dgkh000646 10.3205/dgkh000646 urn:nbn:de:0183-dgkh0006464 Case Report Hinweise auf ambulanten Erwerb einer Carbapenem-resistenten hypervirulenten Klebsiella pneumoniae (CRhvKp) in Deutschland: Fallbericht und Schlussfolgerungen für die Infektionskontrolle Leder Leder Nora Helke NH

Institute for Infectious Diseases and Infection Control, Jena University Hospital, Am Klinikum 1, 07747 Jena, Germany; Phone: +49 (0) 15232187682Institute for Infectious Diseases and Infection Control, Jena University Hospital, Jena, Germany

Nora.leder@med.uni-jena.de author Joean Joean Oana O

Institute for Infectious Diseases and Infection Control, Jena University Hospital, Jena, Germany

author Banz Banz Micha M

Department of Internal Medicine IV (Gastroenterology, Hepatology and Infectious Diseases), Jena University Hospital, Germany

author Stein Stein Claudia C

Institute for Infectious Diseases and Infection Control, Jena University Hospital, Jena, Germany

author Kipp Kipp Frank F

Institute for Infectious Diseases and Infection Control, Jena University Hospital, Jena, Germany

author Rödel Rödel Jürgen J

Institute of Medical Microbiology, Jena University Hospital, Friedrich Schiller University, Jena, Germany

author Trommer Trommer Sabine S

Institute for Infectious Diseases and Infection Control, Jena University Hospital, Jena, Germany

