<i>Klebsiella pneumoniae </i>with capsule type K64 is overrepresented among invasive disease in Vietnam

Bich Vu Thi Ngoc; Sylvain Brisse; Trinh Dao Tuyet; Dung Vu Tien Viet; Kathryn E Holt; Trung Nguyen Vu; Huong Tran Thi Kieu; Diep Nguyen Thi Ngoc; H Rogier van Doorn; Heiman F L Wertheim

doi:10.12688/f1000research.52799.2

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Revised

Klebsiella pneumoniae with capsule type K64 is overrepresented among invasive disease in Vietnam

[version 2; peer review: 1 approved, 2 approved with reservations, 1 not approved]

Bich Vu Thi Ngoc ¹, Sylvain Brisse^2-4, Trinh Dao Tuyet⁵, [...] Dung Vu Tien Viet¹, Kathryn E Holt⁶, Trung Nguyen Vu⁵, Huong Tran Thi Kieu¹, Diep Nguyen Thi Ngoc¹, H Rogier van Doorn^1,7, Heiman F L Wertheim^1,8

Bich Vu Thi Ngoc ¹, Sylvain Brisse^2-4, [...] Trinh Dao Tuyet⁵, Dung Vu Tien Viet¹, Kathryn E Holt⁶, Trung Nguyen Vu⁵, Huong Tran Thi Kieu¹, Diep Nguyen Thi Ngoc¹, H Rogier van Doorn^1,7, Heiman F L Wertheim^1,8

PUBLISHED 17 Jan 2025

Author details Author details

¹ Oxford University Clinical Research Unit - Hanoi, Hanoi, Vietnam
² French National Centre for Scientific Research, Paris, France
³ Microbial Evolutionary Genomics, Institut Pasteur, Microbial Evolutionary Genomics, Paris, France, Paris, France
⁴ Institut Pasteur, Université Paris Cité, Biodiversity and Epidemiology of Bacterial Pathogens, F-75015, Paris, France
⁵ National Hospital of Tropical Diseases, Hanoi, Vietnam
⁶ Department of Biochemistry & Molecular Biology, Centre for Systems Genomics, University of Melbourne, Melbourne, Australia
⁷ Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK
⁸ Department of Medical Microbiology and Radboudumc Center for Infectious Diseases, Radboudumc, Nijmegen, The Netherlands

Bich Vu Thi Ngoc
Roles: Data Curation, Methodology, Writing – Original Draft Preparation

Sylvain Brisse
Roles: Conceptualization, Writing – Review & Editing

Trinh Dao Tuyet
Roles: Methodology, Resources

Dung Vu Tien Viet
Roles: Formal Analysis

Kathryn E Holt
Roles: Conceptualization

Trung Nguyen Vu
Roles: Methodology

Huong Tran Thi Kieu
Roles: Methodology

Diep Nguyen Thi Ngoc
Roles: Methodology

H Rogier van Doorn
Roles: Supervision, Writing – Review & Editing

Heiman F L Wertheim
Roles: Conceptualization, Supervision, Writing – Review & Editing

OPEN PEER REVIEW

REVIEWER STATUS

This article is included in the Pathogens gateway.

Abstract

Introduction

Recent reports indicate the emergence of community-acquired pneumonia associated with K64- Klebsiella pneumoniae (K. pneumoniae). Here, we identify the capsular types and sequence type of invasive and commensal K. pneumoniae isolates from Vietnam.

Methods

We included 93 K. pneumoniae isolates from patients hospitalized at the National Hospital for Tropical Diseases, Hanoi between 2007 and 2011; and 110 commensal isolates from throat swabs from healthy volunteers living in rural and urban Hanoi in 2012. We determined sequence types (STs) by multi-locus sequence typing (MLST) and capsule typing for seven K types by PCR. Antibiotic susceptibility testing was performed using disk diffusion.

Results

The most common detected capsule types were K1 (39/203, 19.2%, mainly ST23) and K2 (31/203, 15.3%, multiple STs: ST65, ST86, ST380). We found significantly more K2 isolates among invasive in comparison to commensal isolates (22.6% vs 9%, p = 0.01) but no significant difference was observed between invasive and commensal K1 isolates (14.5% vs 24.7%, p = 0.075). K64 with varying sequence types were predominantly seen among invasive K. pneumoniae (8 vs. 3) and were isolated from sepsis and meningitis patients. Among K64 isolates, one was carbapenem-resistant with ST799.

Conclusion

Our study confirms that capsule type K64 K. pneumoniae is associated with community-acquired invasive infections in Vietnam. Research is needed to unravel the mechanisms of virulence of capsule type K64 in both community and hospital settings.

Keywords

Klebsiella pneumoniae, K64, capsule type, community-acquired infections, carbapenem-resistant

Corresponding author: Bich Vu Thi Ngoc

Competing interests: No competing interests were disclosed.

Grant information: Wellcome Trust OxTREC, 49-12
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Copyright: © 2025 Vu Thi Ngoc B et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

How to cite: Vu Thi Ngoc B, Brisse S, Dao Tuyet T et al. Klebsiella pneumoniae with capsule type K64 is overrepresented among invasive disease in Vietnam [version 2; peer review: 1 approved, 2 approved with reservations, 1 not approved]. F1000Research 2025, 10:454 (https://doi.org/10.12688/f1000research.52799.2) First published: 08 Jun 2021, 10:454 (https://doi.org/10.12688/f1000research.52799.1) Latest published: 17 Jan 2025, 10:454 (https://doi.org/10.12688/f1000research.52799.2)

Revised Amendments from Version 1

The major differences between the old and new versions include updates based on recent understanding of K. pneumoniae and the K64 type, as well as revisions made in response to reviewer feedback. The methods section has been clarified, particularly regarding antibiotic susceptibility and the statistical methods applied in the analysis. Additionally, Table 1 has been revised to correct a typo that led to bias in the selection of one strain for the study. In the discussion, we address the study's limitations and further suggest the role of the K64 type in K. pneumoniae pathogenicity.

See the authors' detailed response to the review by John L. Kiley

Introduction

In low and middle-income countries in Asia, like Vietnam, K. pneumoniae is an important cause of severe community-acquired infections, including pneumonia, liver abscesses and sepsis.¹ Multidrug-resistance in K. pneumoniae, especially among hospital acquired infections, is an emerging problem associated with high morbidity and mortality.² K. pneumoniae is classified across two main virulence phenotypes, classical (cKp) and hypervirulent (hvKp). Most K. pneumoniae are associated with uncomplicated community acquired infections and nocosomial infections. However, hvKp results in more severe community – acquired infections with manifestations such as pyogenic liver abscess, meningitis, endophthalmitis, and necrotizing fasciitis.³ The polysaccharide capsule is perhaps the most well-known virulence factor of K. pneumoniae, including for the hvKp phenotype. The capsule surrounding K. pneumoniae cells can be divided into at least 79 capsular types (K1 to K79), among which K1, K2, and K64 are common serotypes of the MDR-hvKp group, which is commonly found in Asia.⁴^,⁵ A genomic analysis of diversity and population structure of 288 human and animal K. pneumoniae isolates from six countries, spanning four continents, has shown that K64 was among the important capsule types associated with community acquired pneumonia in Vietnam (n = 3) and Singapore (n = 1).⁵ In addition to cases and outbreaks reported on severe K. pneumoniae infections by K64 capsular type with the convergence of carbapenem-resistant phenotypes,⁶ in one case report, K64-ST1764 K. pneumoniae was found to be a cause of pyogenic liver abscess and endogenous endophthalmitis. K. pneumoniae can asymptomatically colonize the gastrointestinal (proportion between 40% to 66%)⁷ and upper respiratory tract of healthy humans (14.1%)⁸ but carriage of K64 K. pneumoniae in healthy persons has rarely been described. According to previous studies, K1 and K2 are known to be highly virulent capsule types associated with community-acquired and hospital-acquired infections. K54 and K57 are mainly found in the human microbiome, particularly in the upper respiratory tract of healthy individuals. Our literature review indicates that K5 and K20 have been sporadically reported as pathogens, although they are less common. As for K64, reported by K. Holt et al. in 2015, it appears to be an emerging cause of severe disease.⁵^,⁹ Our study aims to investigate the diversity of K. pneumoniae in both community and hospital settings by classifying the diversity of capsular types. Here, we found K64- K. pneumoniae to be more common among invasive isolates as compared to commensal isolates isolated from Vietnamese individuals.

