---
title: "Five-Biomarker Definition Identifies Hypervirulent Klebsiella pneumoniae in Japan Bloodstream Infe"
id: "cdc-emerging-infectious-diseases-journal-2-five-biomarker-definition-for-hypervirulent-klebsiella-pneumoniae-bloodstream"
canonical_url: "https://medichelpline.com/clinical-feed/cdc-emerging-infectious-diseases-journal-2-five-biomarker-definition-for-hypervirulent-klebsiella-pneumoniae-bloodstream"
content_type: "clinical_feed_article"
specialty: "Infectious Disease"
source_name: "CDC Emerging Infectious Diseases Journal"
source_url: "https://wwwnc.cdc.gov/eid/article/32/11/26-0825_article"
published_at: "2026-10-14T04:00:00.000Z"
evidence_level: "Agency Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Five-Biomarker Definition Identifies Hypervirulent Klebsiella pneumoniae in Japan Bloodstream Infe
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/cdc-emerging-infectious-diseases-journal-2-five-biomarker-definition-for-hypervirulent-klebsiella-pneumoniae-bloodstream
- **Specialty:** [Infectious Disease](https://medichelpline.com/clinical-feed/infectious-disease.md)
- **Primary Source:** CDC Emerging Infectious Diseases Journal
- **Source URL:** [Original Journal Publication](https://wwwnc.cdc.gov/eid/article/32/11/26-0825_article)
- **Published At:** 2026-10-14T04:00:00.000Z
- **Evidence Rating:** Agency Feed
## Executive GIST (TL;DR)
- Investigators performed a retrospective cohort study of 207 Klebsiella pneumoniae bloodstream infection episodes at a single tertiary hospital in Japan during 2022–2024. - The team defined hypervirulent K. pneumoniae (**hvKp**) by PCR detection of five genotypic biomarkers: **rmpA**, **rmpA2**, **iucA**, **iroB**, and **peg-344**. Isolates lacking all five were classified as classical K. pneumoniae (cKp). - Overall hvKp frequency was 14% (28/207) of episodes; abscess complications occurred in 61% (17/28) of hvKp episodes versus 13% (23/179) among cKp episodes. - hvKp infections were associated with longer median post–disease onset hospitalization (28 days vs. 14 days) and longer total antimicrobial treatment duration (43 days vs. 14 days) compared with cKp. - Short-read whole-genome sequencing on a subset detected CTX-M–type extended-spectrum β-lactamase genes in 11% (3/28) of hvKp isolates, representing 1.4% (3/207) of all K. pneumoniae episodes; sequencing sampling was enriched for hvKp and selected isolate groups. - Sequence type 23 (ST23) predominated among hvKp abscess-associated episodes (9/10 ST23 episodes involved abscesses). The study assessed lineage-specific genomic features and antimicrobial-resistance convergence. - Clinical data, susceptibility testing methods, and hvKp PCR screening workflow were described; the hvKp classification was assigned retrospectively and not used for clinical decision-making. - The authors noted limited generalizability from a single-center design and that imaging-confirmed abscesses only were counted; methodological details such as PCR primers and sequencing pipelines are referenced in the Appendix.
## Clinical Analysis & Structured Key Points
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2022–2024](https://wwwnc.cdc.gov/eid/article/32/11/26-0825_article) * [ BACK ](https://wwwnc.cdc.gov/eid/article/32/11/26-0825_article) **Five-Biomarker Definition for Hypervirulent Klebsiella pneumoniae Bloodstream Infection and Abscess Complications, Japan, 2022–2024** * [ BACK ](https://wwwnc.cdc.gov/eid/article/32/11/26-0825_article) **Early Release****Five-Biomarker Definition for Hypervirulent Klebsiella pneumoniae Bloodstream Infection and Abscess Complications, Japan, 2022–2024** * [ BACK ](https://wwwnc.cdc.gov/eid/article/32/11/26-0825_article) **Articles****Early Release****Five-Biomarker Definition for Hypervirulent Klebsiella pneumoniae Bloodstream Infection and Abscess Complications, Japan, 2022–2024** * [Figure 1](https://wwwnc.cdc.gov/eid/article/32/11/26-0825-f1) * [Figure 2](https://wwwnc.cdc.gov/eid/article/32/11/26-0825-f2) * [Figure 3](https://wwwnc.cdc.gov/eid/article/32/11/26-0825-f3) * [Table 1](https://wwwnc.cdc.gov/eid/article/32/11/26-0825-t1) * [Table 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[EID Journal](https://wwwnc.cdc.gov/eid/) 2. [Volume 