Hypervirulent, Multidrug Resistant Klebsiella pneumoniae – Emergence of a Superbug of Concern for Eye Care Providers

Classical Klebsiella pneumoniae (cKP) is a common Gram-negative nosocomial pathogen well-known to cause pneumonia, urinary tract infections, meningitis and sepsis in immunocompromised hosts.¹ Approximately 100 years after the identification of cKP by the German pathologist and microbiologist Carl Friedländer in 1882, Liu et al² described a series of seven patients from Taiwan with a particularly aggressive form of KP associated with hepatic abscesses, sepsis, and distant organ metastasis - including endophthalmitis. While five of the patients were 60 years of age or older and four had diabetes mellitus (DM), they were otherwise healthy and the infections appeared to be acquired in the community. Such community-acquired, hypervirulent forms of KP (hvKP) have since been associated with one or more hypervirulence mutations, and while hvKP infections remain most common in Asia, they are seen with increasing frequency worldwide.^3–7 Formal diagnosis of infection by a hvKP species requires genomic sequencing, but can be suggested by demonstration of phenotypic hypermucoviscosity – defined as a positive ‘string test,’ wherein a standard inoculation loop can lift or stretch a mucoviscous string of organisms ≥ 5 mm in length from a culture plate. In addition, recent reports have suggested an increasing rate of multidrug resistance (MDR) in hvKP species, previously identified predominantly in nosocomial cKP infections.^8,9 Together, these factors have led both the Centers for Disease Control and the World Health Organization to declare such emerging MDR and hvKP infections to be urgent public health threats.^10–12 Of note, KP appears to be a common bacterial co-infection in hospitalized patients with COVID-19.^13–15

Since the first report of metastatic KP endophthalmitis by Liu et al² in 1986, many case series of KP-associated endogenous endophthalmitis have been published.^16–51 The vast majority of such cases have occurred in the setting of KP liver abscesses, leading some to suggest the diagnosis of ‘KP invasive liver abscess syndrome (ILAS)’ in such settings. Less often, seeding abscesses may reside in the lung or kidney. Underlying DM and hepatobiliary disease are common. The reason for increased susceptibility in diabetics is unclear, but may reflect impaired neutrophilic killing of hvKP species.⁵² Systemic symptoms can include fever, chills, fatigue, nausea, vomiting and flank, back or abdominal pain. Eye involvement is typically hyperacute or fulminant, frequently with moderate to severe pain and profound loss of vision accompanied by evidence of eyelid swelling, ptosis, chemosis, proptosis, panophthalmitis, and limited extraocular motility. Irreversible and dramatic decrease in vision leading to evisceration or enucleation are common. Up to 25% of cases can be bilateral. Septic shock, multiorgan failure, and death can occur despite treatment. Prompt diagnosis followed by aggressive treatment are essential, therefore. Patients suspected of having ILAS should undergo blood cultures with sensitivities and contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI) of the brain, chest and abdomen to search for systemic sources. Patients should be treated with broad spectrum intravenous and intravitreal (IVT) antibiotics, typically Vancomycin and Ceftazidime, followed by culture and sensitivity-directed systemic and IVT anti-microbial therapy, and, when feasible, pars plana vitrectomy (PPV). Identified abscesses should be drained percutaneously.