Methods

Klebsiella pneumoniae isolates and antibiotic susceptibility testing

From a total of 589 K. pneumoniae that were isolated from patients hospitalized at the National Hospital of Tropical Diseases between 2007 and 2011, 332 isolates were recovered after re-cultivation. Of those, 30 isolates with lacking clinical metadata were excluded, leaving the remaining 302 isolates for downstream analysis. Ninety-three were isolated from otherwise sterile sites, including blood (n = 70), cerebrospinal fluid (CSF) (n = 7), and pus (n = 16). These were re-cultured and re-confirmed using biochemical test strips (API 20E, Biomérieux, Marcy l’Étoile, France). Antibiotic susceptibility testing (AST) using disk diffusion was done according to Clinical and Laboratory Standards Institute (CLSI) guidelines 2019. A phenotypic confirmatory double-disk test was performed for confirmation of ESBL production using CTX (30 mg) and CAZ (30 mg) disks alone and in combination with CA (10 mg) (Mast Diagnostic a GmbH, Reinfeld, Germany).

We collected clinical data from patients infected with these isolates (invasive isolates) and classified their infections based on the definition of healthcare-associated and community-associated infections (https://arpsp.cdc.gov/profile/infections?tab=nhsn). To ensure that the isolates were from community-acquired infections, we used a time difference of ≥48 hours between the time of admission and the time of specimen collection. To compare invasive with commensal isolates, we used randomization tools (https://www.randomizer.org/) to select 110 of 331 K. pneumoniae isolates from throat swabs of healthy volunteers living in rural (Bavi) and urban (DongDa district), Hanoi in 2012. The epidemiology of these healthy volunteers has been described in our previous study which was designed to investigate K. pneumoniae oropharyngeal carriage and rick factors in Vietnam.⁸ Commensal isolates were tested and analysed in the same manner as invasive isolates.

Molecular typing

Invasive and commensal isolates were tested to identify their capsule types (for capsule types K1, K2, K5, K20, K54, K57, and K64) by polymerase chain reaction (PCR) according to previously described methods.^10,11 A specific K64 PCR was developed to detect capsule type K64 that was reported to be common in Southeast Asia⁵ with the following primers: Forward (5′TTC TTT AAG TCT TCT GGG TAT CA3′) and Reverse (5′AGT CTT TAA TCG CCT TCT3′). The PCR cycling program for K64 consisted of 95°C for 15 min, followed by 30 cycles of 95 °C for 30 sec, 60 °C for 30 sec, 72 °C for 1 min 20 sec and the final elongation step was performed for 7 min at 72 °C. The PCR products were loaded on agarose (1.5%) gel electrophoresis. Samples contained PCR products with size equivalent to 782 bp as K64 positive.

Multi-locus sequence typing (MLST) was performed by sequencing the PCR products of seven house-keeping genes including (gapA, infB, mdh, pgi, phoE, rpoB, tonB). The sequence of these genes was analysed using the BIGSdb-Pasteur website (https://bigsdb.pasteur.fr/) for determining the sequence types. Sequence types (STs) were grouped into clonal complexes (CC) as described previously.¹² A clonal complex is defined as a group of STs with at least 6 identical alleles with at least one other member of the group. STs that did not fall within a CC were defined as singletons.

We used Statistical Package of Social Sciences (SPSS) version 25 (IBM corporation, Armonk (NY), USA) for analysis,¹³ p values < 0.05 were considered significant (2-sided).

Ethics statement

This study was approved by the Oxford University Tropical Research Ethics Committee (Oxtrec, 49-12) and the National Hospital for Tropical Diseases Institutional Review Board. Before participation, written informed consent from subjects or, in case of minors, their caregivers, was obtained on a standard study consent form.

Results

Among 203 K. pneumoniae isolates, 100 (49.2%) were positive with one of the seven tested capsule (K) types (K1, K2, K5, K20, K54, K57, K64). The most common K types were K1 (n = 39) and K2 (n = 31). Whereas 36/39 (92.3%) K1 isolates belonged to STs that were classified into clonal complex, CC23, K2 isolates were more diverse: the most frequent clonal complex was CC65 (n = 18), followed by CC86 (n = 8) ( Table 1). While K2 isolates were more prevalent among invasive than among commensal isolates (22.6% vs 9%, Chi-square, p = 0.01), K1 was relatively equally distributed (14.5% vs 24.7%, p = 0.075), and K57 (n = 18) was detected mostly among commensal isolates (15.4% vs 1%, p < 0.0001). We detected seven isolates with K64, five of which were invasive (p < 0.001). Among five invasive K64 K. pneumoniae, two were isolated from sepsis patients, one from meningitis, one from sepsis-meningitis, and one from the blood of a patient with hospital-acquired pneumonia. Most of these invasive K64 isolates (4/5) were from patients on Intensive Care Units (ICU). Of those patients, two had fatal community acquired pneumonia. The seven K64 isolates (two from commensal, five from invasive isolates) were genotyped by MLST: four belonged to the CC231 (ST231, ST799, ST807) and the other to CC65 (ST692).

Table 1. Clonal complex (CCs) as determined by multi-locus sequence typing (MLST) and distribution of capsular types among invasive isolates and commensal isolates of Klebsiella pneumoniae in Vietnam.

P-value were determined by Chi-square (2-sides) test.

Clonal Complex (CC)	Overall	Commensal (n, %)	Invasive (n, %)	p-value
23	63 (31)	35 (31.8)	28 (28)	0.791
65	23 (11.3)	6 (5.5)	17 (18.2)	0.004
231	4 (2)	0 (0)	4 (4.3)
412	9 (4.4)	8 (7.3)	1 (1)
806	6 (3)	1 (1)	5 (5.3)
86	8 (4)	3 (2.7)	5 (5.3)
Others CCs	23 (11.3)	15 (13.6)	7 (7.5)	0.251
Singleton	68 (34)	42 (38.1)	26 (27.9)	0.083
Capsular type
K1	39 (19.2)	16 (14.5)	23 (24.7)	0.075
K2	31 (15.3)	10 (9)	21 (22.6)	0.01
K5	1 (0.5)	0 (0)	1 (1)	0.458
K20	2 (1)	2 (1.8)	0 (0)	0.5
K54	2 (1)	1 (1)	1 (1)	1
K57	18 (9)	17 (15.4)	1 (1)	<0.0001
K64	7 (3.4)	2 (1.8)	5 (5.4)	<0.0001

Overall, antimicrobial resistant proportions of commensal isolates differed significantly from invasive K. pneumoniae ( Table 2). Among K64 isolates, one invasive ST799 isolate from a patient with hospital-acquired pneumonia was multi-drug resistant, with resistance to imipenem, ciprofloxacin, trimethoprim/sulfamethoxazole, piperacillin-tazobactam and gentamicin. Of the remaining K64 isolates, four invasive isolates were non-carbapenem resistant but they either were resistant to trimethoprim/sulfamethoxazole or piperacillin-tazobactam. Whilst, the two commensal isolates with ST1331 and ST1347, were susceptible to all tested antibiotics.¹⁴

Table 2. Comparison of the proportion of antibiotic resistance between invasive versus commensal Klebsiella pneumoniae isolates in Vietnam.

P-value were determined by Chi-square (2-sides) test.

