scholarly journals Bacteriophage Treatment Rescues Mice Infected with Multidrug-Resistant Klebsiella pneumoniae ST258

mBio ◽  
2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Shayla Hesse ◽  
Natalia Malachowa ◽  
Adeline R. Porter ◽  
Brett Freedman ◽  
Scott D. Kobayashi ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Alternative Treatment ◽  
Bacterial Infections ◽  
Phage Therapy ◽  
Treatment Approach ◽  
Multidrug Resistant ◽  
Sequence Type ◽  
Infection Model ◽  
Content Type ◽  
Treatment Groups

ABSTRACT Severe infections caused by multidrug-resistant Klebsiella pneumoniae sequence type 258 (ST258) highlight the need for new therapeutics with activity against this pathogen. Bacteriophage (phage) therapy is an alternative treatment approach for multidrug-resistant bacterial infections that has shown efficacy in experimental animal models and promise in clinical case reports. In this study, we assessed microbiologic, histopathologic, and survival outcomes following systemic administration of phage in ST258-infected mice. We found that prompt treatment with two phages, either individually or in combination, rescued mice with K. pneumoniae ST258 bacteremia. Among the three treatment groups, mice that received combination phage therapy demonstrated the greatest increase in survival and the lowest frequency of phage resistance among bacteria recovered from mouse blood and tissue. Our findings support the utility of phage therapy as an approach for refractory ST258 infections and underscore the potential of this treatment modality to be enhanced through strategic phage selection. IMPORTANCE Infections caused by multidrug-resistant K. pneumoniae pose a serious threat to at-risk patients and present a therapeutic challenge for clinicians. Bacteriophage (phage) therapy is an alternative treatment approach that has been associated with positive clinical outcomes when administered experimentally to patients with refractory bacterial infections. Inasmuch as these experimental treatments are prepared for individual patients and authorized for compassionate use only, they lack the rigor of a clinical trial and therefore cannot provide proof of efficacy. Here, we demonstrate that administration of viable phage provides effective treatment for multidrug-resistant K. pneumoniae (sequence type 258 [ST258]) bacteremia in a murine infection model. Moreover, we compare outcomes among three distinct phage treatment groups and identify potential correlates of therapeutic phage efficacy. These findings constitute an important first step toward optimizing and assessing phage therapy’s potential for the treatment of severe ST258 infection in humans.

scholarly journals Emergence of a Multidrug-Resistant Hypervirulent Klebsiella pneumoniae Sequence Type 23 Strain with a Rare blaCTX-M-24-Harboring Virulence Plasmid

2019 ◽  
Vol 63 (3) ◽  
Author(s):  
Dingxia Shen ◽  
Guannan Ma ◽  
Cuidan Li ◽  
Xinmiao Jia ◽  
Chuan Qin ◽  
...  
Keyword(s):  
Public Health ◽  
Klebsiella Pneumoniae ◽  
Genetic Basis ◽  
Virulence Genes ◽  
Multidrug Resistant ◽  
Sequence Type ◽  
Hybrid Plasmid ◽  
Virulence Plasmid ◽  
Drug Resistant ◽  
Content Type

ABSTRACT Here, we report a multidrug-resistant hypervirulent Klebsiella pneumoniae (MDR-HvKP) strain of sequence type 23 (ST23) with a rare hybrid plasmid harboring virulence genes and blaCTX-M-24, and we analyze the genetic basis for relationship between genotypes and MDR-hypervirulence phenotypes. Further analysis indicates that the hybrid plasmid is formed by IS903D-mediated intermolecular transposition of the blaCTX-M-24 gene into the virulence plasmid. The emergence of MDR-HvKP strains, especially those carrying drug-resistant virulent plasmids, poses unprecedented threats/challenges to public health. This is a dangerous trend and should be closely monitored.

scholarly journals Resistance Evolution against Phage Combinations Depends on the Timing and Order of Exposure

mBio ◽  
2019 ◽  
Vol 10 (5) ◽  
Author(s):  
Rosanna C. T. Wright ◽  
Ville-Petri Friman ◽  
Margaret C. M. Smith ◽  
Michael A. Brockhurst
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Bacterial Infections ◽  
Phage Therapy ◽  
Multidrug Resistant ◽  
Fitness Costs ◽  
Evolutionary Trajectory ◽  
Promising Alternative ◽  
Content Type ◽  
Resistance Evolution