author German Medical Science GMS Publishing House

Düsseldorf

610 hypervirulent Klebsiella pneumoniae infection control carbapenemase multidrug-resistant Gram-negative bacteria hypervirulent Klebsiella pneumoniae Infektionsprävention und -kontrolle Carbapenemase multiresistente gramnegative Bakterien 20260320 engl This is an Open Access article distributed under the terms of the Creative Commons Attribution 4.0 License. Dieser Artikel ist ein Open-Access-Artikel und steht unter den Lizenzbedingungen der Creative Commons Attribution 4.0 License (Namensnennung). 2196-5226 21 GMS Hygiene and Infection Control GMS Hyg Infect Control 37 Ziel: Hypervirulente Klebsiella pneumoniae (hvKp) unterscheiden sich von klassischen Klebsiella pneumoniae-Stämmen durch Virulenzdeterminanten, die schwere invasive Infektionen, auch bei zuvor gesunden Personen, begünstigen. Das zusätzliche Vorliegen einer Carbapenemresistenz (CRhvKp) bei einem Teil dieser Stämme schränkt therapeutische Optionen weiter ein und stellt eine erhebliche klinische Herausforderung im Management der Fälle dar. Nosokomiale Übertragungen von CRhvKp wurden bereits beschrieben, jedoch sind die Übertragungswege sowie die Konsequenzen für das krankenhaushygienische Management bislang unzureichend bekannt. In Deutschland erfolgt in der Routinediagnostik nur selten eine gezielte Identifizierung von hvKp, da die systematische Erfassung entsprechender Virulenzfaktoren in der Regel bisher nicht routinemäßig durchgeführt wird. Außerdem besteht in Deutschland aktuell keine Meldepflicht für hvKp ohne Carbapenemasenachweis.Methoden: In unserer Klinik etablierten wir einen zweistufigen Screening-Ansatz zur routinediagnostischen Detektion von hvKp. Der Workflow kombiniert eine loop-vermittelte isotherme Amplifikation (LAMP) zum Nachweis Hypervirulenz-assoziierter Gene mit anschließenden Ganzgenomsequenzierung (WGS). Eingeschlossen werden alle Carbapenemase-produzierende K. pneumoniae sowie Isolate, bei denen aufgrund ihres Phänotyps oder der klinischen Manifestation ein erhöhtes Risiko für hvKp besteht.Ergebnisse: Ein 1973 geborener Mann mit bekannter Child-Pugh-B-Leberzirrhose stellte sich mit infektgetriggertem akutem Leberversagen und Aszites vor. Der Patient hatte keine kürzlichen Auslandsreisen unternommen, jedoch mehrfach stationäre Aufenthalte in Thüringer Kliniken. Der bei einer Parazentese gewonnene Aszites erwies sich als eitrig; im Rahmen der mikrobiologischen Diagnostik wurde Escherichia coli mit ESBL- und Fluorchinolonresistenz isoliert. Zusätzlich zeigte die Diagnostik eine Infektion der unteren Harnwege durch eine CRhvKp. Diese Infektion wurde als ambulant erworben eingestuft, der genaue Übertragungsweg des Erregers ließ sich nicht bestimmen. Das Isolat gehörte zum Sequenztyp 147 (ST). Mit Hilfe der Ganzgenomsequenzierung konnten die Resistenzgene blaNDM-5 und blaOXA-48 nachgewiesen werden. Der Patient wurde über 14 d mit Cefiderocol (Fetcroja, Shionogi & Co. Ltd.) behandelt. Die für Patienten mit Carbapenem-resistenten Enterobacterales vorgesehenen Infektionspräventionsmaßnahmen wurden umgesetzt. In unserer routinemäßigen WGS-basierten Surveillance ergaben sich keine Hinweise auf eine nosokomiale Übertragung dieses Bakterienklons.Schlussfolgerung: CRhvKp kann bei Patienten ohne epidemiologische oder klinische Risikofaktoren nachgewiesen werden, was auf ein breiteres Reservoir als bisher angenommen hinweist. Weitere Untersuchungen zur Prävalenz, Übertragbarkeit, Umweltpersistenz und Kolonisationsdynamik von CRhvKp-Stämmen sind dringend erforderlich, um ihre Bedeutung für die Krankenhaushygiene und Infektionsprävention in Deutschland fundiert bewerten und nachfolgend erforderliche Präventionsmaßnahmen ableiten zu können. Aim: Hypervirulent Klebsiella pneumoniae (hvKp) has emerged as a disease threat due to a higher morbidity and mortality associated with specific virulence genes. The acquisition of carbapenem-resistance (CRhvKp) in some strains limits treatment options, posing a serious clinical challenge. While healthcare-associated transmissions have been reported, the epidemiological dynamics and infection prevention implications of CRhvKp remain insufficiently elucidated. In Germany, routine diagnostics for Gram-negative pathogens rarely include specific identification of hvKp or systematic detection of its virulence markers, and there is no mandatory notification of CRhvKp cases.Methods: We established a two-step screening approach for the routine diagnostic detection of hvKp, combining loop-mediated isothermal amplification (LAMP) with confimatory whole-genome sequencing (WGS). This workflow was applied to all carbapenemase producing K. pneumoniae and to clinical isolates considered at increased risk for hvKp.Results: We report the case of a 1973-born male patient with a history of Child-Pugh class B cirrhosis who was admitted due to acute liver failure and ascites triggered by infection. The patient had no recent travel history but had been recently admitted to local hospitals in Thuringia, Germany. Ascitic fluid obtained by paracentesis appeared putrid and yielded an ESBL-producing and fluoroquinolone-resistant Escherichia coli. In addition, a lower urinary tract infection due to CRhvKp was identified. The CRhvKp infection was deemed community-acquired, with the route of acquisition remaining unknown. The isolate belonged to ST147 and carried the blaNDM-5 and blaOXA-48 carbapenemase genes. The patient was successfully treated with cefiderocol (Fetcroja, Shionogi & Co. Ltd.) over the course of 14 days. Standard infection prevention precautions for patients with carbapenem-resistant Enterobacterales were applied. No intra-hospital transmission of this strain was detected in our routine WGS-based surveillance. Conclusion: CRhvKp can occur in patients without establishes epidemiological or clinical risk factors, suggesting a broader reservoir than currently assumed. Further research regarding prevalence, transmissibility, environmental persistence, and colonization dynamics of CRhvKp strains are urgently needed to determine their implications for infection prevention