	Overall	Commensal (n, %)	Invasive (n, %)	p-value
ESBL	15 (7.4)	4 (3.6)	11 (11.8)	0.025
CIP (Ciprofloxacin)	7 (3.4)	0 (0)	7 (7.5)	0.002
AMC (Amoxicillin - clavulanate)	16 (7.8)	0 (0)	16 (17.2)	0.004
AMP (Ampicillin)	196 (96.5)	104 (94.5)	92 (98.5)	0.339
FEP (Cefepime)	9 (4.4)	0 (0)	9 (9.6)	0.001
GEN (Gentamicin)	N/A	N/A	14 (15)	N/A
TZP (Piperacillin -tazobactam)	6 (2.9)	0 (0)	6 (6.5)	0.008
SXT (Trimethoprim-sulfamethoxazole)	29 (14.3)	9 (8.1)	20 (21.5)	<0.001
IMP (Imipenem)	1 (0.5)	0 (0)	1 (1)	0.458

Discussion and conclusion

In addition to the emergence of carbapenem-resistant K. pneumoniae worldwide, previous studies have shown that infections caused by hypervirulent carbapenem susceptible K. pneumoniae can also be considered a threat to public health.¹⁵ Our study suggested that besides capsule type K2, capsule type K64 was associated with invasive strains (5.4% vs 1.8%, Chi-square, p < 0.001), consistent with previous studies.^5,16

The capsular type K64 has been reported worldwide, especially from clinical settings in Asia, Europe, and North America and is one of the K types associated with hypervirulent strains, that have shown simultaneous expression of virulence and carbapenem-resistance genes, posing a treatment challenge.¹⁷ ST11-K64 is a common type in China, possibly leading to pyogenic liver abscesses.⁹ Contrarily, our K64 strains were mainly found in sepsis and meningitis patients with varying STs, including: ST231, ST692, ST799, and ST807. Moreover, it is worth noting that K64 has been common in Klebsiella pneumoniae carbapenemase (KPC) producing ST11 strains in China, and the shift from K47 to K64 has been associated with increased virulence in this strain.¹⁸ In our study, the carbapenem-resistant K64-ST799 was isolated from the blood of a hospital-acquired patient in 2011, and was not detected in subsequent years in surveillance efforts.¹⁹ Likely, the K64-ST799 strain might have acquired a mobile element carrying a carbapenemase-producing gene.

In particular, K64 has been recently recognized as a capsular type potentially associated with hypervirulence and invasive disease. Indeed, the presence of K64 with several STs isolated from bacteraemia and meningitis patients in Vietnam and a pyogenic liver abscess patient in China²⁰ provides further evidence that strains with this capsule type are virulent.²¹

The present study has several limitations. Because of the retrospective nature of the analyzed data collection, we missed some clinical data (exposures, alcohol history, out come after treatment) of the patients. The results of this study lack evidence to support the hypothesis that the risk factor of infections may be K. pneumoniae colonizers. In this study, the relatively small number of K64 isolates provided only limited data about the serotype's convergent virulence and carbapenem resistance. Also, we lack the whole genome sequence data of these K64 isolates for further understanding the molecular basis of hypervirulence and the phylogenetic positioning of this rare ST within the genomic taxonomy of K. pneumoniae.²² However, our results led support to the hypothesis that K64 is associated with severe invasive community acquired K. pneumoniae infections, including sepsis and meningitis. In addition, here, only seven capsule types were selected to investigate the diversity of K. pneumoniae isolates. We recognize that this is one of the limitations of our study. Further studies are needed to unravel the mechanisms of virulence of capsule type K64 in K. pneumoniae.

Data availability

Underlying data

Dryad: Klebsiella pneumoniae with capsule type K64 is overrepresented among invasive disease in Vietnam. https://doi.org/10.5061/dryad.h44j0zpjv¹⁴

• Table 1 (Kp_All_AST) provides the detailed information of 203 Klebsiella pneumoniae isolates including source of isolates, date of collection, antibiotic susceptibility profiles, K-serotypes and MLST profiles.
• Serotype_Clinical isolates.rar and Serotype_Community isolates.rar: These folders contain the photographs of the PCR products of agarose gel electrophoresis. Maps of samples on agarose plates are described in two Excel files (Electrophoresis_map.xlsx and Isolate ID on Electrophoresis.gel.xlsx for Clinical isolates and Commensal isolates, respectively).

Data are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication).

Consent

Before participation, written informed consent from subjects or, in case of minors, their caregivers, was obtained on a standard study consent form.

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Version 2

VERSION 2 PUBLISHED 08 Jun 2021

Author details Author details

Bich Vu Thi Ngoc
Roles: Data Curation, Methodology, Writing – Original Draft Preparation

Sylvain Brisse
Roles: Conceptualization, Writing – Review & Editing

Trinh Dao Tuyet
Roles: Methodology, Resources

Dung Vu Tien Viet
Roles: Formal Analysis

Kathryn E Holt
Roles: Conceptualization

Trung Nguyen Vu
Roles: Methodology

Huong Tran Thi Kieu
Roles: Methodology

Diep Nguyen Thi Ngoc
Roles: Methodology

H Rogier van Doorn
Roles: Supervision, Writing – Review & Editing

Heiman F L Wertheim
Roles: Conceptualization, Supervision, Writing – Review & Editing

Competing interests

No competing interests were disclosed.

Grant information

Wellcome Trust OxTREC, 49-12
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Article Versions (2)

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Published: 17 Jan 2025, 10:454

https://doi.org/10.12688/f1000research.52799.2

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https://doi.org/10.12688/f1000research.52799.1

© 2025 Vu Thi Ngoc B et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Vu Thi Ngoc B, Brisse S, Dao Tuyet T et al. Klebsiella pneumoniae with capsule type K64 is overrepresented among invasive disease in Vietnam [version 2; peer review: 1 approved, 2 approved with reservations, 1 not approved]. F1000Research 2025, 10:454 (https://doi.org/10.12688/f1000research.52799.2)

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Version 2

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Reviewer Report 09 Aug 2025

Neris García-González, Instituto de Biomedicina de Valencia (Ringgold ID: 54426), Valencia, Valencian Community, Spain

Approved with Reservations

https://doi.org/10.5256/f1000research.176630.r393103

Peer Review for “Klebsiella pneumoniae with capsule type K64 is overrepresented among invasive disease in Vietnam [version 2]”
The manuscript explores the distribution of Klebsiella pneumoniae capsule types, with a focus on K64, among invasive and commensal isolates in Vietnam. While the topic is relevant and the data valuable, I believe the conclusions are overstated given the limited number of K64 isolates.
Several aspects of the methodology and analysis require clarification or revision, particularly to address the overstatement of key conclusions. Additionally, the overall writing—especially the methods section—would benefit from careful editing for clarity.

Major Comments

The conclusion that “Our study confirms that capsule type K64 K. pneumoniae is associated with community-acquired invasive infections in Vietnam” is, in my view, overstated given the data presented. Of the 100 isolates with a successfully determined capsular type, only 11 were K64 (5 from invasive, 2 from commensal samples). This is a very small number, and the application of statistical tests to such low counts does not support a definitive conclusion.

Similarly, the claim that K64 is “associated with sepsis and meningitis” is unsupported. While some K64 isolates came from such cases, no analysis was done to test specific disease associations. This should be rephrased more cautiously (e.g., “were observed in”).

The statement that “K64-ST799 might have acquired a mobile element carrying a carbapenemase gene” is speculative and not backed by molecular data. Without sequencing or resistance gene analysis, this claim should be softened.
The authors tested for only seven capsule types (K1, K2, K5, K20, K54, K57, K64). It’s unclear why these were chosen—are they the most common in Vietnam, or just associated with hvKp globally? This should be clarified, especially since over half of the isolates were untypeable. Without knowing whether additional relevant types were missed, it is difficult to interpret the significance of the K64 frequency.
The invasive isolates were collected between 2007–2011, while the commensal isolates were collected in 2012. The invasive and commensal isolates were collected in different time periods (2007–2011 vs. 2012), which could introduce temporal bias. This limitation should be acknowledged explicitly.

The manuscript requires substantial revision for clarity. Several sentences are difficult to parse, and the structure of some sections hinders comprehension. For example:

The methodology does not clearly explain how the 589 K. pneumoniae isolates were selected. Were these all from invasive infections? If so, and only 49.2% were typeable, a large proportion of relevant invasive capsule types may have been missed. Alternatively, if this set included both invasive and commensal isolates, it would improve the comparison by providing community data from the same time period. This should be clearly stated and clarified in the manuscript.
The distinction between the two datasets (invasive and commensal) is clear in the abstract but not well explained in the main text. I suggest rephrasing to something similar to: “To compare invasive with commensal isolates, we included commensal isolates from a previous study. These were throat swabs from healthy volunteers in rural and urban Hanoi in 2012. …”
The statement: “To ensure that the isolates were from community-acquired infections, we used a time difference of ≥48 hours…” is confusing. Community-acquired infections are typically defined as those occurring within 48 hours of hospital admission. This should be reworded for clarity.

