Endogenous Endophthalmitis Caused by ST66-K2 Hypervirulent Klebsiella pneumoniae, United States

We describe a case of endogenous endophthalmitis caused by sequence type 66-K2 hypervirulent Klebsiella pneumoniae in a diabetic patient with no travel history outside the United States. Genomic analysis showed the pathogen has remained highly conserved, retaining >98% genetic similarity to the original strain described in Indonesia in 1935.

H ypervirulent Klebsiella pneumoniae (hvKp) strains are mostly community-acquired and can cause invasive infections such as liver abscess with metastatic spread (1,2). The genetic determinants of hypervirulence are found on chromosomal mobile genetic elements, large plasmids, or both. The most common virulence determinants of hvKp include siderophore systems for iron acquisition, increased capsule production, K1 and K2 serotypes, and the colibactin toxin (1). In addition, these hvKp strains demonstrate hypermucoviscosity, as indicated by a positive string test, and are usually susceptible to antimicrobial drugs (1). However, multidrug-resistant hypervirulent strains have emerged in Asia, a region to which hvKp is endemic (1,3). Kp52.145 (laboratory strain B5055), which belongs to sequence type (ST) 66, is one of the most virulent and widely studied K2 strains. The ST66-K2 sublineage contains virulence genes in its chromosome and 2 large plasmids (4,5). ST66-K2 was isolated in Indonesia in 1935; since then, cases have been reported in Australia in 2002 (caused by strain AJ210), Germany in 2017 (caused by strain 18-0005) and France in 2018 (caused by strain SB5881) (6)(7)(8).
The most common hvKp infection metastatic sites are the eyes, lungs, and central nervous system (1).
Endogenous endophthalmitis (EE) caused by hvKp is associated with risk factors such as diabetes mellitus, Asian ancestry, and infection with the K1 serotype (2). Although the prevalence of hvKp is increasing in the United States and Europe (1,2,9), where EE has been documented in patients of Asian and non-Asian descent (9,10), these infections are not well-recognized. Ocular prognoses and clinical outcomes for EE are usually poor and exacerbated by late or missed diagnosis (2). We describe a case of EE caused by a hvKp strain of the ST66-K2 sublineage in the United States.

The Study
A 30-year-old Caucasian man who had a history of poorly controlled type 1 diabetes mellitus and recreational use of methamphetamine and intravenous heroin sought treatment at the emergency department of a local hospital in California, USA, for progressive right eye and ear pain, which had lasted ≈1 week, and vision loss. Hospital staff noted substantial edema and tenderness of the right external auditory canal with otorrhea, along with suspected orbital cellulitis. Computed tomography scans revealed complete opacifi cation of the right middle ear cavity and mastoid air cells, prominent thickening and hyperenhancement of the right posterolateral sclera, and a cystic and necrotic lesion in the left parotid region. He was prescribed vancomycin and cefepime and then transferred to Ronald Reagan UCLA Medical Center ( drainage grew hypermucoviscous K. pneumoniae (Appendix Figure 1, https://wwwnc.cdc.gov/EID/ article/27/8/21-0234-App1.pdf) and methicillin-susceptible Staphylococcus aureus. The K. pnuemoniae isolate was susceptible to all drugs tested, including ampicillin (Appendix Table 1). We prescribed intravitreal injections of vancomycin, ceftazidime, and voriconazole every other day in addition to intravenous ceftriaxone (2 g 2×/d), intravenous voriconazole (4 mg/kg 2×/d), and oral metronidazole (500 mg 3×/d) for ≈2 weeks. We conducted a pars plana vitrectomy to drain the subretinal abscess in the patient's right eye. We sent the vitreous and aqueous samples for bacterial and fungal culturing, which returned negative results. After the surgery, the patient continued to take ceftriaxone, metronidazole, and voriconazole in addition to using eye drops containing prednisolone, ciloxan, and atropine. He was discharged 15 days after admission. Two weeks after discharge, he reported that his pain had resolved but his vision loss continued with minimal light perception.

Conclusions
Ocular prognoses and clinical outcomes for EE are usually poor, often entailing partial or complete vision loss, enucleation or evisceration, or death (2). Late or missed diagnosis delays the initiation of specialized ocular therapy (e.g., intravitreal or source control) and can worsen outcomes. Early treatment is crucial to preserving full or partial vision (1)(2)(3)10). A pooled analysis of clinical studies revealed that most (83.2%) EE infections caused by hvKp were detected >24 hours after admission (2). These data indicate that patients at high risk for EE, especially those with underlying conditions such as diabetes mellitus or K. pneumoniae-associated pyogenic liver abscess, should be monitored closely for EE even when it is not initially apparent. Detection of K1 or K2 capsular serotypes, hypermucoviscous phenotype, and ampicillin susceptibility might suggest disseminated EE caused by hvKp. Although bacteremia is usually a prerequisite for metastatic dissemination, it may not always be detectable (1,2). This infection probably began as otitis externa complicated by otitis media caused by perforated tympanic membrane and otomastoiditis, conditions that subsequently spread to the sinuses and right orbit. In a similar scenario, strain SB5881 also caused invasive infection including acute otitis media in a patient with type 1 diabetes mellitus and chronic alcoholism (8). Despite its emergence in or before 1935, ST66-K2 hvKp infections were not reported until 2002, probably because of the limited availability of high-resolution genomic sequencing tools in the 20th century (8,11). Thus, the prevalence of ST66-K2 hvKp might be largely underestimated.
In summary, we describe a case of EE caused by ST66-K2 hvKp in a Caucasian diabetic man with no travel history outside the United States. This lineage has remained highly conserved, preserving all of its virulence factors and >98% of its genome. Clinicians should be aware of the threat and challenges of EE caused hvKp infections.