32](https://wwwnc.cdc.gov/eid/early-release) 3. [Early Release](https://wwwnc.cdc.gov/eid/early-release#issue-1347) 4. [Main Article](https://wwwnc.cdc.gov/eid/article/32/11/26-0825_article) * [Facebook](https://www.facebook.com/sharer/sharer.php?u=%2Feid%2Farticle%2F32%2F11%2F26-0825_article "Share to Facebook") * [Twitter](http://twitter.com/share?url=%2Feid%2Farticle%2F32%2F11%2F26-0825_article&text= "Share to Twitter") * [LinkedIn](https://www.linkedin.com/shareArticle?url=%2Feid%2Farticle%2F32%2F11%2F26-0825_article&title= "Share to LinkedIn") * [Syndicate](https://tools.cdc.gov/medialibrary/index.aspx#/sharecontent//eid/article/32/11/26-0825_article "Embed this Page") [ Emerging Infectious Disease journal ISSN: 1080-6059 ](https://wwwnc.cdc.gov/eid/) _Disclaimer: Early release articles are not considered as final versions. Any changes will be reflected in the online version in the month the article is officially released._ #### Volume 32, Number 11—November 2026 ##### _Research_ ### Five-Biomarker Definition for Hypervirulent _Klebsiella pneumoniae_ Bloodstream Infection and Abscess Complications, Japan, 2022–2024 On This Page [Materials and Methods](https://wwwnc.cdc.gov/eid/article/32/11/26-0825_article) * * * [Results](https://wwwnc.cdc.gov/eid/article/32/11/26-0825_article) * * * [Discussion](https://wwwnc.cdc.gov/eid/article/32/11/26-0825_article) * * * [Suggested Citation](https://wwwnc.cdc.gov/eid/article/32/11/26-0825_article) Figures [Figure 1](https://wwwnc.cdc.gov/eid/article/32/11/26-0825-f1) * * * [Figure 2](https://wwwnc.cdc.gov/eid/article/32/11/26-0825-f2) * * * [Figure 3](https://wwwnc.cdc.gov/eid/article/32/11/26-0825-f3) Tables [Table 1](https://wwwnc.cdc.gov/eid/article/32/11/26-0825-t1) * * * [Table 2](https://wwwnc.cdc.gov/eid/article/32/11/26-0825-t2) * * * [Table 3](https://wwwnc.cdc.gov/eid/article/32/11/26-0825-t3) Downloads [Appendix ](https://wwwnc.cdc.gov/eid/article/32/11/26-0825-app1.pdf) * * * [RIS [TXT - 2 KB] ](https://wwwnc.cdc.gov/eid/article/32/11/26-0825.ris) Article Metrics [Metric Details](https://wwwnc.cdc.gov/eid/article/32/11/26-0825_article) Related Articles [Novel Macrolide-Resistant _M. pneumoniae_ Subclades](https://wwwnc.cdc.gov/eid/article/32/11/26-0439_article) * * * [KPC-Producing _K. pneumoniae_ with PBP3 Insertions](https://wwwnc.cdc.gov/eid/article/32/6/26-0478_article) * * * [Novel Recombinant HAdV-B117, China](https://wwwnc.cdc.gov/eid/article/32/6/25-0940_article) * * * [More articles on Pneumonia](https://wwwnc.cdc.gov/eid/spotlight/pneumonia) Naoki Watanabe[![Comments to Author](https://wwwnc.cdc.gov/eid/content/images/icon/email.gif)](https://wwwnc.cdc.gov/eid/article/32/11/26-0825_article#comment) , Tomohisa Watari, Yoshihito Otsuka, and Tomoh Matsumiya Author affiliation: Hirosaki University Graduate School of Health Sciences, Hirosaki, Japan (N. Watanabe, T. Matsumiya); Kameda Medical Center, Kamogawa, Japan (T. Watari, Y. Otsuka) [Suggested citation for this article](https://wwwnc.cdc.gov/eid/article/32/11/26-0825_article#suggestedcitation) ### Abstract Hypervirulent _Klebsiella pneumoniae_ (hvKp) is an emerging cause of invasive infection, but clinical relevance of a 5-biomarker genotypic definition remains unclear. We analyzed 207 episodes of _K. pneumoniae_ bloodstream infection at a tertiary hospital in Japan during 2022–2024. We defined hvKp by PCR detection of all 5 biomarkers: _rmpA_ , _rmpA2_ , _iucA_ , _iroB_ , and _peg-344_. Overall, hvKp accounted for 14% (28/207) of episodes. Abscess complications occurred in 61% (17/28) of hvKp episodes and 13% (23/179) of classical _K. pneumoniae_ episodes. hvKp case-patients had longer median hospitalization (28 vs. 14 days) and duration of antimicrobial drug treatment (43 vs. 14 days) than those with classical _K. pneumoniae_. Most (9/10) sequence type 23 hvKp episodes involved abscesses. Short-read whole-genome sequencing detected CTX-M–type extended-spectrum β-lactamase genes in 11% (3/28) of hvKp isolates, representing 1.4% (3/207) of all _K. pneumoniae_ episodes. The 5-biomarker definition delineated a clinically distinct subgroup, demonstrating its value for genomic surveillance of emerging hvKp. _Klebsiella pneumoniae_ is a leading cause