Minor Comments

Define MDR (multidrug-resistant) on first mention.
In Tables 1 and 2, “Overall” column should also have (n, %)
Correct spelling of “nocosomial” to “nosocomial.”

Is the work clearly and accurately presented and does it cite the current literature?

Partly
Is the study design appropriate and is the work technically sound?

Partly
Are sufficient details of methods and analysis provided to allow replication by others?

Yes
If applicable, is the statistical analysis and its interpretation appropriate?

Partly
Are all the source data underlying the results available to ensure full reproducibility?

No source data required
Are the conclusions drawn adequately supported by the results?

Partly

Competing Interests: No competing interests were disclosed.

Reviewer Expertise: microbial genomics

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above.

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Reviewer Report 06 Jun 2025

Ning Dong, Zhejiang University School of Medicine, Hangzhou, China

Not Approved

https://doi.org/10.5256/f1000research.176630.r383866

In this study on Klebsiella pneumoniae, the authors analyzed 203 clinical isolates and found that capsular K64 was significantly enriched in invasive infections, mainly associated with sepsis and meningitis, and some K64 strains (such as ST799) were multidrug resistant. This study suggests that K64 is an important pathogen of community-acquired invasive infections in Vietnam. I suggest the following directions for further improvement of the study:
The theoretical basis for capsule type selection was supplemented, and the latest literature (such as studies on the global prevalence of K64 after 2023) was cited to complete the discussion section.
The sample size was small and underrepresented. The sample size of K64 strains was only 7 strains (5 invasive strains and 2 commensal strains), which was too small to support the conclusion that K64 was significantly enriched in invasive infections, which may lead to limited reliability of statistical results. Second, the commensal strains lack sample coverage from multiple regions and time points to fully reflect the epidemiological characteristics of community-acquired infections in Vietnam.
The results "K64 with varying sequence types were predominantly seen among invasive K. pneumoniae (8 vs. 3)" was inconsistent with the table data in the text (5 invasive strains, 2 commensal strains).
The whole genome sequencing data was supplemented to analyze the virulence genes (such as rmpA and magA) and drug resistance genes (such as KPC and NDM) of K64 strain, and to clarify its pathogenic mechanism at the molecular level.
There is a logical jump between the conclusion and the data. The title and conclusion use the word "overrepresented", which is misleading. Because the proportion of K64 in invasive strains was only 5.4% (5/93), which was much lower than that of K1 (24.7%) and K2 (22.6%). Second, it was mentioned that K64 was associated with carbapenem resistance (such as the ST799 strain). However, the finding of only one drug-resistant strain cannot support the inference that the K64 strain is generally resistant to carbapenem, and more data are needed to verify it.

Is the work clearly and accurately presented and does it cite the current literature?

Partly
Is the study design appropriate and is the work technically sound?

Yes
Are sufficient details of methods and analysis provided to allow replication by others?

Yes
If applicable, is the statistical analysis and its interpretation appropriate?

Yes
Are all the source data underlying the results available to ensure full reproducibility?

Yes
Are the conclusions drawn adequately supported by the results?

Partly

Competing Interests: No competing interests were disclosed.

Reviewer Expertise: Epidemiology of infectious diseases

I confirm that I have read this submission and believe that I have an appropriate level of expertise to state that I do not consider it to be of an acceptable scientific standard, for reasons outlined above.

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Reviewer Report 28 Jan 2025

Frank R. DeLeo, Laboratory of Bacteriology, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT, 59840, USA

Approved

https://doi.org/10.5256/f1000research.176630.r360165

Revised version ... Continue reading

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Reviewer Report 28 Jun 2024

Frank R. DeLeo, Laboratory of Bacteriology, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT, 59840, USA

Approved with Reservations

https://doi.org/10.5256/f1000research.56121.r287539

Ngoc et al. report capsule type and multilocus sequence type of Klebsiella pneumoniae clinical isolates from patients hospitalized at National Hospital for Tropical Diseases in Hanoi from 2007 to 2011. The authors compared these isolates to commensal isolates obtained by throat swab from healthy volunteers in 2012. The study is interesting and adds to our understanding of the distribution of the K. pneumoniae capsule types associated with human infections. I have a few comments for the authors to consider.

Please verify numbers of isolates in Table 1 compared with what is stated in the text. By my count, there are 110 commensal isolates (correct in the text) and 94 (stated as 93 in the text) invasive isolates. These numbers are concordant with the sum of the numbers in the Overall column, which total 204 isolates (the text indicates 203). Please verify for accuracy.
It would be optimal to provide text in the Table 1 legend that states what the p-value refers to from a comparison standpoint, and indicate the test used here as well.
I recommend providing the rationale for selecting the seven capsule types used to screen isolates in this study. Why were these seven capsule types chosen among others?
A conclusion of the study is that “capsule type K64 is overrepresented among invasive strains”. In reality there are only seven K64 isolates out of 204 total isolates and only five of these were from invasive disease. This is 5.4% of the total number of invasive isolates and much less than either K1 or K2. In addition, the Conclusion text on the title page states that K64 K. pneumoniae is associated with community-acquired invasive infections in Vietnam.” Please provide the criteria in the Methods section that were used to determine whether an infection is a bona fide community-acquired infection. It would be fair to state that K64 contributes to invasive disease and is among the top three capsule types tested that are associated with invasive infections. However, the term “overrepresented among invasive strains” might best be restated as “there were significantly more capsule type K64 isolates recovered from patients with invasive infections compared to healthy individuals with commensal isolates” or something along those lines.

Minor points.
Introduction: “A genomic analysis of diversity and population structure of 288 human and animal K. pneumoniae isolates from six countries, spanning four continents, has shown that K64 mostly found in Vietnam (n = 3) and Singapore (n = 1), was among the important capsule types associated with community acquired pneumonia.” is not easy to read.

Consider revising to:
“A genomic analysis of diversity and population structure of 288 human and animal K. pneumoniae isolates from six countries, spanning four continents, has shown that K64 was among the important capsule types associated with community acquired pneumonia in Vietnam (n = 3) and Singapore (n = 1).”

Introduction, penultimate sentence: change K64 capsular to K64 capsule types

Is the work clearly and accurately presented and does it cite the current literature?

Partly
Is the study design appropriate and is the work technically sound?

Yes
Are sufficient details of methods and analysis provided to allow replication by others?

Partly
If applicable, is the statistical analysis and its interpretation appropriate?

I cannot comment. A qualified statistician is required.
Are all the source data underlying the results available to ensure full reproducibility?

Partly
Are the conclusions drawn adequately supported by the results?

Partly

Competing Interests: No competing interests were disclosed.

Reviewer Expertise: Bacterial pathogenesis and host defense. Primary focus on Staphylococcus aureus, Klebsiella pneumoniae, and human neutrophil biology.

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Reviewer Report 12 Oct 2021

John L. Kiley, Brooke Army Medical Center, San Antonio, TX, USA

Approved with Reservations

https://doi.org/10.5256/f1000research.56121.r93803

This paper describes the epidemiology of K64 Klebsiella pneumoniae isolates with a particular focus on K64 from a hospital in Vietnam.

Introduction

"...but K64 capsular have rarely been described in healthy carriers." in the introductory

This paper describes the epidemiology of K64 Klebsiella pneumoniae isolates with a particular focus on K64 from a hospital in Vietnam.

Introduction

"...but K64 capsular have rarely been described in healthy carriers." in the introductory paragraph reads a bit unclearly.
Adding a bit more about the importance of K64 and the differences between classic and hypervirulent types of Klebsiella spp. (as well as how capsules might play a role in this) would better situate the authors' opening argument as to why they are performing this current study.

Methods

"302 K. pneumoniae were isolated..." are these all isolates from the hospital during this time period?

Results

I note that ESBL production was determined in Table 2 - please clarify how you determined this in the methods.