and control in hospitals in Germany. IntroductionHypervirulent Klebsiella pneumoniae (hvKp) can cause severe infections in previously healthy individuals, including pyogenic liver abscesses, meningitis, and disseminated infections with metastatic spread. In contrast, classical Klebsiella pneumoniae (cKp) predominantly causes healthcare-associated infections in multimorbid patients .Although no universally accepted definition of hvKp exists, it is most commonly characterized by the presence of genes encoding for capsular polysaccharides (rmpA, rmpA2), leading to a hypermucoviscous phenotype, and siderophore systems (iro, iuc, ybt) that enhance the iron uptake , , . The Kleborate scoring system estimates the combined effect of possible biomarker parings between the siderophores aerobactin (Iuc) and salmochelin (Iro), capsular polysaccharides (rmpA, rmpA2) and the genotoxin colibactin (Clb) to anticipate the virulence of K. pneumoniae isolates in a virulence score from 1 to 5. This scoring system takes into account existing evidence and was created to estimate the virulence of any Klebsiella isolate regardless of the presence of resistance determinants . Rödel et al. selected rmpA/A2, iuC, iroC, ybt, clb, in reference to the Kleborate virulence score to detect hvKp isolates. Wahl et al. suggest clinical manifestation and hypermucoviscious phenotype in combination with a Kleborate score >3 or the presence of iuC, ybt and rmpA or rmpA2 as definition for hvKp. Russo et al. proposed a set of biomarkers for K. pneumoniae with acquired resistance, comprising of iucA, rmpA, rmpA2, peg-344 and iroB, which are linked to the canonical pLVPK virulence plasmid. HvKp strains were first identified in the Asian and Pacific region and have since been reported worldwide . In endemic areas like China, hvKp might replace cKp as dominant pathogen in hospital settings . Globally, sequence type (ST) 23, ST65, and ST86 are among the most frequently detected hvKp lineages . Although hvKp infections remain less frequently reported in Europe than in endemic regions, sporadic cases and small outbreaks suggest that its true prevalence may be underestimated, partly due to limited diagnostic capabilities and awareness.Hypervirulence and multidrug resistance have historically rarely co-occurred in K. pneumoniae. Their combination in carbapenem-resistant hvKp (CRhvKp) is therefore of particular concern, as it unites the ability to cause severe, invasive disease with severely limited treatment options. The gain of carbapenem-resistance in hvKp is often due to the acquisition of plasmids carrying carbapenemase genes , . In a rapid risk assessment, the European Centre for Disease Prevention and Control (ECDC) reported an increase in reports of CRhvKp ST23 in Europe and highlighted the importance of timely detection of CRhvKp as well as the importance of infection prevention measures to mitigate further spread . Sequence types described in Europe are ST11, ST147, and ST395, but due to the lack in mandatory reporting the dissemination of these strains in Europe cannot fully be evaluated , . In Germany, CRhvKp of ST147, ST395 and ST231 have been documented . Due to the absence of national surveillance data, to date the prevalence of CRhvKp in Germany remains unknown.The absence of standardized diagnostic methods remains a major factor for the current lack of reliable surveillance data on hvKp . Furthermore, no internationally standardized gene panel exists for hvKp detection; current approaches rely on varying sets of virulence-associated genes proposed by different research groups. The gold standard is to confirm the hypervirulent phenotype in infection models, such as in vivo mouse models, which are reported to have the highest accuracy for hvKp detection . However, these approaches are time-consuming and not feasible in a routine microbiology setting. While a positive string test to assess for hypermucoviscous phenotype is an easy to employ screening tool, the phenomenon is not present across all hvKp isolates, rendering it insufficient as a standalone diagnostic method and therefore not sensitive enough as sole detection method of hvKp , . Molecular methods like polymerase chain reaction (PCR) and loop-mediated isothermal amplification-based methods (LAMP) enable the detection of predefined virulence genes , but they are inherently limited to the selected genetic targets. In contrast, whole genome sequencing (WGS) provides a comprehensive, target-independent analysis of virulence and resistance determinants, supports retrospective genomic investigation, and allows assessment of transmission events, which offers valuable insights from an infection prevention perspective .Reports of healthcare associated transmissions of both hvKp and CRhvKp underline the need to better understand their transmission dynamics in healthcare settings. Whether the presence of virulence determinants in hvKp or CR-hvKp increases their potential for patient-to-patient spread remains unclear. Notably, a recent study identified disinfectant resistance genes in hvKp isolates , raising additional concerns regarding their persistence in the healthcare environment. Despite these observations, the infection prevention and control implications of CRhvKp remain insufficiently elucidated .Neither current guidelines for carbapenemase-producing Enterobacterales (CPE) nor evidence-based recommendations address the specific infection prevention needs of hvKp or CRhvKp, leaving institutions to adapt infection prevention strategies on a case-by-case basis. Here, we report a case of CRhvKp identified in a patient without classical risk factors, illustrating the diagnostic challenges and infection prevention considerations associated with this emerging pathogen. Case descriptionWe report the case of a 1973-born male who was referred to our tertiary care university hospital with decompensated alcoholic liver cirrhosis and recurrent massive ascites. His past medical history included chronic pancreatitis, arterial hypertension, and diabetes mellitus. In the months preceding the current admission, the