of bloodstream infection and was linked to ≈790,000 deaths globally in 2019 ([_1_](https://wwwnc.cdc.gov/eid/article/32/11/26-0825_article#r1 "1")). Classical _K. pneumoniae_ (cKp) predominantly causes infections in patients with underlying or immunocompromising conditions. Conversely, hypervirulent _K. pneumoniae_ (hvKp) can cause invasive, metastatic infections, including liver abscess, endophthalmitis, and meningitis, even in persons without underlying conditions ([_2_](https://wwwnc.cdc.gov/eid/article/32/11/26-0825_article#r2 "2")). Reports of hvKp acquiring carbapenem-resistance genes triggered alerts from the World Health Organization and European Centre for Disease Prevention and Control, highlighting the need for reliable identification of this pathotype ([_3_](https://wwwnc.cdc.gov/eid/article/32/11/26-0825_article#r3 "3"),[_4_](https://wwwnc.cdc.gov/eid/article/32/11/26-0825_article#r4 "4")). Definitions of hvKp vary across studies, but the combination of 5 genotypic biomarkers (_iucA_ , _iroB_ , _peg-344_ , _rmpA_ , and _rmpA2_) has demonstrated high diagnostic accuracy for identifying hvKp ([_5_](https://wwwnc.cdc.gov/eid/article/32/11/26-0825_article#r5 "5")–[ _7_](https://wwwnc.cdc.gov/eid/article/32/11/26-0825_article#r7 "7")). Among _K. pneumoniae_ bloodstream infections, hvKp prevalence varies across geographic settings, from 4% in the United States and Norway to 26% in Japan ([_8_](https://wwwnc.cdc.gov/eid/article/32/11/26-0825_article#r8 "8")–[ _10_](https://wwwnc.cdc.gov/eid/article/32/11/26-0825_article#r10 "10")). However, direct comparisons across studies are complicated by variations in hvKp definitions. Moreover, epidemiologic and clinical data specifically on the basis of the 5-biomarker definition remain limited. Consequently, whether 5 biomarker–defined hvKp identifies a clinically and epidemiologically distinct subgroup of bloodstream infections and whether its effects differ across lineages remain unclear. We conducted a retrospective cohort study at a tertiary hospital in Japan to compare the clinical characteristics of 5 biomarker–defined hvKp and cKp bloodstream infections. The primary aim was to determine whether 5 biomarker–defined hvKp was more frequently associated with abscess complications. Secondary aims were to estimate post–disease onset length of stay (LOS; i.e., hospitalization), total antibiotic duration, and 30-day mortality risk. We also summarized the lineage-specific genomic features of hvKp isolates and assessed convergence between hypervirulence and antimicrobial resistance. ### Materials and Methods ##### Study Design and Data Collection This single-center, retrospective cohort study was conducted at Kameda Medical Center, a 907-bed tertiary hospital in Kamogawa, Japan. We included consecutive patients from whom _K. pneumoniae_ species complex was isolated in >1 set of blood cultures during January 1, 2022–December 31, 2024. Patients with bloodstream infections had routine consultations for infectious diseases at the institution. For patients with multiple bloodstream infection episodes, we included only the first episode. Figure 1 ![Flow diagram of episode inclusion in study of 5-biomarker definition for hvKp bloodstream infection and abscess complications, Japan, 2022–2024. Of 290 first episodes of Klebsiella pneumoniae complex bloodstream infection, 207 K. pneumoniae episodes were included in the clinical analysis. Whole-genome sequencing was performed on 164 isolates by using an enriched sampling strategy comprising all hvKp isolates, all isolates with 1–4 biomarkers, all 3GCR isolates, and a random sample of the cKp isolates with overlap between categories. 