Discussion and conclusion

I think some discussion about the small numbers of K64 isolates would also be helpful in the limitations of the paper. The second paragraph starts off by suggesting K64 has "been little reported so far," but I think the data from China would argue against this.
- Zhang et al., 2020 reported Chinese epidemiological data on K64¹.
- Walker et al., 2020 for general discussion of hypervirulence and association with capsular type².
- Catalán-Nájera et al., 2017 for hypermucoviscious, hypervirulent differences/discussion³.

Great paper overall!

Is the work clearly and accurately presented and does it cite the current literature?

Partly
Is the study design appropriate and is the work technically sound?

Yes
Are sufficient details of methods and analysis provided to allow replication by others?

Yes
If applicable, is the statistical analysis and its interpretation appropriate?

Yes
Are all the source data underlying the results available to ensure full reproducibility?

Yes
Are the conclusions drawn adequately supported by the results?

Yes

References

1. Zhang Y, Jin L, Ouyang P, Wang Q, et al.: Evolution of hypervirulence in carbapenem-resistant Klebsiella pneumoniae in China: a multicentre, molecular epidemiological analysis. Journal of Antimicrobial Chemotherapy. 2020; 75 (2): 327-336 Publisher Full Text
2. Walker KA, Miller VL: The intersection of capsule gene expression, hypermucoviscosity and hypervirulence in Klebsiella pneumoniae.Curr Opin Microbiol. 54: 95-102 PubMed Abstract | Publisher Full Text
3. Catalán-Nájera J, Garza-Ramos U, Barrios-Camacho H: Hypervirulence and hypermucoviscosity: Two different but complementaryKlebsiella spp. phenotypes?. Virulence. 2017; 8 (7): 1111-1123 Publisher Full Text

Competing Interests: No competing interests were disclosed.

Reviewer Expertise: Multi drug resistant Gram-negative infections

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Author Response 17 Jan 2025

Bich Vu Thi Ngoc, Oxford University Clinical Research Unit - Hanoi, Hanoi, Vietnam

17 Jan 2025

Author Response

We would like to thank reviewer for your valuable comments. We have addressed all the reviewers’ comments in the revised manuscript, including with additional information, and responded in the point-to-point ... Continue reading We would like to thank reviewer for your valuable comments. We have addressed all the reviewers’ comments in the revised manuscript, including with additional information, and responded in the point-to-point rebuttal below. We hope our revisions are adequate and make our manuscript clear and publishable.
Reviewer 1
This paper describes the epidemiology of K64 Klebsiella pneumoniae isolates with a particular focus on K64 from a hospital in Vietnam.
Comment 1: Introduction
"...but K64 capsular have rarely been described in healthy carriers." in the introductory paragraph reads a bit unclearly.
Response: Thank you very much for your comment. We have now revised the sentence in the updated version as below:
“…but carriage of K64 K. pneumoniae in healthy persons has rarely been described.”
Comment 2:
Adding a bit more about the importance of K64 and the differences between classic and hypervirulent types of Klebsiella spp. (as well as how capsules might play a role in this) would better situate the authors' opening argument as to why they are performing this current study.
Response: Thank you very much for your recommendation. We have now included the following sentences in the introduction of the manuscript:
K pneumoniae is classified across two main virulence phenotypes, classical (cKp) and hypervirulent (hvKp). Most K. pneumoniae are associated with uncomplicated community acquired infections and nocosomial infections. However, hvKp results in more severe community – acquired infections with manifestations such as pyogenic liver abscess, meningitis, endophthalmitis, and necrotizing fasciitis. The polysaccharide capsule is perhaps the most well-known virulence factor of K. pneumoniae, including for the hvKp phenotype. The capsule surrounding K. pneumoniae cells can be divided into at least 79 capsular types (K1 to K79), among which K1, K2, and K64 are common serotypes of the MDR-hvKp group, which is commonly found in Asia.
Comment 3: Methods
"302 K. pneumoniae were isolated..." are these all isolates from the hospital during this time period?
Response:
Thank you very much for your question. The total number of isolates from the hospital during this time was 589 isolates; however, because this was a retrospective study, we performed re-culture, and 332/589 isolates were recovered. Of those, 30 isolates had no associated clinical metadata, and were excluded from the study.
We now have clarified this in the manuscript as below:
“From a total of 589 K. pneumoniae that were isolated from patients hospitalized at the National Hospital of Tropical Diseases between 2007 and 2011, 332 isolates were recovered after re-cultivation. Of those, 30 isolates with lacking clinical metadata were excluded, leaving the remaining 302 isolates for downstream analysis.”
Comment 4: Results
I note that ESBL production was determined in Table 2 - please clarify how you determined this in the methods.
Response:
Thank you very much for your comment. We have added the information into the updated version as below:
“A phenotypic confirmatory double-disk test was performed for confirmation of ESBL production using CTX (30 mg) and CAZ (30 mg) disks alone and in combination with CA (10 mg) (Mast Diagnostic a GmbH, Reinfeld, Germany).”
Comment 5: Discussion and conclusion
I think some discussion about the small numbers of K64 isolates would also be helpful in the limitations of the paper. The second paragraph starts off by suggesting K64 has "been little reported so far," but I think the data from China would argue against this.
Response: Thank you for your recommendation.
We agree that data from China would argue against our statement in the second paragraph starts off by suggesting K64 has "been little reported so far,". We now have revised the sentence as below:
“The capsular type K64 has been reported worldwide, especially from clinical settings in Asia, Europe, and North America and is one of the K types associated with hypervirulent strains, that have shown simultaneous expression of virulence and carbapenem-resistance genes, posing a treatment challenge.”

Regarding the small numbers of K64 isolates in our study, we have added into the limitation:
“In this study, the relatively small number of K64 isolates provided only limited data about the serotype's convergent virulence and carbapenem resistance. Also, we lack the whole genome sequence data of these K64 isolates for further understanding of the molecular basis of hypervirulence and the phylogenetic positioning of this rare ST within the genomic taxonomy of K. pneumoniae. However, our results led support to the hypothesis that K64 is associated with severe invasive community acquired K. pneumoniae infections, including sepsis and meningitis. In addition, here, only seven capsule types were selected to investigate the diversity of K. pneumoniae isolates. We recognize that this is one of the limitations of our study. Further studies are needed to unravel the mechanisms of virulence of capsule type K64 in K. pneumoniae.”
We would like to thank reviewer for your valuable comments. We have addressed all the reviewers’ comments in the revised manuscript, including with additional information, and responded in the point-to-point rebuttal below. We hope our revisions are adequate and make our manuscript clear and publishable.
Reviewer 1
This paper describes the epidemiology of K64 Klebsiella pneumoniae isolates with a particular focus on K64 from a hospital in Vietnam.
Comment 1: Introduction
"...but K64 capsular have rarely been described in healthy carriers." in the introductory paragraph reads a bit unclearly.
Response: Thank you very much for your comment. We have now revised the sentence in the updated version as below:
“…but carriage of K64 K. pneumoniae in healthy persons has rarely been described.”
Comment 2:
Adding a bit more about the importance of K64 and the differences between classic and hypervirulent types of Klebsiella spp. (as well as how capsules might play a role in this) would better situate the authors' opening argument as to why they are performing this current study.
Response: Thank you very much for your recommendation. We have now included the following sentences in the introduction of the manuscript:
K pneumoniae is classified across two main virulence phenotypes, classical (cKp) and hypervirulent (hvKp). Most K. pneumoniae are associated with uncomplicated community acquired infections and nocosomial infections. However, hvKp results in more severe community – acquired infections with manifestations such as pyogenic liver abscess, meningitis, endophthalmitis, and necrotizing fasciitis. The polysaccharide capsule is perhaps the most well-known virulence factor of K. pneumoniae, including for the hvKp phenotype. The capsule surrounding K. pneumoniae cells can be divided into at least 79 capsular types (K1 to K79), among which K1, K2, and K64 are common serotypes of the MDR-hvKp group, which is commonly found in Asia.
Comment 3: Methods
"302 K. pneumoniae were isolated..." are these all isolates from the hospital during this time period?
Response:
Thank you very much for your question. The total number of isolates from the hospital during this time was 589 isolates; however, because this was a retrospective study, we performed re-culture, and 332/589 isolates were recovered. Of those, 30 isolates had no associated clinical metadata, and were excluded from the study.
We now have clarified this in the manuscript as below:
“From a total of 589 K. pneumoniae that were isolated from patients hospitalized at the National Hospital of Tropical Diseases between 2007 and 2011, 332 isolates were recovered after re-cultivation. Of those, 30 isolates with lacking clinical metadata were excluded, leaving the remaining 302 isolates for downstream analysis.”
Comment 4: Results
I note that ESBL production was determined in Table 2 - please clarify how you determined this in the methods.
Response:
Thank you very much for your comment. We have added the information into the updated version as below:
“A phenotypic confirmatory double-disk test was performed for confirmation of ESBL production using CTX (30 mg) and CAZ (30 mg) disks alone and in combination with CA (10 mg) (Mast Diagnostic a GmbH, Reinfeld, Germany).”
Comment 5: Discussion and conclusion
I think some discussion about the small numbers of K64 isolates would also be helpful in the limitations of the paper. The second paragraph starts off by suggesting K64 has "been little reported so far," but I think the data from China would argue against this.
Response: Thank you for your recommendation.
We agree that data from China would argue against our statement in the second paragraph starts off by suggesting K64 has "been little reported so far,". We now have revised the sentence as below:
“The capsular type K64 has been reported worldwide, especially from clinical settings in Asia, Europe, and North America and is one of the K types associated with hypervirulent strains, that have shown simultaneous expression of virulence and carbapenem-resistance genes, posing a treatment challenge.”