patient underwent multiple hospitalizations in various facilities across Thuringia, Germany, due to recurrent cirrhotic decompensations. In one of these admissions, a rectal colonization and subsequent bloodstream infection with meropenem-resistant K. pneumoniae as well as a rectal colonization with extended-spectrum β-lactamase (ESBL)-producing Escherichia (E.) coli was reported. The patient was admitted to our hospital before, but in previous admissions, no multi-drug-resistant organisms (MDRO) were detected and the patient did not have contact to patients with known carriage of MDRO. The patient hadn’t travelled outside Germany in the past years. On admission, he presented with abdominal pain, nausea, fatigue, and dysuria. Abdominal ultrasonography and computed tomography revealed septated ascites; paracentesis yielded purulent from which an ESBL-producing and fluoroquinolone-resistant E. coli was isolated. Empiric treatment with meropenem (Hikma Pharmaceuticals, 1 g three times daily) and linezolid (Panpharma, 600 mg twice daily) for five days was initiated, as a hospital-acquired infection was suspected in light of his recent hospitalizations. Given the additional suspicion of a urinary tract infection, urine samples revealed a white blood cell (WBC) count of 4,799 per µl. Culturing yielded a carbapenem-resistant K. pneumoniae with a count of 100,000 colony-forming units per milliliter. In our hospital, we established a workflow for the detection of hvKp. This workflow included isolates with carbapenemase production, isolates from invasive deep tissue infections, periprosthetic infections, abscesses, meningitis, otitis and ocular infections, as well as isolates exhibiting a distinctive morphology combined with a positive string test. The two-stepped approach includes a loop-mediated isothermal amplification (LAMP)-based screening for hypervirulence-associated genes rmpA/A2, iuC, iroC, ybt, clb using the IVDR-approved eazyplex® hvKp (AmplexDiagnostics, Gars-Bahnhof, Germany) with subsequent whole genome sequencing (WGS) as previously described for genomic surveillance. In addition to hvKp, our genomic surveillance includes all carbapenemase-producing Enterobacterales detected in our hospital.The K. pneumoniae isolate belonged to ST147. Molecular testing confirmed the presence of hypervirulence-associated genes iucA, iucB, iuC, iucB and ybt. The isolate scored 4 points in the Kleborate Virulence-Score. The strain carried both blaNDM-5 and blaOXA-48 carbapenemases genes. Based on these findings, antibiotic therapy was switched to cefiderocol (Fetcroja, Shionogi & Co. Ltd.) for 14 days.In accordance with national recommendations for the management of carbapenem-resistant organisms , the patient was isolated in a single room for the entire hospital stay, with healthcare personal adhering to personal protective equipment protocols, and a thorough terminal disinfecting cleaning protocol for the patient´s room after discharge was conducted. To date, no genomically related isolates were detected during or after his hospitalization in our routine WGS-based molecular surveillance. DiscussionHere, we presented the case of CRhvKp-detection in a patient without recent travel to regions where CRhvKp is considered endemic. The isolate carried two out of five biomarkers selected for our LAMP-based screening, namely iuC (aerobactin) and ybt (yersiniabactin) . The cooccurrence of aerobactin and yersiniabactin has repeatedly been identified as key constellation in isolates with suspected hypervirulence , and corresponds with a high level of suspected virulence in the Kleborate score . Contrarily, rmpA/rmpA2 were not detected. Although these genes are included in several diagnostic panels for hvKp, none of the commonly used frameworks define rmpA/rmpA2 or the associated hypermucoviscousity phenotype as mandatory criteria for hvKp classification , , . Application of the biomarker set published by Russo predicted a low probability of hypervirulence . These contradicting assessments highlight the ongoing lack of consensus regarding molecular definitions of hvKp. The criteria for hvKp proposed by Wahl et al. advocate for a nuanced expert assessment of isolates and emphasize the combination of molecular biomarkers, phenotypical characteristics and the clinical presentation. Notably, the isolate presented in this case study was recovered from a clinically relevant specimen in the context of infection. The patient also previously experienced a bloodstream infection caused by a carbapenem-resistant K. pneumoniae, however, due to the absence of molecular characterization of that isolate, it remains unclear whether both episodes were caused by the same strain or shared virulence or resistance determinants. In evaluation of the detected biomarkers and the clinical presentation, we opted to prioritize the Kleborate score and assessed the isolate as CRhvKp.The suspected urinary tract infection caused by the CRhvKp was successfully treated with cefiderocol, which is recommended for infections caused by carbapenem-resistant Gram-negative bacteria , . However, cases of cefiderocol resistance in CRhvKp have been reported . In a recent in vitro study, CRhvKp isolates had a higher siderophore production compared to carbapenem-resistant K. pneumoniae lacking hypervirulence traits, potentially reducing cefiderocol susceptibility . Further studies are needed to clarify the effect of siderophore-mediated virulence on the clinical effectiveness of cefiderocol in treating CRhvKp infections. While an antibiotic treatment was initialized, asymptomatic bacteriuria in combination with abdominal pain and dysuria caused by the ascites could not be excluded for this patient. Despite the detection of CRhvKp, the indication for treatment has to be evaluated thoroughly to avoid overtreatment for the patient and reduce the selective pressure. From an antimicrobial stewardship and infection prevention perspective, expert clinical consultation is essential to avoid relying solely on scoring systems such as the Kleborate score. Rather, therapeutic decisions should be guided primarily