ABSTRACTPhage therapy is a promising alternative to chemotherapeutic antibiotics for the treatment of bacterial infections. However, despite recent clinical uses of combinations of phages to treat multidrug-resistant infections, a mechanistic understanding of how bacteria evolve resistance against multiple phages is lacking, limiting our ability to deploy phage combinations optimally. Here, we show, usingPseudomonas aeruginosaand pairs of phages targeting shared or distinct surface receptors, that the timing and order of phage exposure determine the strength, cost, and mutational basis of resistance. Whereas sequential exposure allowed bacteria to acquire multiple resistance mutations effective against both phages, this evolutionary trajectory was prevented by simultaneous exposure, resulting in quantitatively weaker resistance. The order of phage exposure determined the fitness costs of sequential resistance, such that certain sequential orders imposed much higher fitness costs than the same phage pair in the reverse order. Together, these data suggest that phage combinations can be optimized to limit the strength of evolved resistances while maximizing their associated fitness costs to promote the long-term efficacy of phage therapy.IMPORTANCEGlobally rising rates of antibiotic resistance have renewed interest in phage therapy where combinations of phages have been successfully used to treat multidrug-resistant infections. To optimize phage therapy, we first need to understand how bacteria evolve resistance against combinations of multiple phages. Here, we use simple laboratory experiments and genome sequencing to show that the timing and order of phage exposure determine the strength, cost, and mutational basis of resistance evolution in the opportunistic pathogenPseudomonas aeruginosa. These findings suggest that phage combinations can be optimized to limit the emergence and persistence of resistance, thereby promoting the long-term usefulness of phage therapy.

scholarly journals Colistin Resistance Gene mcr-8 in a High-Risk Sequence Type 15 Klebsiella pneumoniae Isolate from Kenya

2020 ◽  
Vol 9 (39) ◽  
Author(s):  
Cecilia Kyany’a ◽  
Lillian Musila
Keyword(s):  
High Risk ◽  
Klebsiella Pneumoniae ◽  
Resistance Gene ◽  
Resistance Genes ◽  
Multidrug Resistant ◽  
Sequence Type ◽  
Colistin Resistance ◽  
Content Type ◽  
Global Concern ◽  
Hospitalized Patient

ABSTRACT The emergence and rise of mobile colistin resistance genes are of great global concern due to the ease of transfer of resistance to other bacteria. This report describes the genome of a colistin- and multidrug-resistant Klebsiella pneumoniae isolate bearing mcr-8, obtained from a hospitalized patient in Kenya.

scholarly journals In Vitro Discordance with In Vivo Activity: Humanized Exposures of Ceftazidime-Avibactam, Aztreonam, and Tigecycline Alone and in Combination against New Delhi Metallo-β-Lactamase-Producing Klebsiella pneumoniae in a Murine Lung Infection Model

2017 ◽  
Vol 61 (7) ◽  
Author(s):  
M. L. Monogue ◽  
L. M. Abbo ◽  
R. Rosa ◽  
J. F. Camargo ◽  
O. Martinez ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Lung Infection ◽  
Multidrug Resistant ◽  
Infection Model ◽  
New Delhi ◽  
Beta Lactamase ◽  
Bacterial Reduction ◽  
Content Type

ABSTRACT The management of infections with New Delhi metallo-beta-lactamase-1 (NDM)-producing bacteria remains clinically challenging given the multidrug resistant (MDR) phenotype associated with these bacteria. Despite resistance in vitro, ceftazidime-avibactam previously demonstrated in vivo activity against NDM-positive Enterobacteriaceae. Herein, we observed in vitro synergy with ceftazidime-avibactam and aztreonam against an MDR Klebsiella pneumoniae harboring NDM. In vivo, humanized doses of ceftazidime-avibactam monotherapy resulted in >2 log10 CFU bacterial reduction; therefore, no in vivo synergy was observed.