Regarding the small numbers of K64 isolates in our study, we have added into the limitation:
“In this study, the relatively small number of K64 isolates provided only limited data about the serotype's convergent virulence and carbapenem resistance. Also, we lack the whole genome sequence data of these K64 isolates for further understanding of the molecular basis of hypervirulence and the phylogenetic positioning of this rare ST within the genomic taxonomy of K. pneumoniae. However, our results led support to the hypothesis that K64 is associated with severe invasive community acquired K. pneumoniae infections, including sepsis and meningitis. In addition, here, only seven capsule types were selected to investigate the diversity of K. pneumoniae isolates. We recognize that this is one of the limitations of our study. Further studies are needed to unravel the mechanisms of virulence of capsule type K64 in K. pneumoniae.”
Competing Interests: We do not have any competing interests to disclose Close
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COMMENTS ON THIS REPORT

Author Response 17 Jan 2025

Bich Vu Thi Ngoc, Oxford University Clinical Research Unit - Hanoi, Hanoi, Vietnam

17 Jan 2025

Author Response

We would like to thank reviewer for your valuable comments. We have addressed all the reviewers’ comments in the revised manuscript, including with additional information, and responded in the point-to-point ... Continue reading We would like to thank reviewer for your valuable comments. We have addressed all the reviewers’ comments in the revised manuscript, including with additional information, and responded in the point-to-point rebuttal below. We hope our revisions are adequate and make our manuscript clear and publishable.
Reviewer 1
This paper describes the epidemiology of K64 Klebsiella pneumoniae isolates with a particular focus on K64 from a hospital in Vietnam.
Comment 1: Introduction
"...but K64 capsular have rarely been described in healthy carriers." in the introductory paragraph reads a bit unclearly.
Response: Thank you very much for your comment. We have now revised the sentence in the updated version as below:
“…but carriage of K64 K. pneumoniae in healthy persons has rarely been described.”
Comment 2:
Adding a bit more about the importance of K64 and the differences between classic and hypervirulent types of Klebsiella spp. (as well as how capsules might play a role in this) would better situate the authors' opening argument as to why they are performing this current study.
Response: Thank you very much for your recommendation. We have now included the following sentences in the introduction of the manuscript:
K pneumoniae is classified across two main virulence phenotypes, classical (cKp) and hypervirulent (hvKp). Most K. pneumoniae are associated with uncomplicated community acquired infections and nocosomial infections. However, hvKp results in more severe community – acquired infections with manifestations such as pyogenic liver abscess, meningitis, endophthalmitis, and necrotizing fasciitis. The polysaccharide capsule is perhaps the most well-known virulence factor of K. pneumoniae, including for the hvKp phenotype. The capsule surrounding K. pneumoniae cells can be divided into at least 79 capsular types (K1 to K79), among which K1, K2, and K64 are common serotypes of the MDR-hvKp group, which is commonly found in Asia.
Comment 3: Methods
"302 K. pneumoniae were isolated..." are these all isolates from the hospital during this time period?
Response:
Thank you very much for your question. The total number of isolates from the hospital during this time was 589 isolates; however, because this was a retrospective study, we performed re-culture, and 332/589 isolates were recovered. Of those, 30 isolates had no associated clinical metadata, and were excluded from the study.
We now have clarified this in the manuscript as below:
“From a total of 589 K. pneumoniae that were isolated from patients hospitalized at the National Hospital of Tropical Diseases between 2007 and 2011, 332 isolates were recovered after re-cultivation. Of those, 30 isolates with lacking clinical metadata were excluded, leaving the remaining 302 isolates for downstream analysis.”
Comment 4: Results
I note that ESBL production was determined in Table 2 - please clarify how you determined this in the methods.
Response:
Thank you very much for your comment. We have added the information into the updated version as below:
“A phenotypic confirmatory double-disk test was performed for confirmation of ESBL production using CTX (30 mg) and CAZ (30 mg) disks alone and in combination with CA (10 mg) (Mast Diagnostic a GmbH, Reinfeld, Germany).”
Comment 5: Discussion and conclusion
I think some discussion about the small numbers of K64 isolates would also be helpful in the limitations of the paper. The second paragraph starts off by suggesting K64 has "been little reported so far," but I think the data from China would argue against this.
Response: Thank you for your recommendation.
We agree that data from China would argue against our statement in the second paragraph starts off by suggesting K64 has "been little reported so far,". We now have revised the sentence as below:
“The capsular type K64 has been reported worldwide, especially from clinical settings in Asia, Europe, and North America and is one of the K types associated with hypervirulent strains, that have shown simultaneous expression of virulence and carbapenem-resistance genes, posing a treatment challenge.”

Regarding the small numbers of K64 isolates in our study, we have added into the limitation:
“In this study, the relatively small number of K64 isolates provided only limited data about the serotype's convergent virulence and carbapenem resistance. Also, we lack the whole genome sequence data of these K64 isolates for further understanding of the molecular basis of hypervirulence and the phylogenetic positioning of this rare ST within the genomic taxonomy of K. pneumoniae. However, our results led support to the hypothesis that K64 is associated with severe invasive community acquired K. pneumoniae infections, including sepsis and meningitis. In addition, here, only seven capsule types were selected to investigate the diversity of K. pneumoniae isolates. We recognize that this is one of the limitations of our study. Further studies are needed to unravel the mechanisms of virulence of capsule type K64 in K. pneumoniae.”
We would like to thank reviewer for your valuable comments. We have addressed all the reviewers’ comments in the revised manuscript, including with additional information, and responded in the point-to-point rebuttal below. We hope our revisions are adequate and make our manuscript clear and publishable.
Reviewer 1
This paper describes the epidemiology of K64 Klebsiella pneumoniae isolates with a particular focus on K64 from a hospital in Vietnam.
Comment 1: Introduction
"...but K64 capsular have rarely been described in healthy carriers." in the introductory paragraph reads a bit unclearly.
Response: Thank you very much for your comment. We have now revised the sentence in the updated version as below:
“…but carriage of K64 K. pneumoniae in healthy persons has rarely been described.”
Comment 2:
Adding a bit more about the importance of K64 and the differences between classic and hypervirulent types of Klebsiella spp. (as well as how capsules might play a role in this) would better situate the authors' opening argument as to why they are performing this current study.
Response: Thank you very much for your recommendation. We have now included the following sentences in the introduction of the manuscript:
K pneumoniae is classified across two main virulence phenotypes, classical (cKp) and hypervirulent (hvKp). Most K. pneumoniae are associated with uncomplicated community acquired infections and nocosomial infections. However, hvKp results in more severe community – acquired infections with manifestations such as pyogenic liver abscess, meningitis, endophthalmitis, and necrotizing fasciitis. The polysaccharide capsule is perhaps the most well-known virulence factor of K. pneumoniae, including for the hvKp phenotype. The capsule surrounding K. pneumoniae cells can be divided into at least 79 capsular types (K1 to K79), among which K1, K2, and K64 are common serotypes of the MDR-hvKp group, which is commonly found in Asia.
Comment 3: Methods
"302 K. pneumoniae were isolated..." are these all isolates from the hospital during this time period?
Response:
Thank you very much for your question. The total number of isolates from the hospital during this time was 589 isolates; however, because this was a retrospective study, we performed re-culture, and 332/589 isolates were recovered. Of those, 30 isolates had no associated clinical metadata, and were excluded from the study.
We now have clarified this in the manuscript as below:
“From a total of 589 K. pneumoniae that were isolated from patients hospitalized at the National Hospital of Tropical Diseases between 2007 and 2011, 332 isolates were recovered after re-cultivation. Of those, 30 isolates with lacking clinical metadata were excluded, leaving the remaining 302 isolates for downstream analysis.”
Comment 4: Results
I note that ESBL production was determined in Table 2 - please clarify how you determined this in the methods.
Response:
Thank you very much for your comment. We have added the information into the updated version as below:
“A phenotypic confirmatory double-disk test was performed for confirmation of ESBL production using CTX (30 mg) and CAZ (30 mg) disks alone and in combination with CA (10 mg) (Mast Diagnostic a GmbH, Reinfeld, Germany).”
Comment 5: Discussion and conclusion
I think some discussion about the small numbers of K64 isolates would also be helpful in the limitations of the paper. The second paragraph starts off by suggesting K64 has "been little reported so far," but I think the data from China would argue against this.
Response: Thank you for your recommendation.
We agree that data from China would argue against our statement in the second paragraph starts off by suggesting K64 has "been little reported so far,". We now have revised the sentence as below:
“The capsular type K64 has been reported worldwide, especially from clinical settings in Asia, Europe, and North America and is one of the K types associated with hypervirulent strains, that have shown simultaneous expression of virulence and carbapenem-resistance genes, posing a treatment challenge.”