by the patient’s clinical presentation. Infection prevention measures were applied due to the isolate’s carbapenem resistance. Further research needs to investigate, if infection prevention measures established for CPOs should also be applied to carbapenem-susceptible hvKp. Environmental sampling of the patient’s room was not performed in this case. However, K. pneumoniae can persist on surfaces for several weeks and carbapenem-resistant K. pneumoniae from biofilm reservoirs has recently been described as sources of hospital-associated transmission . Further studies need to investigate the role of the hypervirulence-associated genes in persistence, replication capacity and transmissibility of hvKp.In our case report, the CRhvKp isolate was classified as community-acquired, but the route of acquisition could not be determined and acquisition during previous hospital admissions to another regional hospital cannot be ruled out. The isolate belonged to ST147, which has also recently been reported in Ukraine , the UK , Italy and Ghana . Given the patient’s history, a recent acquisition from an endemic region appears unlikely. Alternatively, undetected acquisition within the German healthcare system is conceivable. While CRhvKp strains have occasionally been reported in Germany , the absence of standardized detection methods and mandatory reporting hampers an accurate assessment of their spread.With our two-stepped approach, we established a structured workflow within routine diagnostics aimed at systematically identifying a high proportion of hvKp isolates in our hospital. The LAMP-based screening enabled rapid identification of hvKp-associated gene loci to support clinical decisions, while the WGS-based surveillance enabled comprehensive assessment of the virulence and resistance gene repertoire and enables prospective monitoring of the molecular epidemiology and potential intrahospital transmission events. A multistep approach combining string test, PCR with magA, iutA, rmpA and rmpA2 as targets, together with WGS, was previously demonstrated as a viable way to detect hvKp in a study from Neumann et al. . While a PCR-based-screening offers fast detection of the targets, the absence of a universal definition of hvKp-associated genes limits broader implementation. Heiden et al. used WGS to thoroughly characterize virulence genes of CRhvKp in combination with experiments for phenotypic assays such as biofilm formation, hypermucoviscosity, and siderophore secretion in an outbreak setting in a German hospital . Dogan et al. combined WGS with in vivo infection models to characterize the virulence of hvKp isolates. While such approaches provide comprehensive insights into pathogenicity, they are not feasible for routine diagnostics due to their high workload, complexity, and long turnaround times. Non-resistant hvKp strains are not systematically captured through our surveillance program. Instead, our workflow follows a cost- and workload-effective approach by only screening K. pneumoniae isolates from invasive deep tissue infections, periprosthetic infections, abscesses, meningitis, otitis and ocular infections, as well as isolates harbouring carbapenemase genes, rather than screening all K. pneumoniae isolates for hypervirulence. Consequently, the diagnostic yield of our workflow depends on which K. pneumoniae isolates are selected for inclusion in the diagnostic pathway. Our approach offers broader genomic resolution than PCR-based methods and is more feasible for routine diagnostics than in vivo model–based workflows. ConclusionsThe presented case demonstrates CRhvKp-detection in a patient without travel to endemic regions, suggesting a broader reservoir than currently anticipated. It highlights the diagnostic and infection prevention challenges posed by CRhvKp and illustrates the value of incorporating structured hypervirulence screening and genomic surveillance into routine workflows. Such an approach enables rapid identification in combination with prospective molecular surveillance needed to guide local infection prevention measures in the absence of national or international guidance. Further research on CRhvKp, especially regarding prevalence, transmissibility, environmental persistence, and colonization dynamics of CRhvKp strains are urgently needed to determine the infection prevention implications of CRhvKp in Germany to guide a larger scale public health response.Given the lack of a universally accepted molecular definition of hvKp and the resulting diagnostic uncertainty, close interdisciplinary collaboration between clinical microbiology, infectious diseases, infection prevention and control, and genomic epidemiology is essential to ensure appropriate interpretation of results and to translate molecular findings into proportionate clinical and infection control actions. NotesCompeting interestsThe authors declare that they have no competing interests.Authors’ ORCIDs Leder NH: https://orcid.org/0009-0005-1465-1853Joean O: https://orcid.org/0000-0002-5995-4605Banz M: https://orcid.org/0000-0001-8813-5388Stein C: https://orcid.org/0000-0002-5899-3485Kipp F: https://orcid.org/0009-0006-3360-489XTrommer S: https://orcid.org/0009-0007-2482-1398FundingNone. Gonzalez-Ferrer S Peñaloza HF Budnick JA Bain WG Nordstrom HR Lee JS Van Tyne D Finding Order in the Chaos: Outstanding Questions in Klebsiella pneumoniae Pathogenesis 2021 Infect Immun Gonzalez-Ferrer S, Peñaloza HF, Budnick JA, Bain WG, Nordstrom HR, Lee JS, Van Tyne D. Finding Order in the Chaos: Outstanding Questions in Klebsiella pneumoniae Pathogenesis. Infect Immun. 2021 Mar;89(4):. DOI: 10.1128/IAI.00693-20 https://doi.org/10.1128/IAI.00693-20 Rödel J Pfeifer Y Fischer MA Edel B Stoll S Pfister W Löffler B Screening of Isolates for Carbapenemase and Hypervirulence-Associated Genes by Combining the Eazyplex Superbug CRE and hvKp Assays 2023 Antibiotics (Basel) Rödel J, Pfeifer Y, Fischer MA, Edel B, Stoll S, Pfister W, Löffler B. Screening of Isolates for Carbapenemase and Hypervirulence-Associated Genes by Combining the Eazyplex Superbug CRE and hvKp Assays. Antibiotics (Basel). 