scholarly journals Klebsiella pneumoniae Sequence Type 11 from Companion Animals Bearing ArmA Methyltransferase, DHA-1 β-Lactamase, and QnrB4

2013 ◽  
Vol 57 (9) ◽  
pp. 4532-4534 ◽  
Author(s):  
Laura Hidalgo ◽  
Belen Gutierrez ◽  
Cristina M. Ovejero ◽  
Laura Carrilero ◽  
Stephanie Matrat ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Multilocus Sequence Typing ◽  
Companion Animals ◽  
Multidrug Resistant ◽  
Sequence Type ◽  
Resistance Determinant ◽  
Epidemic Clone ◽  
Content Type ◽  
First Report

ABSTRACTSevenKlebsiella pneumoniaeisolates from dogs and cats in Spain were found to be highly resistant to aminoglycosides, and ArmA methyltransferase was responsible for this phenotype. All isolates were typed by multilocus sequence typing (MLST) as ST11, a human epidemic clone reported worldwide and associated with, among others, OXA-48 and NDM carbapenemases. In the seven strains,armAwas borne by an IncR plasmid, pB1025, of 50 kb. The isolates were found to coproduce DHA-1 and SHV-11 β-lactamases, as well as the QnrB4 resistance determinant. This first report of the ArmA methyltransferase in pets illustrates their importance as a reservoir for human multidrug-resistantK. pneumoniae.

scholarly journals Phage Therapy for a Multidrug-Resistant Acinetobacter baumannii Craniectomy Site Infection

2018 ◽  
Vol 5 (4) ◽  
Author(s):  
Stephanie LaVergne ◽  
Theron Hamilton ◽  
Biswajit Biswas ◽  
M Kumaraswamy ◽  
R T Schooley ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Antibiotic Resistance ◽  
Acinetobacter Baumannii ◽  
Alternative Treatment ◽  
Bacterial Infections ◽  
Phage Therapy ◽  
Treatment Options ◽  
Multidrug Resistant ◽  
Site Infection ◽  
Bacteriophage Therapy

Abstract In the era of antibiotic resistance, alternative treatment options for multidrug-resistant bacterial infections are being explored. We present a case of multidrug-resistant Acinetobacter baumannii infection treated with bacteriophages. Clinical trials are needed to further investigate bacteriophage therapy as an option to treat multidrug-resistant bacterial infections.

scholarly journals Emergence of an NDM-5-Producing Hypervirulent Klebsiella pneumoniae Sequence Type 35 Strain with Chromosomal Integration of an Integrative and Conjugative Element, ICEKp1

2019 ◽  
Vol 64 (1) ◽  
Author(s):  
Zhen Shen ◽  
Qianqian Gao ◽  
Juanxiu Qin ◽  
Yao Liu ◽  
Min Li
Keyword(s):  
Klebsiella Pneumoniae ◽  
Iron Acquisition ◽  
Sequence Type ◽  
Infection Model ◽  
Virulence Plasmid ◽  
Chromosomal Integration ◽  
Content Type ◽  
High Virulence ◽  
Serum Killing ◽  
Integrative And Conjugative Element

ABSTRACT Here, we report an NDM-5-producing sequence type 35 (ST35) hypervirulent Klebsiella pneumoniae strain, isolated from the blood of a male patient. It showed a remarkable resistance to serum killing and neutrophil phagocytosis and high virulence in a mouse peritonitis infection model. Instead of carrying a pLVPK-like virulence plasmid, chromosomal integration of ICEKp1 (∼76 kb) was identified in a specific asparagine-tRNA gene, harboring the iron acquisition system salmochelin genes (iroBCDN), a yersiniabactin gene, and a variant of the rmpA gene.

scholarly journals Evaluation of Gallium Citrate Formulations against a Multidrug-Resistant Strain of Klebsiella pneumoniae in a Murine Wound Model of Infection

2015 ◽  
Vol 59 (10) ◽  
pp. 6484-6493 ◽  
Author(s):  
Mitchell G. Thompson ◽  
Vu Truong-Le ◽  
Yonas A. Alamneh ◽  
Chad C. Black ◽  
Jeff Anderl ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Bacterial Infections ◽  
Multidrug Resistant ◽  
Health Care Facilities ◽  
Topical Formulation ◽  
Promising Alternative ◽  
Content Type ◽  
Wound Model ◽  
Alternative Treatment Strategy

