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. 2025 Aug 7;14(1):97.
doi: 10.1186/s13756-025-01614-6.

Incidence, clinical and genomic trends of hospital- and Non-hospital-onset KPC-producing Klebsiella pneumoniae infections before and during the COVID-19 era: a ten-year interrupted time series study

Manuel Recio-Rufián #  1   2   3 , Teresa López-Viñau #  1   2   4 , Víctor Gálvez-Soto  1 , Ángela Cano  1   2   3 , Rafael Ruiz-Montero  1   5 , Belén Gutiérrez-Gutiérrez  2   6   7   8 , Irene Gracia-Ahufinger  1   2   9   10 , Germán Peñalva  2   8   11 , Juan Antonio Marín-Sanz  1 , Miriam Marín-Sanz  1 , David Segorbe  1 , Juan Jesús Pineda-Capitán  12 , Montserrat Muñoz-Rosa  1   2   9 , Cristina Riazzo  1   9 , Federico Giovagnorio  13 , Elisa Ruiz-Arabi  1   3 , José David Torres-Peña  1   14   15 , Juan José Castón  1   2   3 , Isabel Machuca  1   2   3 , Inmaculada Salcedo-Leal  1   5 , Luis Martínez-Martínez  1   2   9   10 , Elena Pérez-Nadales  16   17   18 , Julián Torre-Cisneros  1   2   3   15 ; KLEBMAN study group
Collaborators, Affiliations

Incidence, clinical and genomic trends of hospital- and Non-hospital-onset KPC-producing Klebsiella pneumoniae infections before and during the COVID-19 era: a ten-year interrupted time series study

Manuel Recio-Rufián et al. Antimicrob Resist Infect Control. .

Abstract

Background: Infections caused by KPC-producing Klebsiella pneumoniae (KPC-KP) represent a persistent public health challenge. This prospective study examines ten-year trends, clinical features, and genomic epidemiology of hospital-onset (HOI) and non-hospital-onset (non-HOI, including healthcare-associated [HcAI] and community-acquired [CA]) KPC-KP infections following a 2012 outbreak. We evaluated the impacts of a 2014 antimicrobial stewardship program (ASP) and COVID-19-related infection prevention and control (IPC) measures, with emphasis on hospital-to-community dissemination.

Methods: We analysed a prospective, longitudinal cohort of patients (2012-2022) in a tertiary referral hospital. Interrupted time series and ARIMA models assessed ASP and IPC impacts on incidence density (ID). Cross-correlation analysis explored temporal associations between HOI and non-HOI trends. Whole-genome sequencing and PERMANOVA evaluated the genomic structure of ST512/KPC-3 isolates. Multivariable regression analysed the association between infection type and clinical outcomes.

Results: Among 467 patients, 33.2% had non-HOI (ID 0.53/1,000 admissions/month) and 66.8% HOI (ID 0.30, p = 0.39). Urinary tract infections predominated in non-HOI (52.9%), while bloodstream and respiratory infections were more common in HOI. Incidence density of HOI and non-HOI infections declined significantly following ASP implementation, with a 4-month lag suggesting sequential transmission dynamics. These reductions were maintained during the pandemic. Genomic data confirmed ST512/KPC-3 dominance and hospital-to-community spread, with temporal factors-rather than acquisition type-explaining genetic variation. Adjusted analyses showed similar 30-day mortality and treatment responses across HOI and non-HOI.

Conclusions: ASP and COVID-19 IPC measures contributed to maintaining low KPC-KP incidence. Genomic evidence underscores the role of temporal dynamics and clonal expansion in ST512/KPC-3 dissemination. Non-HOI infections are clinically significant and require targeted, system-wide surveillance and control strategies.

Keywords: Antimicrobial stewardship program (ASP); COVID-19 infection prevention and control (IPC); Community-acquired infections; Genomic epidemiology; Healthcare-associated infections; Hospital-onset infections; Incidence trends; KPC-producing Klebsiella pneumoniae; Multidrug-resistant organisms (MDRO); ST512/KPC-3 clone.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: This study was approved by Reina Sofía University Hospital Institutional Review Board (code HURS-4785), which waived the requirement for written informed consent. Consent for publication: Not applicable. Competing interests: J.T.C. received honoraria for participating in an advisory board and educational activities for Pfizer, MSD and Shionogy, and research grants from Pfizer and MSD. AC received honoraria for participating in educational activities for Pfizer and Angelini. L.M.M. has been a consultant for MSD and Shionogi, has served as speaker for Merck, Astra-Zeneca, Astellas, Fastinov, Menarini and Shionogi and has received research support from Shionogi, Pfizer and MSD. All other authors declare no competing interest.

Figures

Fig. 1
Fig. 1
Study flow diagram. KPC-KP, KPC-producing Klebsiella pneumoniae; HOI, hospital-onset infections; non-HOI, non-hospital-onset infections; HcAI, healthcare-associated infections; CA, community-acquired infections. *Reactivation of a KPC-KP infection within 30 days of the first diagnosis
Fig. 2
Fig. 2
Incidence density (ID) of hospital-onset (HOI) and non-hospital onset (non-HOI) infections before and after implementation of 2014 antimicrobial stewardship program (ASP) and 2020 COVID-19 infection prevention and control measures (IPC, dotted lines)
Fig. 3
Fig. 3
Interrupted time series analysis (ITSA) evaluating the impact of the antimicrobial stewardship program and COVID-19 infection prevention and control measures on the incidence density of KPC-producing Klebsiella pneumoniae infections: A) Non-hospital-onset (non-HOI) and B) hospital-onset (HOI) infections. Data are presented as monthly isolates per 1000 occupied bed days (OBDs). Solid grey line: KPC-KP incidence density time series. Solid black lines: pre-intervention and intervention trends. ASP, Antimicrobial Stewardship Program; IPC, Infection Prevention and Control intervention
Fig. 4
Fig. 4
Temporal signal outweighs acquisition type in genomic clustering of ST512/KPC-3 isolates. A Phylogeny of 315 ST512/KPC-3 K. pneumoniae genomes obtained from community-acquired (CA), healthcare-associated (HcAI) and hospital-onset (HOI) infections. A maximum likelihood phylogenetic tree was generated based on SNPs analysis. Colors indicate the time period of isolation. Numbers refer to individual KPC-KP isolates. B Results of PERMANOVA evaluating the association between cophenetic distances and acquisition type (HOI, HcAI, CA) and year of isolation
See this image and copyright information in PMC

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