Regarding the small numbers of K64 isolates in our study, we have added into the limitation:
“In this study, the relatively small number of K64 isolates provided only limited data about the serotype's convergent virulence and carbapenem resistance. Also, we lack the whole genome sequence data of these K64 isolates for further understanding of the molecular basis of hypervirulence and the phylogenetic positioning of this rare ST within the genomic taxonomy of K. pneumoniae. However, our results led support to the hypothesis that K64 is associated with severe invasive community acquired K. pneumoniae infections, including sepsis and meningitis. In addition, here, only seven capsule types were selected to investigate the diversity of K. pneumoniae isolates. We recognize that this is one of the limitations of our study. Further studies are needed to unravel the mechanisms of virulence of capsule type K64 in K. pneumoniae.”
Competing Interests: We do not have any competing interests to disclose Close
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John L. Kiley, Brooke Army Medical Center, San Antonio, USA
Frank R. DeLeo, National Institutes of Health, Hamilton, USA
Ning Dong, Zhejiang University School of Medicine, Hangzhou, China
Neris García-González, Instituto de Biomedicina de Valencia (Ringgold ID: 54426), Valencia, Spain

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09 Aug 2025 | for Version 2

Neris García-González, Instituto de Biomedicina de Valencia (Ringgold ID: 54426), Valencia, Valencian Community, Spain

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The conclusion that “Our study confirms that capsule type K64 K. pneumoniae is associated with community-acquired invasive infections in Vietnam” is, in my view, overstated given the data presented. Of the 100 isolates with a successfully determined capsular type, only 11 were K64 (5 from invasive, 2 from commensal samples). This is a very small number, and the application of statistical tests to such low counts does not support a definitive conclusion.

The statement that “K64-ST799 might have acquired a mobile element carrying a carbapenemase gene” is speculative and not backed by molecular data. Without sequencing or resistance gene analysis, this claim should be softened.
The authors tested for only seven capsule types (K1, K2, K5, K20, K54, K57, K64). It’s unclear why these were chosen—are they the most common in Vietnam, or just associated with hvKp globally? This should be clarified, especially since over half of the isolates were untypeable. Without knowing whether additional relevant types were missed, it is difficult to interpret the significance of the K64 frequency.
The invasive isolates were collected between 2007–2011, while the commensal isolates were collected in 2012. The invasive and commensal isolates were collected in different time periods (2007–2011 vs. 2012), which could introduce temporal bias. This limitation should be acknowledged explicitly.

The manuscript requires substantial revision for clarity. Several sentences are difficult to parse, and the structure of some sections hinders comprehension. For example:

The methodology does not clearly explain how the 589 K. pneumoniae isolates were selected. Were these all from invasive infections? If so, and only 49.2% were typeable, a large proportion of relevant invasive capsule types may have been missed. Alternatively, if this set included both invasive and commensal isolates, it would improve the comparison by providing community data from the same time period. This should be clearly stated and clarified in the manuscript.
The distinction between the two datasets (invasive and commensal) is clear in the abstract but not well explained in the main text. I suggest rephrasing to something similar to: “To compare invasive with commensal isolates, we included commensal isolates from a previous study. These were throat swabs from healthy volunteers in rural and urban Hanoi in 2012. …”
The statement: “To ensure that the isolates were from community-acquired infections, we used a time difference of ≥48 hours…” is confusing. Community-acquired infections are typically defined as those occurring within 48 hours of hospital admission. This should be reworded for clarity.

Minor Comments

Define MDR (multidrug-resistant) on first mention.
In Tables 1 and 2, “Overall” column should also have (n, %)
Correct spelling of “nocosomial” to “nosocomial.”

Is the work clearly and accurately presented and does it cite the current literature?

Partly
Is the study design appropriate and is the work technically sound?

Partly
Are sufficient details of methods and analysis provided to allow replication by others?

Yes
If applicable, is the statistical analysis and its interpretation appropriate?

Partly
Are all the source data underlying the results available to ensure full reproducibility?

No source data required
Are the conclusions drawn adequately supported by the results?

Partly

Competing Interests

No competing interests were disclosed.

Reviewer Expertise

microbial genomics

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4 Views

06 Jun 2025 | for Version 2

Ning Dong, Zhejiang University School of Medicine, Hangzhou, China

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Not Approved

Is the work clearly and accurately presented and does it cite the current literature?

Partly
Is the study design appropriate and is the work technically sound?

Yes
Are sufficient details of methods and analysis provided to allow replication by others?

Yes
If applicable, is the statistical analysis and its interpretation appropriate?

Yes
Are all the source data underlying the results available to ensure full reproducibility?

Yes
Are the conclusions drawn adequately supported by the results?

Partly

Competing Interests

No competing interests were disclosed.

Reviewer Expertise

Epidemiology of infectious diseases

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9 Views

28 Jan 2025 | for Version 2

Frank R. DeLeo, Laboratory of Bacteriology, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT, 59840, USA

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Approved

Revised version is appropriate.

Competing Interests

No competing interests were disclosed.

Reviewer Expertise

Bacterial pathogenesis and host defense. Primary focus on Staphylococcus aureus, Klebsiella pneumoniae, and human neutrophil biology.

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.

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18 Views

28 Jun 2024 | for Version 1

Frank R. DeLeo, Laboratory of Bacteriology, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT, 59840, USA

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Approved With Reservations

Please verify numbers of isolates in Table 1 compared with what is stated in the text. By my count, there are 110 commensal isolates (correct in the text) and 94 (stated as 93 in the text) invasive isolates. These numbers are concordant with the sum of the numbers in the Overall column, which total 204 isolates (the text indicates 203). Please verify for accuracy.
It would be optimal to provide text in the Table 1 legend that states what the p-value refers to from a comparison standpoint, and indicate the test used here as well.
I recommend providing the rationale for selecting the seven capsule types used to screen isolates in this study. Why were these seven capsule types chosen among others?
A conclusion of the study is that “capsule type K64 is overrepresented among invasive strains”. In reality there are only seven K64 isolates out of 204 total isolates and only five of these were from invasive disease. This is 5.4% of the total number of invasive isolates and much less than either K1 or K2. In addition, the Conclusion text on the title page states that K64 K. pneumoniae is associated with community-acquired invasive infections in Vietnam.” Please provide the criteria in the Methods section that were used to determine whether an infection is a bona fide community-acquired infection. It would be fair to state that K64 contributes to invasive disease and is among the top three capsule types tested that are associated with invasive infections. However, the term “overrepresented among invasive strains” might best be restated as “there were significantly more capsule type K64 isolates recovered from patients with invasive infections compared to healthy individuals with commensal isolates” or something along those lines.