ABSTRACTSkin and soft tissue infections (SSTIs) are a common occurrence in health care facilities with a heightened risk for immunocompromised patients.Klebsiella pneumoniaehas been increasingly implicated as the bacterial agent responsible for SSTIs, and treatment can be challenging as more strains become multidrug resistant (MDR). Therefore, new treatments are needed to counter this bacterial pathogen. Gallium complexes exhibit antimicrobial activity and are currently being evaluated as potential treatment for bacterial infections. In this study, we tested a topical formulation containing gallium citrate (GaCi) for the treatment of wounds infected withK. pneumoniae. First, the MIC againstK. pneumoniaeranged from 0.125 to 2.0 μg/ml GaCi. After thisin vitroefficacy was established, two topical formulations with GaCi (0.1% [wt/vol] and 0.3% [wt/vol]) were tested in a murine wound model of MDRK. pneumoniaeinfection. Gross pathology and histopathology revealedK. pneumoniae-infected wounds appeared to close faster with GaCi treatment and were accompanied by reduced inflammation compared to those of untreated controls. Similarly, quantitative indications of infection remediation, such as reduced weight loss and wound area, suggested that treatment improved outcomes compared to those of untreated controls. Bacterial burdens were measured 1 and 3 days following inoculation, and a 0.5 to 1.5 log reduction of CFU was observed. Lastly, upon scanning electron microscopy analysis, GaCi treatment appeared to prevent biofilm formation on dressings compared to those of untreated controls. These results suggest that with more preclinical testing, a topical application of GaCi may be a promising alternative treatment strategy forK. pneumoniaeSSTI.

scholarly journals Emergence of Carbapenem-Resistant Serotype K1 Hypervirulent Klebsiella pneumoniae Strains in China

2015 ◽  
Vol 60 (1) ◽  
pp. 709-711 ◽  
Author(s):  
Rong Zhang ◽  
Dachuan Lin ◽  
Edward Wai-chi Chan ◽  
Danxia Gu ◽  
Gong-Xiang Chen ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Virulence Genes ◽  
Multidrug Resistant ◽  
Sequence Type ◽  
Zhejiang Province ◽  
Content Type ◽  
Carbapenem Resistant ◽  
Surgical Wounds ◽  
Hospital Patients

ABSTRACTWe report the emergence of five carbapenem-resistant K1 hypervirulentKlebsiella pneumoniae(hvKP) strains which caused fatal infections in hospital patients in Zhejiang Province, China, upon entry through surgical wounds. Genotyping results revealed the existence of three genetically related strains which exhibited a new sequence type, ST1797, and revealed that all strains harbored themagAandwcaGvirulence genes and a plasmid-borneblaKPC-2gene. These findings indicate that K1 hvKP is simultaneously hypervirulent, multidrug resistant, and transmissible.

scholarly journals KPC-Producing, Multidrug-Resistant Klebsiella pneumoniae Sequence Type 258 as a Typical Opportunistic Pathogen

2013 ◽  
Vol 57 (10) ◽  
pp. 5144-5146 ◽  
Author(s):  
L. S. Tzouvelekis ◽  
V. Miriagou ◽  
S. D. Kotsakis ◽  
K. Spyridopoulou ◽  
E. Athanasiou ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Lethal Dose ◽  
Opportunistic Pathogen ◽  
Multidrug Resistant ◽  
Antimicrobial Treatment ◽  
Sequence Type ◽  
Content Type ◽  
Serum Killing

ABSTRACTThe virulence of a KPC-producingKlebsiella pneumoniaesequence type 258 (ST258) strain representing those circulating in Greece was assessed in a mouse septicemia model. The strain was virtually avirulent (50% lethal dose, >108and 5 × 107CFU for immunocompetent and neutropenic animals, respectively). Also, it was highly susceptible to serum killing, rapidly phagocytosedin vitro, and classified as K41, which is not among the virulent capsular types. The findings indirectly support the notion that high ST258-associated mortality is largely due to inefficient antimicrobial treatment.

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