In this issue of Ocular Immunology and Inflammation (OII), Zhu et al⁵³ retrospectively described four patients seen at a tertiary referral center in Jiangsu Province, China, who developed KP-associated endogenous endophthalmitis as the presenting, metastatic manifestation of asymptomatic liver abscesses. Two of the four patients were male and three had DM as an underlying immunosuppressive condition. Patient age ranged from 33 to 63 years with presenting vision in the affected eyes poor in each case and ranging from counting fingers to light perception. All patients received intravitreal Ceftazidime 2.25 mg/0.1 ml and Vancomycin 1 mg/0.1 ml, and two patients underwent PPV. Eventually, all affected eyes underwent evisceration and one patient died from septic shock. The presence of one or more hepatic abscess was confirmed with contrast enhanced CT or MRI, and cultures ultimately grew KP in all cases – confirming the diagnosis. The isolated organisms were neither tested for antibiotic sensitivities, nor sequenced for evidence of either hypervirulence or drug resistance mutations. The authors noted that while KP-associated endogenous endophthalmitis is most often metastatic from liver abscesses, such sites of infection may be asymptomatic, and that DM is an important risk factor for such infections. They added that in their limited experience enhanced CT and MRI appeared to be more sensitive hepatic imaging tools than ultrasonography. Although not achievable in each of their patients, the authors stressed the importance of early PPV to maximize chances of retaining vision and the eye.

Also in this issue of OII, Kohli et al⁵⁴ reported a series of 35 eyes from 35 patients from a referral center in Punjab, India, that developed inflammation suspicious for endophthalmitis following IVT Bevacizumab drawn from a single vial of Bevacizumab in a single day, including 27 after IVT injection alone and eight after IVT Bevacizumab in the setting of planned cataract extraction. Eyes that underwent combined IVT Bevacizumab with phacoemulsification received intracameral Moxifloxacin, 0.5 mg/0.1 ml, at the time of the procedure. Indications for IVT Bevacizumab injection included diabetic macular edema (n = 20), retinal vein occlusion with macular edema (n = 9), and choroidal neovascularization (n = 14). All subjects were seen six to eight hours after their injection and those suspected of having endophthalmitis based on the presence of anterior chamber and vitreous inflammation, with or without aqueous fibrin or hypopyon formation, received IVT Ceftaxidime, 2.25 mg/0.1 ml, and Vancomycin, 1 mg/0.1 ml. Twenty-two subjects (78.6%) showed worsening of their inflammation on the following day and underwent PPV and repeat IVT Ceftaxidime and Vancomycin injection. Of the 28 eyes suspected of having endophthalmitis, seven showed Gram-negative bacilli on vitreous tap Gram-stain. While vitreous cultures were negative for each subject, the source Bevacizumab vial was culture positive for KP, with antibiotic sensitivity to Moxifloxacin, Vancomycin, and Ceftazidime. Follow-up ranged from one to 36 months, with best-corrected vision improving in 32 of 35 eyes (91.4%), and remaining stable or improving in 20 of 22 eyes (90.9%) that underwent PPV. Seven of the eight eyes that underwent combined IVT Bevacizumab and cataract extraction, accompanied by intracameral Moxifloxicin injection at the end of the case developed inflammation limited to the anterior chamber that was controlled with topical and systemic corticosteroids alone. The authors suggested that their routine of same-day evaluation followed by prompt and aggressive intervention in those suspected of having endophthalmitis, including PPV as indicated, allowed for relatively good outcomes despite the often severe nature of KP endophthalmitis. Others have reported less encouraging outcomes for or post-procedural KP-associated endophthalmitis.^{54, 55}

Together, these studies highlight the often serious, sight and life-threatening nature of KP infections. Klebsiella-associated endogenous endophthalmitis should be suspected in all patients who present with hyperacute or fulminant panophthalmitis, particularly those with DM and/or known hepatobiliary disease, or in who septic abscesses are either documented or suspected. Patients found to be culture positive for KP should be tested for evidence of hypervirulence, using either genomic sequencing or the culture plate-based ‘string test.’ While initial treatment with intravenous and IVT Vancomycin and Ceftazidime is recommended, the final choice of antibiotic therapy should be based on culture and sensitivity analyses, as rates of MDR in hvKP species appear to be increasing. Pars plana vitrectomy is recommended for those able to undergo the procedure. Identified abscesses should be drained percutaneously. While ocular outcomes are typically poor despite prompt diagnosis and aggressive systemic and ocular treatment, such interventions can be lifesaving.

Disclosure statement

No potential conflict of interest was reported by the author(s).