2023 May;12(6):. DOI: 10.3390/antibiotics12060959 https://doi.org/10.3390/antibiotics12060959 Lei TY Liao BB Yang LR Wang Y Chen XB Hypervirulent and carbapenem-resistant Klebsiella pneumoniae: A global public health threat 2024 Microbiol Res 127839 Lei TY, Liao BB, Yang LR, Wang Y, Chen XB. Hypervirulent and carbapenem-resistant Klebsiella pneumoniae: A global public health threat. Microbiol Res. 2024 Nov;288:127839. DOI: 10.1016/j.micres.2024.127839 https://doi.org/10.1016/j.micres.2024.127839 Shon AS Bajwa RP Russo TA Hypervirulent (hypermucoviscous) Klebsiella pneumoniae: a new and dangerous breed 2013 Virulence 107-18 Shon AS, Bajwa RP, Russo TA. Hypervirulent (hypermucoviscous) Klebsiella pneumoniae: a new and dangerous breed. Virulence. 2013 Feb;4(2):107-18. DOI: 10.4161/viru.22718 https://doi.org/10.4161/viru.22718 Lam MMC Wick RR Watts SC Cerdeira LT Wyres KL Holt KE A genomic surveillance framework and genotyping tool for Klebsiella pneumoniae and its related species complex 2021 Nat Commun 4188 Lam MMC, Wick RR, Watts SC, Cerdeira LT, Wyres KL, Holt KE. A genomic surveillance framework and genotyping tool for Klebsiella pneumoniae and its related species complex. Nat Commun. 2021 Jul;12(1):4188. DOI: 10.1038/s41467-021-24448-3 https://doi.org/10.1038/s41467-021-24448-3 Wahl A Fischer MA Klaper K Müller A Borgmann S Friesen J Hunfeld KP Ilmberger A Kolbe-Busch S Kresken M Lippmann N Lübbert C Marschner M Neumann B Pfennigwerth N Probst-Kepper M Rödel J Schulze MH Zautner AE Werner G Pfeifer Y Presence of hypervirulence-associated determinants in Klebsiella pneumoniae from hospitalised patients in Germany 2024 Int J Med Microbiol 151601 Wahl A, Fischer MA, Klaper K, Müller A, Borgmann S, Friesen J, Hunfeld KP, Ilmberger A, Kolbe-Busch S, Kresken M, Lippmann N, Lübbert C, Marschner M, Neumann B, Pfennigwerth N, Probst-Kepper M, Rödel J, Schulze MH, Zautner AE, Werner G, Pfeifer Y. Presence of hypervirulence-associated determinants in Klebsiella pneumoniae from hospitalised patients in Germany. Int J Med Microbiol. 2024 Mar;314:151601. DOI: 10.1016/j.ijmm.2024.151601 https://doi.org/10.1016/j.ijmm.2024.151601 Russo TA Alvarado CL Davies CJ Drayer ZJ Carlino-MacDonald U Hutson A Luo TL Martin MJ Corey BW Moser KA Rasheed JK Halpin AL McGann PT Lebreton F Differentiation of hypervirulent and classical with acquired drug resistance 2024 mBio e0286723 Russo TA, Alvarado CL, Davies CJ, Drayer ZJ, Carlino-MacDonald U, Hutson A, Luo TL, Martin MJ, Corey BW, Moser KA, Rasheed JK, Halpin AL, McGann PT, Lebreton F. Differentiation of hypervirulent and classical with acquired drug resistance. mBio. 2024 Feb;15(2):e0286723. DOI: 10.1128/mbio.02867-23 https://doi.org/10.1128/mbio.02867-23 Spadar A Perdigão J Campino S Clark TG Large-scale genomic analysis of global Klebsiella pneumoniae plasmids reveals multiple simultaneous clusters of carbapenem-resistant hypervirulent strains 2023 Genome Med 3 Spadar A, Perdigão J, Campino S, Clark TG. Large-scale genomic analysis of global Klebsiella pneumoniae plasmids reveals multiple simultaneous clusters of carbapenem-resistant hypervirulent strains. Genome Med. 2023 Jan;15(1):3. DOI: 10.1186/s13073-023-01153-y https://doi.org/10.1186/s13073-023-01153-y Liu C Du P Xiao N Ji F Russo TA Guo J Hypervirulent is emerging as an increasingly prevalent pathotype responsible for nosocomial and healthcare-associated infections in Beijing, China 2020 Virulence 1215-1224 Liu C, Du P, Xiao N, Ji F, Russo TA, Guo J. Hypervirulent is emerging as an increasingly prevalent pathotype responsible for nosocomial and healthcare-associated infections in Beijing, China. Virulence. 2020 Dec;11(1):1215-1224. DOI: 10.1080/21505594.2020.1809322 https://doi.org/10.1080/21505594.2020.1809322 Al Ismail D Campos-Madueno EI Donà V Endimiani A Hypervirulent (hv): Overview, Epidemiology, and Laboratory Detection 2024 Pathog Immun 80-119 Al Ismail D, Campos-Madueno EI, Donà V, Endimiani A. Hypervirulent (hv): Overview, Epidemiology, and Laboratory Detection. Pathog Immun. 2024;10(1):80-119. DOI: 10.20411/pai.v10i1.777 https://doi.org/10.20411/pai.v10i1.777 European Centre for Disease Prevention and Control 2021 Emergence of hypervirulent Klebsiella pneumoniae ST23 carrying carbapenemase genes in EU/EEA countries, 17 March 2021 European Centre for Disease Prevention and Control. Emergence of hypervirulent Klebsiella pneumoniae ST23 carrying carbapenemase genes in EU/EEA countries, 17 March 2021. ECDC: Stockholm; 2021. Available from: https://www.ecdc.europa.eu/en/publications-data/risk-assessment-emergence-hypervirulent-klebsiella-pneumoniae-eu-eea https://www.ecdc.europa.eu/en/publications-data/risk-assessment-emergence-hypervirulent-klebsiella-pneumoniae-eu-eea Turton J Davies F Turton J Perry C Payne Z Pike R Hybrid Resistance and Virulence Plasmids in "High-Risk" Clones of, Including Those Carrying 2019 Microorganisms Turton J, Davies F, Turton J, Perry C, Payne Z, Pike R. Hybrid Resistance and Virulence Plasmids in "High-Risk" Clones of, Including Those Carrying. Microorganisms. 2019 Sep;7(9):. DOI: 10.3390/microorganisms7090326 https://doi.org/10.3390/microorganisms7090326 Sattler J Ernst CM Zweigner J Hamprecht A High frequency of acquired virulence factors in carbapenemase-producing isolates from a large German university hospital, 2013-2021 2024 Antimicrob Agents Chemother e0060224 Sattler J, Ernst CM, Zweigner J, Hamprecht A. High frequency of acquired virulence factors in carbapenemase-producing isolates from a large German university hospital, 2013-2021. Antimicrob Agents Chemother. 2024 Nov;68(11):e0060224. DOI: 10.1128/aac.00602-24 https://doi.org/10.1128/aac.00602-24 Shi Q Lan P Huang D Hua X Jiang Y Zhou J Yu Y Diversity of virulence level phenotype of hypervirulent Klebsiella pneumoniae from different sequence type lineage 2018 BMC Microbiol 94 Shi Q, Lan P, Huang D, Hua X, Jiang Y, Zhou J, Yu Y. Diversity of virulence level phenotype of hypervirulent Klebsiella pneumoniae from different sequence type lineage. BMC Microbiol. 