A case of laboratory-acquired Salmonella Typhi infection due to phage typing in Japan: whole-genome sequencing confirms the source of infection
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Introduction. Typhoid fever, caused by Salmonella enterica serovar Typhi, is a systemic infection. Approximately 40 cases occur annually in Japan, most of which are imported. In August 2023, a researcher engaged in phage typing of S . Typhi was diagnosed with typhoid fever.
Case Presentation. A 48-year-old man presented with high fever, diarrhoea, malaise and loss of appetite. Initial findings, including liver dysfunction and severe inflammation, led to a suspected diagnosis of autoimmune disease. However, blood cultures identified S . Typhi, confirming typhoid fever. Comparative genomic analysis demonstrated clonality between the strain handled in the laboratory and the patient isolates, indicating a laboratory-acquired infection.
Conclusion. This case underscores the need for ongoing vigilance regarding the risk of laboratory-acquired infections and highlights the value of whole-genome sequencing for tracking. It would be also emphasized that this is the first reported case in Japan linked to phage typing, a conventional typing method for S . Typhi. This raises the urgency of transitioning from phage typing to genotyping and recommends mandatory typhoid vaccination for laboratory personnel working with S . Typhi to minimize infection risk.
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Thank you for the careful and thoughtful way you have addressed the reviewers’ comments. The revisions have strengthened the clarity and balance of the manuscript, particularly in the interpretation of the antimicrobial susceptibility findings and the genomic analyses. We are pleased to be able to accept this interesting and important case report for publication in Access Microbiology.
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The reviewers have highlighted minor concerns with the work presented. Please ensure that you address their comments.
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Comments to Author
This paper covers a recent case of laboratory acquired typhoid in Japan. The infected individual was diagnosed by a positive blood culture for S. Typhi, alongside a clear clinical report indicating typhoid. The infection was acquired by someone performing a phase typing test, a classical way of typing S. Typhi. Laboratory infection was confirmed using whole genome sequencing of patient and typing samples of S. Typhi linked to a phylogenetic analysis using S. Typhi Ty2 as reference. This analysis clearly indicated a recent laboratory-acquired infection during the typing processing. The paper had already gone through one excellent review and had been amended by the authors. The paper is acceptable aside from one point. The statement 'The results of the antimicrobial 86 susceptibility testing are …
Comments to Author
This paper covers a recent case of laboratory acquired typhoid in Japan. The infected individual was diagnosed by a positive blood culture for S. Typhi, alongside a clear clinical report indicating typhoid. The infection was acquired by someone performing a phase typing test, a classical way of typing S. Typhi. Laboratory infection was confirmed using whole genome sequencing of patient and typing samples of S. Typhi linked to a phylogenetic analysis using S. Typhi Ty2 as reference. This analysis clearly indicated a recent laboratory-acquired infection during the typing processing. The paper had already gone through one excellent review and had been amended by the authors. The paper is acceptable aside from one point. The statement 'The results of the antimicrobial 86 susceptibility testing are summarised in Table 1. This suggests that the relapse was not attributable to 87 antimicrobial resistance but rather to the limited intracellular penetration of ceftriaxone, which may 88 have allowed S. Typhi to persist within host cells. As the S. Typhi clearly harbours mutations in the gyrA gene that contribute to antibiotic resistance this is statement needs revision. It is highly likely that a second mutation influencing drug update is involved but not identified. I would simply replace the statement that a mutation in gyrA (identified in the paper) alongside another likely unidentified mutation are involved in drug resistance. Nothing else is required. Otherwise, very nice paper and a useful contribution to the field.
Please rate the quality of the presentation and structure of the manuscript
Very good
To what extent are the conclusions supported by the data?
Strongly support
Do you have any concerns of possible image manipulation, plagiarism or any other unethical practices?
No
Is there a potential financial or other conflict of interest between yourself and the author(s)?
No
If this manuscript involves human and/or animal work, have the subjects been treated in an ethical manner and the authors complied with the appropriate guidelines?
