactin is an example of siderophores that are produced by Klebsiella pneumoniae, and has the highest affinity to iron. Consequently, this works as an advantage to scavenge iron from a host. Endophthalmitis itself may be the presenting manifestation of hypervirulent Klebsiella pneumoniae infection.,

The initial presentation of Klebsiella endophthalmitis may be deceiving at times, as it may take up atypical features such as panuveitis, as seen in our second case. Greenwald et al. also acknowledged the difficulty in making a prompt diagnosis of metastatic endophthalmitis. Additionally, limited laboratory analytical instruments to detect Klebsiella hypervirulent capsular antigens, such as immunochromatographic strip assay and polymerase chain reaction, further complicate the management of Klebsiella endophthalmitis. In our study, all the patients were affected over the RE, owing to the proximity and direct arterial blood flow to the right carotid.,

Comorbidities

Chronic illness, such as diabetes mellitus, is a recognised risk factor for Klebsiella infection.,,,,, A similar finding was reported by Rosiah et al. and Kuo et al., who found that diabetes mellitus was the most common comorbidity associated with endogenous endophthalmitis, followed by renal failure and malignancy., Our patient in Case 1 is a diabetic patient, while the one in Case 3 is a colon cancer patient.

Outcome

Metastatic endophthalmitis, generally, can be classified into focal (anterior or posterior), anterior or posterior diffuse, and panophthalmitis. Focal endophthalmitis usually results in a better visual outcome, while panophthalmitis is often associated with a worse visual outcome. This has been shown in several studies, in which the visual outcome prognoses are based on the extent of the ocular infection. Chung et al. reported that the presence of hypopyon and diffuse posterior segment involvement were poor prognostic factors for Klebsiella endophthalmitis.

Treatment

Some studies have reported that gram-negative bacteremia results in elevated inflammatory markers such as C-reactive protein and interleukin-6 in the blood compared to gram-positive bacterial infection. This could be another diagnostic tool in deciding the appropriate antibiotics while waiting for the culture results. As there were no specific guidelines for Klebsiella endophthalmitis treatment, and the management of endophthalmitis in our centre was based on the Endophthalmitis Vitrectomy Study (EVS), all the patients in our study were given intravitreal vancomycin and ceftazidime empirically. Chung et al. stated that intravenous ceftriaxone was recommended in the treatment of Klebsiella endophthalmitis, as it had a good vitreous and cerebral spinal fluid penetration. A few studies concluded that early vitrectomy in endogenous endophthalmitis remained debatable., The rationale for early vitrectomy is to reduce the inflammatory mediators and bacterial load that cause tissue damage, and to facilitate the diffusion of antibiotics from the bloodstream to the vitreous cavity., To the best of our knowledge, there are no reviews on or meta-analyses of the specific treatment of Klebsiella endophthalmitis, hence more studies are required to establish effective antimicrobial and surgical treatments. Generally, Klebsiella endophthalmitis carries a grave prognosis as most of the cases either eviscerate due to complication, or become phthisical. As we saw, of the three patients, the Case 1 patient underwent evisceration, while those in Cases 2 and 3 became phthisical. All three patients are subject to regular follow-ups for assessment regarding complications of phthisical bulbi, such as ocular irritation and pain, or potential long-term complications, such as sympathetic ophthalmia, ulceration, and perforation.

Conclusion

We should be aware of the devastating complications of metastatic endophthalmitis due to Klebsiella pneumoniae as part of its invasive syndrome spectrum. A complete systemic and ocular examination should be advocated early in patients with focal endophthalmitis or Klebsiella septicaemia to avoid the sight-threatening complications of Klebsiella endophthalmitis.

Source of funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Conflict of interest

The authors have no conflict of interest to declare.

Ethical approval

By Ministry of Health, Malaysia, National Medical Register. Ethical Approval ID- NMRR-21-402-59110. Approval Date 26/03/21. Informed consent was obtained from all patients.

Authors contributions

All the authors contributed to the patient management, literature review, and preparation of the manuscript. All the authors read and approved the final manuscript.

RC was responsible for the conceptualisation of the study, methodology, software, investigation, data curation, and writing of the original draft. TT assisted with the writing of the original draft, methodology, and investigation. CMY reviewed the manuscript, clinical supervision, and editing of the manuscript. CMF was mainly involved in the clinical supervision and case management. NQZ contributed by reviewing the manuscript writing and editing. Last, AY contributed to the conceptualisation, review, and editing of the manuscript, and to the project administration. All authors have critically reviewed and approved the final draft and are responsible for the content and similarity index of the manuscript.