2018 Aug;18(1):94. DOI: 10.1186/s12866-018-1236-2 https://doi.org/10.1186/s12866-018-1236-2 Russo TA Olson R Fang CT Stoesser N Miller M MacDonald U Hutson A Barker JH La Hoz RM Johnson JR Identification of Biomarkers for Differentiation of Hypervirulent Klebsiella pneumoniae from Classical K. pneumoniae 2018 J Clin Microbiol Russo TA, Olson R, Fang CT, Stoesser N, Miller M, MacDonald U, Hutson A, Barker JH, La Hoz RM, Johnson JR. Identification of Biomarkers for Differentiation of Hypervirulent Klebsiella pneumoniae from Classical K. pneumoniae. J Clin Microbiol. 2018 Sep;56(9):. DOI: 10.1128/JCM.00776-18 https://doi.org/10.1128/JCM.00776-18 Quainoo S Coolen JPM van Hijum SAFT Huynen MA Melchers WJG van Schaik W Wertheim HFL Whole-Genome Sequencing of Bacterial Pathogens: the Future of Nosocomial Outbreak Analysis 2017 Clin Microbiol Rev 1015-1063 Quainoo S, Coolen JPM, van Hijum SAFT, Huynen MA, Melchers WJG, van Schaik W, Wertheim HFL. Whole-Genome Sequencing of Bacterial Pathogens: the Future of Nosocomial Outbreak Analysis. Clin Microbiol Rev. 2017 Oct;30(4):1015-1063. DOI: 10.1128/CMR.00016-17 https://doi.org/10.1128/CMR.00016-17 Brennan C DeLappe N Cormican M Tuohy A Tobin A Moran L Doyle M Fielding C A geographic cluster of healthcare-associated carbapenemase-producing hypervirulent Klebsiella pneumoniae sequence type 23 2022 Eur J Clin Microbiol Infect Dis Brennan C, DeLappe N, Cormican M, Tuohy A, Tobin A, Moran L, Doyle M, Fielding C. A geographic cluster of healthcare-associated carbapenemase-producing hypervirulent Klebsiella pneumoniae sequence type 23. Eur J Clin Microbiol Infect Dis. 2022 Dec;:. DOI: 10.1007/s10096-022-04535-z https://doi.org/10.1007/s10096-022-04535-z Jin Z Wang Z Gong L Yi L Liu N Luo L Gong W Molecular epidemiological characteristics of carbapenem-resistant Klebsiella pneumoniae among children in China 2022 AMB Express 89 Jin Z, Wang Z, Gong L, Yi L, Liu N, Luo L, Gong W. Molecular epidemiological characteristics of carbapenem-resistant Klebsiella pneumoniae among children in China. AMB Express. 2022 Jul;12(1):89. DOI: 10.1186/s13568-022-01437-3 https://doi.org/10.1186/s13568-022-01437-3 Russo TA Marr CM Hypervirulent Klebsiella pneumoniae 2019 Clin Microbiol Rev Russo TA, Marr CM. Hypervirulent Klebsiella pneumoniae. Clin Microbiol Rev. 2019 Jun;32(3):. DOI: 10.1128/CMR.00001-19 https://doi.org/10.1128/CMR.00001-19 Mellmann A Bletz S Böking T Kipp F Becker K Schultes A Prior K Harmsen D Real-Time Genome Sequencing of Resistant Bacteria Provides Precision Infection Control in an Institutional Setting 2016 J Clin Microbiol 2874-2881 Mellmann A, Bletz S, Böking T, Kipp F, Becker K, Schultes A, Prior K, Harmsen D. Real-Time Genome Sequencing of Resistant Bacteria Provides Precision Infection Control in an Institutional Setting. J Clin Microbiol. 2016 Dec;54(12):2874-2881. DOI: 10.1128/JCM.00790-16 https://doi.org/10.1128/JCM.00790-16 Anonym Hygienemaßnahmen bei Infektionen oder Besiedlung mit multiresistenten gramnegativen Stäbchen. Empfehlung der Kommission für Kranken-haushygiene und Infektionsprävention (KRINKO) beim Robert Koch-Institut (RKI) 2012 Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 1311-54 Hygienemaßnahmen bei Infektionen oder Besiedlung mit multiresistenten gramnegativen Stäbchen. Empfehlung der Kommission für Kranken-haushygiene und Infektionsprävention (KRINKO) beim Robert Koch-Institut (RKI) [Hygiene measures for infection or colonization with multidrug-resistant gram-negative bacilli. Commission recommendation for hospital hygiene and infection prevention (KRINKO) at the Robert Koch Institute (RKI)]. Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz. 2012 Oct;55(10):1311-54. DOI: 10.1007/s00103-012-1549-5 https://doi.org/10.1007/s00103-012-1549-5 Bassetti M Echols R Matsunaga Y Ariyasu M Doi Y Ferrer R Lodise TP Naas T Niki Y Paterson DL Portsmouth S Torre-Cisneros J Toyoizumi K Wunderink RG Nagata TD Efficacy and safety of cefiderocol or best available therapy for the treatment of serious infections caused by carbapenem-resistant Gram-negative bacteria (CREDIBLE-CR): a randomised, open-label, multicentre, pathogen-focused, descriptive, phase 3 trial 2021 Lancet Infect Dis 226-240 Bassetti M, Echols R, Matsunaga Y, Ariyasu M, Doi Y, Ferrer R, Lodise TP, Naas T, Niki Y, Paterson DL, Portsmouth S, Torre-Cisneros J, Toyoizumi K, Wunderink RG, Nagata TD. Efficacy and safety of cefiderocol or best available therapy for the treatment of serious infections caused by carbapenem-resistant Gram-negative bacteria (CREDIBLE-CR): a randomised, open-label, multicentre, pathogen-focused, descriptive, phase 3 trial. Lancet Infect Dis. 2021 Feb;21(2):226-240. DOI: 10.1016/S1473-3099(20)30796-9 https://doi.org/10.1016/S1473-3099(20)30796-9 Candel FJ Santerre Henriksen A Longshaw C Yamano Y Oliver A In vitro activity of the novel siderophore cephalosporin, cefiderocol, in Gram-negative pathogens in Europe by site of infection 2022 Clin Microbiol Infect 447.e1-447 Candel FJ, Santerre Henriksen A, Longshaw C, Yamano Y, Oliver A. In vitro activity of the novel siderophore cephalosporin, cefiderocol, in Gram-negative pathogens in Europe by site of infection. Clin Microbiol Infect. 2022 Mar;28(3):447.e1-447.e6. DOI: 10.1016/j.cmi.2021.07.018 https://doi.org/10.1016/j.cmi.2021.07.018 Zhao J Pu D Li Z Liu X Zhang Y Wu Y Zhang F Li C Zhuo X Lu B Cao B activity of cefiderocol, a siderophore cephalosporin, against carbapenem-resistant hypervirulent in China 2023 Antimicrob Agents Chemother e0073523 Zhao J, Pu D, Li Z, Liu X, Zhang Y, Wu Y, Zhang F, Li C, Zhuo X, Lu B, Cao B. activity of cefiderocol, a siderophore cephalosporin, against carbapenem-resistant hypervirulent in China. Antimicrob Agents Chemother. 