3GCR, third-generation cephalosporin–resistant; cKp, classical K. pneumoniae; hvKp, hypervirulent K. pneumoniae.](https://wwwnc.cdc.gov/eid/images/26-0825-F1-tn.jpg) [Figure 1](https://wwwnc.cdc.gov/eid/article/32/11/26-0825-f1 "Figure 1"). Flow diagram of episode inclusion in study of 5-biomarker definition for hvKp bloodstream infection and abscess complications, Japan, 2022–2024. Of 290 first episodes of _Klebsiella pneumoniae_ complex bloodstream infection,... Of 290 unique episodes of _K. pneumoniae_ species complex bloodstream infections identified, we excluded 2 because clinical data were insufficient or no stored isolate was available ([Figure 1](https://wwwnc.cdc.gov/eid/article/32/11/26-0825-f1)). We excluded 81 other episodes because species-level differentiation by PCR ([_11_](https://wwwnc.cdc.gov/eid/article/32/11/26-0825_article#r11 "11")) identified _K. variicola_ or _K. quasipneumoniae_ isolates. Thus, we had a total of 207 _K. pneumoniae_ isolates for analysis. We collected clinical and microbiological data from electronic medical records and laboratory information systems and recorded patient sex according to medical records. We processed blood cultures by using the BD BACTEC FX system (Becton, Dickinson and Company, [External Link](https://www.bd.com)) and performed species identification by using a MALDI Biotyper (Bruker Daltonics GmbH, [External Link](https://www.bruker.com)) for matrix-assisted laser desorption/time-of-flight mass spectrometry. We used a Dry Plate Eiken (Eiken Chemical Co., Ltd., [External Link](https://www.eiken.co.jp)) to perform antimicrobial susceptibility testing by the broth microdilution method. We tested for susceptibility to the following antimicrobial agents: piperacillin, ampicillin/sulbactam, amoxicillin/clavulanate, piperacillin/tazobactam, cefazolin, ceftriaxone, cefepime, cefmetazole, imipenem, meropenem, aztreonam, gentamicin, tobramycin, amikacin, levofloxacin, ciprofloxacin, minocycline, and trimethoprim/sulfamethoxazole. We interpreted susceptibility results according to Clinical and Laboratory Standards Institute standards ([_12_](https://wwwnc.cdc.gov/eid/article/32/11/26-0825_article#r12 "12")). This study was approved by the Research Ethics Committee of the Kameda Medical Center (approval no. 25-016) with a waiver for informed consent and an opt-out process. ##### Definitions We classified isolates as hvKp or cKp according to the 5-biomarker definition and assessed antimicrobial resistance phenotypes separately. We defined hvKp as presence of all 5 genotypic biomarkers (_iucA_ , _iroB_ , _peg-344_ , _rmpA_ , and _rmpA2_), as proposed by others ([_5_](https://wwwnc.cdc.gov/eid/article/32/11/26-0825_article#r5 "5")–[ _7_](https://wwwnc.cdc.gov/eid/article/32/11/26-0825_article#r7 "7")). We classified isolates that did not meet the 5-biomarker definition as cKp. We performed PCR-based screening by using previously published primers for _rmpA_ , _rmpA2_ , _iucA_ , _iroB_ , and _peg-344_ ([_5_](https://wwwnc.cdc.gov/eid/article/32/11/26-0825_article#r5 "5")) ([Appendix](https://wwwnc.cdc.gov/eid/article/32/11/26-0825-app1.pdf) Table 1). We performed screening sequentially: first, we tested for _rmpA_ ; then, we tested for the other markers only in _rmpA_ -positive isolates. We assigned the hvKp classification retrospectively for study analyses; the classification was not available to the treating clinicians during routine care. We defined third-generation cephalosporin resistance (3GCR) as nonsusceptibility to ceftriaxone and multidrug resistance as nonsusceptibility to >1 agent in >3 antimicrobial categories ([_13_](https://wwwnc.cdc.gov/eid/article/32/11/26-0825_article#r13 "13")). We classified infection onset as community-acquired if the index blood culture was collected within 48 hours of admission without prior healthcare exposure. We classified all other episodes as healthcare-associated. We calculated Charlson comorbidity index (CCI) after excluding age points ([_14_](https://wwwnc.cdc.gov/eid/article/32/11/26-0825_article#r14 "14")). We defined abscess complications only on the basis of imaging findings and excluded clinically suspected abscesses without imaging confirmation. We defined metastatic infection as a secondary infectious focus anatomically distinct from the presumed primary source of bloodstream infection, including abscesses and nonsuppurative manifestations, such as endophthalmitis. We defined post–disease onset LOS as the number of days from index blood culture collection to hospital discharge or transfer. We determined total antibiotic duration as the total number of days of antimicrobial therapy for a bloodstream infection episode and its complications, including oral therapy after di
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