Yes
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Comments to Author
The manuscript submitted by Morita and colleagues is very engaging and informative. It also serves as an important reminder of the daily occupational risks faced by healthcare workers, as well as the need for enhanced training and stricter implementation of biosafety measures. I believe the manuscript could be further improved by providing more genomic data and a clearer timeline of the events. Lines 79-89: This entire section is confusing, as readers are not able to fully follow the timeline of events. Please clarify how many times the S. Typhi sample was isolated and at which time points antimicrobial susceptibility testing was performed. A flowchart could help summarize the information and improve comprehension for readers. Line 81: Was the patient treated empirically with ceftriaxone, or was this …
Comments to Author
The manuscript submitted by Morita and colleagues is very engaging and informative. It also serves as an important reminder of the daily occupational risks faced by healthcare workers, as well as the need for enhanced training and stricter implementation of biosafety measures. I believe the manuscript could be further improved by providing more genomic data and a clearer timeline of the events. Lines 79-89: This entire section is confusing, as readers are not able to fully follow the timeline of events. Please clarify how many times the S. Typhi sample was isolated and at which time points antimicrobial susceptibility testing was performed. A flowchart could help summarize the information and improve comprehension for readers. Line 81: Was the patient treated empirically with ceftriaxone, or was this therapy guided by drug-susceptibility testing? Lines 84-85: Please write the amino acid substitution appropriately: Serine-83 → Phenylalanine. Also, clarify how this mutation was detected: whole-genome sequencing or PCR amplification followed amplicon sequencing? Considering that the sample was sequenced, the authors could have explored the genomic features of this isolate in greater detail (such as AMR and virulence genes, plasmids, phages, MLST, etc.). This can be easily performed using free web-based tools (e.g., VFAnalyzer, Center for Genomic Epidemiology).
Please rate the quality of the presentation and structure of the manuscript
Good
To what extent are the conclusions supported by the data?
Strongly support
Do you have any concerns of possible image manipulation, plagiarism or any other unethical practices?
No
Is there a potential financial or other conflict of interest between yourself and the author(s)?
No
If this manuscript involves human and/or animal work, have the subjects been treated in an ethical manner and the authors complied with the appropriate guidelines?
Yes
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Thank you for submitting this well-prepared and timely case report describing a laboratory-acquired Salmonella Typhi infection. The manuscript has several notable strengths. The clinical case is described with clarity and sufficient detail, and the use of whole-genome sequencing provides robust evidence of clonality between the patient and laboratory isolates. The emphasis on the risks of phage typing and the need to transition towards genotyping approaches is highly relevant, especially in the context of international shifts toward whole-genome sequencing in public health microbiology. Before this work can be considered further, however, I believe the manuscript would benefit from substantial revision. My initial recommendations are intended to strengthen both the clinical and microbiological insights so that the paper will make the …
Thank you for submitting this well-prepared and timely case report describing a laboratory-acquired Salmonella Typhi infection. The manuscript has several notable strengths. The clinical case is described with clarity and sufficient detail, and the use of whole-genome sequencing provides robust evidence of clonality between the patient and laboratory isolates. The emphasis on the risks of phage typing and the need to transition towards genotyping approaches is highly relevant, especially in the context of international shifts toward whole-genome sequencing in public health microbiology. Before this work can be considered further, however, I believe the manuscript would benefit from substantial revision. My initial recommendations are intended to strengthen both the clinical and microbiological insights so that the paper will make the widest possible contribution. The novelty of this case should be more clearly articulated. Similar events have been documented elsewhere, but this report is important in the Japanese context where phage typing is still used. Making this distinction explicit will help highlight why the case matters and what new lessons it provides. The discussion of exposure risks requires further development. It would be helpful to analyse more closely how transmission could have occurred despite biosafety precautions, including which specific aspects of phage typing procedures are inherently hazardous and how droplets or aerosols may arise. Linking this analysis to published literature on laboratory-acquired infections will allow readers to draw practical lessons for their own laboratory settings. The clinical aspects also deserve greater depth. The relapse following ceftriaxone therapy raises important points for clinical microbiology. Please clarify whether antimicrobial susceptibility testing was performed and whether resistance determinants or virulence factors were identified in the genomic analysis. A short discussion of possible explanations for relapse, including intracellular persistence or gallbladder carriage, would add important clinical context. The recommendation for mandatory vaccination is reasonable but would be stronger if framed against international guidance such as WHO, CDC or ECDC policies, so that readers can understand where this aligns or diverges from global best practice. Likewise, the discussion of transitioning to whole-genome sequencing-based genotyping would benefit from a short consideration of feasibility, costs and implementation in public health laboratories. Finally, the presentation of figures and tables should be refined. The phylogenetic tree would benefit from clearer annotation for non-specialist readers, and the table of isolates should make the implicated laboratory strain more distinct. Reducing some of the repetitive phrasing in the text would also improve readability. Overall, this is a well-written and relevant case report with clear clinical and biosafety implications, but it requires major revision before being suitable for peer review. I strongly encourage you to revise along the lines suggested above. Doing so will strengthen the manuscript considerably and ensure it makes a valuable contribution to the literature on laboratory-acquired infections and microbiological safety.
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