2023 Dec;67(12):e0073523. DOI: 10.1128/aac.00735-23 https://doi.org/10.1128/aac.00735-23 Kramer A Lexow F Bludau A Köster AM Misailovski M Seifert U Eggers M Rutala W Dancer SJ Scheithauer S How long do bacteria, fungi, protozoa, and viruses retain their replication capacity on inanimate surfaces? A systematic review examining environmental resilience versus healthcare-associated infection risk by "fomite-borne risk assessment" 2024 Clin Microbiol Rev e0018623 Kramer A, Lexow F, Bludau A, Köster AM, Misailovski M, Seifert U, Eggers M, Rutala W, Dancer SJ, Scheithauer S. How long do bacteria, fungi, protozoa, and viruses retain their replication capacity on inanimate surfaces? A systematic review examining environmental resilience versus healthcare-associated infection risk by "fomite-borne risk assessment". Clin Microbiol Rev. 2024 Dec;37(4):e0018623. DOI: 10.1128/cmr.00186-23 https://doi.org/10.1128/cmr.00186-23 Heireman L Hamerlinck H Vandendriessche S Boelens J Coorevits L De Brabandere E De Waegemaeker P Verhofstede S Claus K Chlebowicz-Flissikowska MA Rossen JWA Verhasselt B Leroux-Roels I Toilet drain water as a potential source of hospital room-to-room transmission of carbapenemase-producing Klebsiella pneumoniae 2020 J Hosp Infect 232-239 Heireman L, Hamerlinck H, Vandendriessche S, Boelens J, Coorevits L, De Brabandere E, De Waegemaeker P, Verhofstede S, Claus K, Chlebowicz-Flissikowska MA, Rossen JWA, Verhasselt B, Leroux-Roels I. Toilet drain water as a potential source of hospital room-to-room transmission of carbapenemase-producing Klebsiella pneumoniae. J Hosp Infect. 2020 Oct;106(2):232-239. DOI: 10.1016/j.jhin.2020.07.017 https://doi.org/10.1016/j.jhin.2020.07.017 Ljungquist O Magda M Giske CG Tellapragada C Nazarchuk O Dmytriiev D Thofte O Öhnström V Matuschek E Blom AM Riesbeck K Pandrug-resistant Klebsiella pneumoniae isolated from Ukrainian war victims are hypervirulent 2024 J Infect 106312 Ljungquist O, Magda M, Giske CG, Tellapragada C, Nazarchuk O, Dmytriiev D, Thofte O, Öhnström V, Matuschek E, Blom AM, Riesbeck K. Pandrug-resistant Klebsiella pneumoniae isolated from Ukrainian war victims are hypervirulent. J Infect. 2024 Dec;89(6):106312. DOI: 10.1016/j.jinf.2024.106312 https://doi.org/10.1016/j.jinf.2024.106312 Turton JF Perry C McGowan K Turton JA Hope R Sequence type 147: a high-risk clone increasingly associated with plasmids carrying both resistance and virulence elements 2024 J Med Microbiol Turton JF, Perry C, McGowan K, Turton JA, Hope R. Sequence type 147: a high-risk clone increasingly associated with plasmids carrying both resistance and virulence elements. J Med Microbiol. 2024 Apr;73(4):. DOI: 10.1099/jmm.0.001823 https://doi.org/10.1099/jmm.0.001823 Martin MJ Corey BW Sannio F Hall LR MacDonald U Jones BT Mills EG Harless C Stam J Maybank R Kwak Y Schaufler K Becker K Hübner NO Cresti S Tordini G Valassina M Cusi MG Bennett JW Russo TA McGann PT Lebreton F Docquier JD Anatomy of an extensively drug-resistant outbreak in Tuscany, Italy 2021 Proc Natl Acad Sci U S A Martin MJ, Corey BW, Sannio F, Hall LR, MacDonald U, Jones BT, Mills EG, Harless C, Stam J, Maybank R, Kwak Y, Schaufler K, Becker K, Hübner NO, Cresti S, Tordini G, Valassina M, Cusi MG, Bennett JW, Russo TA, McGann PT, Lebreton F, Docquier JD. Anatomy of an extensively drug-resistant outbreak in Tuscany, Italy. Proc Natl Acad Sci U S A. 2021 Nov;118(48):. DOI: 10.1073/pnas.2110227118 https://doi.org/10.1073/pnas.2110227118 Ofosu-Appiah F Acquah EE Mohammed J Sakyi Addo C Agbodzi B Ofosu DAS Myers CJ Mohktar Q Ampomah O-W Ablordey A Amissah NA ST147 harboring, multidrug resistance and hypervirulence plasmids 2024 Microbiol Spectr e0301723 Ofosu-Appiah F, Acquah EE, Mohammed J, Sakyi Addo C, Agbodzi B, Ofosu DAS, Myers CJ, Mohktar Q, Ampomah O-W, Ablordey A, Amissah NA. ST147 harboring, multidrug resistance and hypervirulence plasmids. Microbiol Spectr. 2024 Mar;12(3):e0301723. DOI: 10.1128/spectrum.03017-23 https://doi.org/10.1128/spectrum.03017-23 Becker L Kaase M Pfeifer Y Fuchs S Reuss A von Laer A Sin MA Korte-Berwanger M Gatermann S Werner G Genome-based analysis of Carbapenemase-producing isolates from German hospital patients, 2008-2014 2018 Antimicrob Resist Infect Control 62 Becker L, Kaase M, Pfeifer Y, Fuchs S, Reuss A, von Laer A, Sin MA, Korte-Berwanger M, Gatermann S, Werner G. Genome-based analysis of Carbapenemase-producing isolates from German hospital patients, 2008-2014. Antimicrob Resist Infect Control. 2018;7:62. DOI: 10.1186/s13756-018-0352-y https://doi.org/10.1186/s13756-018-0352-y Neumann B Stürhof C Rath A Kieninger B Eger E Müller JU von Poblocki A Gerlitz N Wollschläger P Schneider-Brachert W Schaufler K Klaper K Steinmann J Detection and characterization of putative hypervirulent Klebsiella pneumoniae isolates in microbiological diagnostics 2023 Sci Rep 19025 Neumann B, Stürhof C, Rath A, Kieninger B, Eger E, Müller JU, von Poblocki A, Gerlitz N, Wollschläger P, Schneider-Brachert W, Schaufler K, Klaper K, Steinmann J. Detection and characterization of putative hypervirulent Klebsiella pneumoniae isolates in microbiological diagnostics. Sci Rep. 2023 Nov;13(1):19025. DOI: 10.1038/s41598-023-46221-w https://doi.org/10.1038/s41598-023-46221-w Heiden SE Hübner NO Bohnert JA Heidecke CD Kramer A Balau V Gierer W Schaefer S Eckmanns T Gatermann S Eger E Guenther S Becker K Schaufler K A Klebsiella pneumoniae ST307 outbreak clone from Germany demonstrates features of extensive drug resistance, hypermucoviscosity, and enhanced iron acquisition 2020 Genome Med 113 Heiden SE, Hübner NO, Bohnert JA, Heidecke CD, Kramer A, Balau V, Gierer W, Schaefer S, Eckmanns T, Gatermann S, Eger E, Guenther S, Becker K, Schaufler K. A Klebsiella pneumoniae ST307 outbreak clone from Germany demonstrates features of extensive drug resistance, hypermucoviscosity, and enhanced iron acquisition. Genome Med. 2020 Dec;12(1):113. DOI: 10.1186/s13073-020-00814-6 https://doi.org/10.1186/s13073-020-00814-6 Doğan E Schaufler K Heiden SE Kohler C Langheinrich M Becker K Eger E Idelevich EA Prevalence, characteristics and clinical features of hypervirulent Klebsiella pneumoniae in a German university hospital 2025 Int J Med Microbiol 151662 Doğan E, Schaufler K, Heiden SE, Kohler C, Langheinrich M, Becker K, Eger E, Idelevich EA. Prevalence, characteristics and clinical features of hypervirulent Klebsiella pneumoniae in a German university hospital. Int J Med Microbiol. 2025 Sep;320:151662. DOI: 10.1016/j.ijmm.2025.151662 https://doi.org/10.1016/j.ijmm.2025.151662 0 0 0 0