Is the work clearly and accurately presented and does it cite the current literature?

Partly
Is the study design appropriate and is the work technically sound?

Yes
Are sufficient details of methods and analysis provided to allow replication by others?

Partly
If applicable, is the statistical analysis and its interpretation appropriate?

I cannot comment. A qualified statistician is required.
Are all the source data underlying the results available to ensure full reproducibility?

Partly
Are the conclusions drawn adequately supported by the results?

Partly

Competing Interests

No competing interests were disclosed.

Reviewer Expertise

Bacterial pathogenesis and host defense. Primary focus on Staphylococcus aureus, Klebsiella pneumoniae, and human neutrophil biology.

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35 Views

12 Oct 2021 | for Version 1

John L. Kiley, Brooke Army Medical Center, San Antonio, TX, USA

35 Views Cite this report Responses(1)

Approved With Reservations

This paper describes the epidemiology of K64 Klebsiella pneumoniae isolates with a particular focus on K64 from a hospital in Vietnam.

Introduction

"...but K64 capsular have rarely been described in healthy carriers." in the introductory paragraph reads a bit unclearly.
Adding a bit more about the importance of K64 and the differences between classic and hypervirulent types of Klebsiella spp. (as well as how capsules might play a role in this) would better situate the authors' opening argument as to why they are performing this current study.

Methods

"302 K. pneumoniae were isolated..." are these all isolates from the hospital during this time period?

Results

I note that ESBL production was determined in Table 2 - please clarify how you determined this in the methods.

Discussion and conclusion

I think some discussion about the small numbers of K64 isolates would also be helpful in the limitations of the paper. The second paragraph starts off by suggesting K64 has "been little reported so far," but I think the data from China would argue against this.
- Zhang et al., 2020 reported Chinese epidemiological data on K64¹.
- Walker et al., 2020 for general discussion of hypervirulence and association with capsular type².
- Catalán-Nájera et al., 2017 for hypermucoviscious, hypervirulent differences/discussion³.

Great paper overall!

Is the work clearly and accurately presented and does it cite the current literature?

Partly
Is the study design appropriate and is the work technically sound?

Yes
Are sufficient details of methods and analysis provided to allow replication by others?

Yes
If applicable, is the statistical analysis and its interpretation appropriate?

Yes
Are all the source data underlying the results available to ensure full reproducibility?

Yes
Are the conclusions drawn adequately supported by the results?

Yes

References

Competing Interests

No competing interests were disclosed.

Reviewer Expertise

Multi drug resistant Gram-negative infections

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Author Response

17 Jan 2025

Bich Vu Thi Ngoc, Oxford University Clinical Research Unit - Hanoi, Hanoi, Vietnam

We would like to thank reviewer for your valuable comments. We have addressed all the reviewers’ comments in the revised manuscript, including with additional information, and responded in the point-to-point rebuttal below. We hope our revisions are adequate and make our manuscript clear and publishable.
Reviewer 1
This paper describes the epidemiology of K64 Klebsiella pneumoniae isolates with a particular focus on K64 from a hospital in Vietnam.
Comment 1: Introduction
"...but K64 capsular have rarely been described in healthy carriers." in the introductory paragraph reads a bit unclearly.
Response: Thank you very much for your comment. We have now revised the sentence in the updated version as below:
“…but carriage of K64 K. pneumoniae in healthy persons has rarely been described.”
Comment 2:
Adding a bit more about the importance of K64 and the differences between classic and hypervirulent types of Klebsiella spp. (as well as how capsules might play a role in this) would better situate the authors' opening argument as to why they are performing this current study.
Response: Thank you very much for your recommendation. We have now included the following sentences in the introduction of the manuscript:
K pneumoniae is classified across two main virulence phenotypes, classical (cKp) and hypervirulent (hvKp). Most K. pneumoniae are associated with uncomplicated community acquired infections and nocosomial infections. However, hvKp results in more severe community – acquired infections with manifestations such as pyogenic liver abscess, meningitis, endophthalmitis, and necrotizing fasciitis. The polysaccharide capsule is perhaps the most well-known virulence factor of K. pneumoniae, including for the hvKp phenotype. The capsule surrounding K. pneumoniae cells can be divided into at least 79 capsular types (K1 to K79), among which K1, K2, and K64 are common serotypes of the MDR-hvKp group, which is commonly found in Asia.
Comment 3: Methods
"302 K. pneumoniae were isolated..." are these all isolates from the hospital during this time period?
Response:
Thank you very much for your question. The total number of isolates from the hospital during this time was 589 isolates; however, because this was a retrospective study, we performed re-culture, and 332/589 isolates were recovered. Of those, 30 isolates had no associated clinical metadata, and were excluded from the study.
We now have clarified this in the manuscript as below:
“From a total of 589 K. pneumoniae that were isolated from patients hospitalized at the National Hospital of Tropical Diseases between 2007 and 2011, 332 isolates were recovered after re-cultivation. Of those, 30 isolates with lacking clinical metadata were excluded, leaving the remaining 302 isolates for downstream analysis.”
Comment 4: Results
I note that ESBL production was determined in Table 2 - please clarify how you determined this in the methods.
Response:
Thank you very much for your comment. We have added the information into the updated version as below:
“A phenotypic confirmatory double-disk test was performed for confirmation of ESBL production using CTX (30 mg) and CAZ (30 mg) disks alone and in combination with CA (10 mg) (Mast Diagnostic a GmbH, Reinfeld, Germany).”
Comment 5: Discussion and conclusion
I think some discussion about the small numbers of K64 isolates would also be helpful in the limitations of the paper. The second paragraph starts off by suggesting K64 has "been little reported so far," but I think the data from China would argue against this.
Response: Thank you for your recommendation.
We agree that data from China would argue against our statement in the second paragraph starts off by suggesting K64 has "been little reported so far,". We now have revised the sentence as below:
“The capsular type K64 has been reported worldwide, especially from clinical settings in Asia, Europe, and North America and is one of the K types associated with hypervirulent strains, that have shown simultaneous expression of virulence and carbapenem-resistance genes, posing a treatment challenge.”

Regarding the small numbers of K64 isolates in our study, we have added into the limitation:
“In this study, the relatively small number of K64 isolates provided only limited data about the serotype's convergent virulence and carbapenem resistance. Also, we lack the whole genome sequence data of these K64 isolates for further understanding of the molecular basis of hypervirulence and the phylogenetic positioning of this rare ST within the genomic taxonomy of K. pneumoniae. However, our results led support to the hypothesis that K64 is associated with severe invasive community acquired K. pneumoniae infections, including sepsis and meningitis. In addition, here, only seven capsule types were selected to investigate the diversity of K. pneumoniae isolates. We recognize that this is one of the limitations of our study. Further studies are needed to unravel the mechanisms of virulence of capsule type K64 in K. pneumoniae.”

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Competing Interests

We do not have any competing interests to disclose

Alongside their report, reviewers assign a status to the article:

Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested

Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.

Not approved - fundamental flaws in the paper seriously undermine the findings and conclusions

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Klebsiella pneumoniae with capsule type K64 is overrepresented among invasive disease in Vietnam

Abstract

Introduction

Methods

Results

Conclusion

Keywords

Revised Amendments from Version 1

Introduction

Methods

Klebsiella pneumoniae isolates and antibiotic susceptibility testing

Molecular typing

Ethics statement

Results

Table 1. Clonal complex (CCs) as determined by multi-locus sequence typing (MLST) and distribution of capsular types among invasive isolates and commensal isolates of Klebsiella pneumoniae in Vietnam.

Table 2. Comparison of the proportion of antibiotic resistance between invasive versus commensal Klebsiella pneumoniae isolates in Vietnam.

Discussion and conclusion

Data availability

Underlying data

Consent

References

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